APC mutations have been reported in lung squamous cell carcinoma and small-cell lung carcinoma, but rarely in lung adenocarcinoma. However, variants in the APC gene have not been well characterized in lung adenocarcinoma and their clinical significance is unclear. According to ClinVar, this particular variant is a likely benign germline variant (https://preview.ncbi.nlm.nih.gov/clinvar/variation/829/).

ATM alterations have been reported as germline variants which predispose to inherited cancer syndromes and as somatic (acquired) variants in tumors. ATM is part of many signalling networks, including cell metabolism and growth, oxidative stress, and chromatin remodelling, all of which can affect cancer progression. Although ATM is considered to be a tumour suppressor, ATM signaling may be advantageous to cancer cells in some settings, particularly in resistance to radio- and chemotherapeutic treatment. For this reason, the use of ATM inhibitors in cancer therapy is under exploration.

Somatic mutations in BRAF have been found in 1-4% of all NSCLC most of which are adenocarcinomas and may be a potential therapeutic target in some settings. Drug: Vemurafenib, Dabrafenib, Dabrafenib + Trametinib

Somatic mutations in BRAF have been found in 1-4% of all NSCLC most of which are adenocarcinomas. The G469A mutation results in an amino acid substitution at position 469 in BRAF, occurs within the highly conserved motif of the kinase domain. Most mutant BRAF proteins, such as G469A, have increased kinase activity and are transforming in vitro. In preclinical studies, lung cancer cell lines harboring the BRAF G469A mutation were not sensitive to dasatinib

Somatic mutations in BRAF have been found in up to 10% of all NSCLC, more common in adenocarcinomas. The G464V mutation results in an amino acid substitution within the highly conserved motif of the kinase domain. This specific mutation is a low frequency cancer-associated variant classified as an intermediate activity mutant that moderately increases ERK activation and can transform cells. The predictive significance of this mutation needs further study. Clinical correlation is recommended.

Somatic mutations in BRAF have been found in 1-4% of all NSCLC most of which are adenocarcinomas. The K601E mutation results in an amino acid substitution at position 601 in BRAF, occurs within the highly conserved motif of the kinase domain. Most mutant BRAF proteins, such as K601E, have increased kinase activity and are transforming in vitro. Preclinical studies suggest that downstream signaling induced by the K601E mutant may be blocked by the BRAF inhibitor, vemurafenib.

CTNNB1 encodes the protein b-catenin, a transcriptional activator involved in the WNT signaling pathway. Somatic gain-of-function mutations in CTNNB1 result in aberrant accumulation of the b-catenin protein and are prevalent in a wide range of solid tumors, including endometrial carcinoma, ovarian carcinoma, hepatocellular carcinoma, and colorectal carcinoma, among others. Genetic alterations in CTNNB1 have been identified in 4% of non-small cell lung cancers. The CTNNB1 S45P mutation is likely oncogenic, but no real progress has been made in targeting oncogenic mutant forms of CTNNB1 in lung cancer. However, CTNNB1 mutation-positive cancers are presumed to be resistant to pharmacologic inhibition of upstream components of the WNT pathway, instead requiring direct inhibition of b-catenin function. In one study pharmacological inhibition of b-catenin suppressed EGFR-L858R/T790M mutated lung tumor and genetic deletion of the b-catenin gene dramatically reduced lung tumor formation in transgenic mice, suggesting that b-catenin plays an essential role in lung tumorigenesis and that targeting the b-catenin pathway may provide novel strategies to prevent lung cancer development or overcome resistance to EGFR TKIs. These results should be interpreted in the clinical context.

Somatic mutations of CDKN2A are present in various tumor types, including, squamous cell carcinoma of the lung, clear cell sarcoma, head and neck cancer, melanoma and esophageal cancer. Majority of the CDKN2A mutations span exon 2 and result in loss or decreased binding to CDK4/6 leading to uncontrolled cell growth through inactivation of Rb and p53 pathways. Multiple preclinical and clinical studies are ongoing for CDKN2A deficient tumors in multiple tumor types.

Somatic mutations of CDKN2A are present in various tumor types, including, squamous cell carcinoma of the larynx, clear cell sarcoma, head and neck cancer, melanoma and esophageal cancer, among other cancer types. Majority of the CDKN2A mutations span exon 2 and result in loss or decreased binding to CDK4/6 leading to uncontrolled cell growth through inactivation of Rb and p53 pathways. Multiple preclinical and clinical studies are ongoing for CDKN2A deficient tumors in multiple tumor types.

ERBB2 (also HER2) is a transmembrane receptor that is a member of the ERBB family of receptor tyrosine kinases. ERBB2 is altered by amplification and/or overexpression in various cancers, most frequently in breast, esophagogastric and endometrial cancers. Somatic mutations in ERBB2 have been identified in a series of tumors including lobular breast, lung adenocarcinoma, and gastric cancers, among others, with recurrent hotspot alterations in both the extracellular and kinase domains. Preclinical and clinical studies have demonstrated that many of these mutations are transforming and sensitive to FDA-approved ERBB targeted therapies, including trastuzumab, ado-trastuzumab emtansine, lapatinib, and pertuzumab. The ERBB2 p.G776delinsVC variant is one of the in-frame insertions in exon 20 of ERBB2 that have been described in lung adenocarcinoma. Overall, in-frame ERRB2 insertions in exon 20 have been reported in approximately 6% of cases of lung adenocarcinoma which are negative for EGFR, KRAS, ALK alterations and these variants are more frequent in patients who were never-smokers. In vitro studies have shown that this specific variant is associated with constitutive kinase activation and is associated with sensitivity to some ERBB2 inhibitors and therefore, it may represent a targetable mutation in some clinical settings. Please refer to clinicaltrials.gov for additional information. Recommend correlation with other clinical and laboratory findings.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to EGFR inhibitors. Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions , EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions , EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. Erlotinib Afatinib Gefitinib Osimertinib

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions , EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M.

EGFR D770N in Exon 20 has been reported. The significance is unknown.

EGFR exon 20 insertion testing identifies a distinct subset of lung adenocarcinomas, accounting for at least 9% of all EGFR-mutated cases and by molecular modeling, are predicted to have potentially different effects on erlotinib binding. Studies show that in contrast to the more classic activating EGFR mutations, these insertions have been associated with de novo resistance to approved EGFR-TKIs (erlotinib and gefitinib). In a recent study, patients with advanced lung adenocarcinoma harboring exon 20 insertions demonstrated no response or partial response following treatment with TK inhibitors. Exon 20 insertion mutations in EGFR may be associated with clinical trials (https://clinicaltrials.gov/).

EGFR exon 20 insertion testing identifies a distinct subset of lung adenocarcinomas, accounting for at least 9% of all EGFR-mutated cases and by molecular modeling, are predicted to have potentially different effects on erlotinib binding. Studies show that in contrast to the more classic activating EGFR mutations, these insertions have been associated with de novo resistance to approved EGFR-TKIs (erlotinib and gefitinib). In a recent study, patients with advanced lung adenocarcinoma harboring exon 20 insertions demonstrated no response or partial response following treatment with TK inhibitors. This rare complex mutation (p.H773_V774delinsLM) results in the H773L/V774 mutation compound at the same allele, potentially weakening the inactive state and leading to constitutional activation of EGFR. A recent clinical report suggests this mutation is insensitive to the reversible TKI gefitinib, but can be suppressed by the irreversible TKI osimertinib, leading to sustained disease control (Yang et al., Lung Cancer, 121:1-4, 2018). Exon 20 insertion mutations in EGFR may be associated with clinical trials (https://clinicaltrials.gov/).

The EGFR D761 mutation is associated with acquired resistance to EGFR-TKIs (Balak et al., 2006). The functional significance of this alteration is being investigated.

A low frequency mutation detected in lung and gastric cancer. Functional significance of this alteration has not yet been described. However, a single NSCLC patient with this mutation in a clinical trial shows partial response to gefitinb therapy

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions , EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The L861Q mutation is one of the less common mutations which is an activating mutation that is believed to confer sensitivity to the targeted EGFR tyrosine kinase inhibitors although this mutation may confer reduced response to these inhibitors compared to the more common mutations.

Compound (dual) mutations in EGFR have been previously reported in lung adenocarcinoma and typically include a strong activating mutation combined with a weaker activating mutation. These cases appear to respond well to the EGFR targetted therapies if they include mutations that are known to provide sensitivity to EGFR inhibitor therapies. L858R is a well known activating mutation in exon 21 that is associated with sensitivity to EGFR inhibitors. In vitro functional characterization of mutations at E709 have also been reported to be activivating mutations that are also associated with sensitivity to EGFR inhibitors in vitro. Mutations in E709 often occur together with other muations in EGFR including the L858R mutation.

FBXW7 is a tumor suppressor gene that is mutated in several tumors including colorectal, liver, bladders and ovarian cancers. It is also mutated in endometrial and head and neck squamous cancers. Preclinical data suggest that FBXW7 mutations may sensitize cells to mTOR inhibitors.

This GNAS mutation causes constitutive activation of the G-protein complex and activates adenylate cyclase to produce cyclic-AMP (cAMP) that can activate oncogenic pathways. The R201 mutation in GNAS was thought to both drive tumor progression and confer exceptional chemo-sensitivity in a patient with an unclassified kidney cancer.

IDH-mutant tumors have aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in several malignancies including AML, central nervous system and billary tract. Strikingly, IDH1 mutations were rarely detected in the other solid tumor types. Reports have shown that melanoma cases can harbor IDH1 mutations. An IDH1 R132C mutation was found in a melanoma metastasis to the lung. IDH1 mutations were found to coexist with BRAF or KIT mutations, and all were detected in metastatic lesions. Coexistence of IDH1 R132C mutation with KRAS has also been reported in a single case of lung adenocarcinoma (Sequist et al., Ann Oncol., 22:2616-2624, 2011). The clinical significance of this mutation with regards to response to anti-IDH1 therapy in lung cancer is unknown.

KRAS belongs to the RAS family of oncogenes. In lung, KRAS mutations are detected in approximately 20% to 25% of adenocarcinoma and less than 10% of squamous cell carcinoma which demonstrate a minor glandular component. KRAS mutations in NSCLC most often occur in codons 12 or 13 and with a lower frequency in codon 61. Mutations in KRAS are usually mutually exclusive with other oncogenic driver aberrations including EGFR, BRAF, HER2 mutations and ALK and ROS1 rearrangements. Contrary to most other oncogenic driver mutations, KRAS is more often found in smokers and is detected at lower frequency in East Asian patient cohorts. The prognostic as well as predictive role of KRAS mutations continues to be studied. Although various attempts inhibiting KRAS have been made, there is no established therapy specific for this large patient subpopulation. Recommend correlation with other clinical and lab findings.

KRAS belongs to the RAS family of oncogenes. KRAS mutations are detected in approximately 20% to 25% of lung adenocarcinoma. Contrary to most other oncogenic driver mutations, KRAS is more often found in smokers and is detected at lower frequency in East Asian patient cohorts. Mutations in KRAS are usually mutually exclusive with other oncogenic driver aberrations including EGFR, BRAF, HER2 mutations and ALK and ROS1 rearrangements. KRAS mutations in NSCLC most often occur in codons 12 or 13 and with a lower frequency in codon 61. The prognostic as well as predictive role of KRAS mutations continues to be studied. Although various attempts inhibiting KRAS have been made, there is no established therapy specific for this large patient subpopulation.

Nonsynonymous mutations in the MET gene have been described in non-small cell lung cancer (NSCLC) and (small cell lung cancer) SCLC. Increased expression of MET protein was associated with improved progression free survival and overall survival in patients who received MetMAb (an anti-MET antibody) and erlotinib. The activity of MET inhibitors in NSCLC or SCLC tumors with non-kinase domain MET mutations is not yet known.

The MET p. E168D mutation has been reported in various tumors including lung cancer according to the COSMIC database. Some studies indicate that this mutation may be associated with higher affinity for ligand, HGF. In vitro studies in cell lines with cells expressing MET p.E168D may show increased sensitivity to MET inhibitor. According to ClinVar, this particular variant is a likely benign germline variant (https://preview.ncbi.nlm.nih.gov/clinvar/variation/41627/). The clinical significance of this variant remains to be fully elucidated.

The MET p.T1010I variant has been reported in some tumor types and also has been reported as a germline variant present in less than 1% of the general population. Its role in tumor development and progression continues to be studied. The utility of MET pathway inhibitors also continues to be explored.

The MLH1 V384D polymorphism has been associated with cancer risk in some tumor types. In addition, according to one report, MLH1 V384D polymorphism has been reported to be associated with primary resistance to EGFR-TKIs in patients with EGFR L858R-positive lung adenocarcinoma and may potentially be a novel biomarker to guide treatment decisions for those patients. The effect of this MLH1 polymorphism when present with other EGFR-TKI sensitizing mutations such as Exon 19 deletions in EGFR remains to be clarified. Some studies have shown that patients carrying the MLH1 V384D variant have an increased risk of the development of microsatellite-instable as well as -stable colorectal cancer. This variant has an allele frequency of 4% in the East Asian population. Of note, this variant is reported as a benign germline variant in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/41632/). Clinical correlation is recommended.

NRAS is a member of the RAS family of oncogenes and activating mutations of NRAS have been reported in about 1% of NSCLCs and are mostly exclusive of other known driver mutations. The Q61 codon is most frequently affected. In preclinical studies, cell lines harboring NRAS mutation(s) showed variable sensitivities to pathway inhibitors.

Somatic mutations in PIK3CA have been found in 1–3% of NSCLC. These mutations typically occur within specific hotspot regions. PIK3CA mutations appear to be more common in squamous cell histology compared to adenocarcinoma and can occur with or without a history of smoking. PIK3CA mutations can co-occur with EGFR mutations and PIK3CA mutations have been detected in a small percentage (approximately 5%) of EGFR-mutated lung cancers with acquired resistance to EGFR TKI therapy.

Somatic mutations in PTEN have been found in 4-8% of non-small cell carcinomas (NSCLC) including adenocarcinomas and squamous cell carcinomas. PTEN is a tumor suppressor gene, and loss of PTEN results in upregulation of the PI3K/ AKT pathway. Loss of PTEN is most commonly due to promoter hypermethylation, while homozygous deletion and nonsense mutations with loss of heterozygosity (LOH) may also occur. PTEN mutations may occur in multiple exons. In preclinical studies, PTEN loss is associated with decreased sensitivity of EGFR mutant lung tumors to EGFR TKIs. Clinical trials assessing the efficacy of PI3K inhibitors in PTEN loss are being explored.

Homozygous mutations causing SMAD4 loss are found in approximately 3% of lung adenocarcinomas and squamous cell carcinomas cases. SMAD4 loss tends to act synergistically with TP53 and KRAS mutations to increase lymphatic metastasis and tumor size. Experimental work in a mouse model has demonstrated increased susceptibility to DNA topoisomerase inhibitors with homozygous SMAD4 loss of function mutation coupled with KRAS G12D activating mutations.

Based on reports in the literature, EGFR and KRAS mutations can occasionally coexist in the same bronchial-pulmonary carcinoma. The biological implications of this coexistence are still poorly understood mainly because these cases are not frequent. It is therefore necessary to study larger series of cases with the two mutations to better understand the biological, clinical and therapeutic implications. Patients with coexisting EGFR and KRAS variants may have a partial response to EGFR TKI.

JAK3 is a non-receptor protein tyrosine kinase involved in the interferon-alpha/beta/gamma pathway and is a member of the JAK/STAT signaling pathway. The JAK3 V722I variant has been reported as a likely benign germline polymorphism (ClinVar, https://preview.ncbi.nlm.nih.gov/clinvar/variation/134573/) and also as an acquired somatic variant in some tumors. It has been reported to be an activating variant of JAK3 and initial in vitro studies suggest that this variant may play a role in the regulation of PD-L1 expression. Also, V722I resulted in constitutive phosphorylation of Jak3 and was transforming in cell culture. Clinical correlation is recommended.

Somatic mutations in TP53 are frequent in human cancer. Germline TP53 mutations cause of Li-Fraumeni syndrome, which is associated with a range of early-onset cancers. The types and positions of TP53 mutations are diverse. TP53 mutations may be potential prognostic and predictive markers in some tumor types, as well as targets for pharmacological intervention in some clinical settings. The IARC TP53 Database (http://www-p53.iarc.fr/) is a useful resource which catalogues TP53 mutations found in cancer.

Activating extracellular domain ERBB2 mutations (S310F, S310Y, R157W) have been identified in urothelial carcinoma (enriched in micropapillary variant) and adenocarcinomas of breast and lung. These activating mutations may have therapeutic potential in some clinical settings.

ERBB2 exon 20 insertions occur within exon 20, which encodes part of the kinase domain. These mutations occur with a frequency of approximately 2--4% of all NSCLC. Overall, in-frame ERRB2 insertions in exon 20 have been reported in approximately 6% of cases of lung adenocarcinoma which are negative for EGFR, KRAS, ALK alterations and these variants are more frequent in patients who were never-smokers. Mutations in ERRB2 do not have an independent prognostic value in lung adenocarcinoma, according to a recent study. In vitro studies have shown that this specific variant is associated with constitutive kinase activation and is associated with sensitivity to some ERBB2 inhibitors and therefore, it may represent a targetable mutation in some clinical settings. Please refer to clinicaltrials.gov for additional information. Recommend correlation with other clinical and laboratory findings.

KRAS belongs to the RAS family of oncogenes. KRAS mutations are detected in approximately 20% to 25% of lung adenocarcinoma. Contrary to most other oncogenic driver mutations, KRAS is more often found in smokers and is detected at lower frequency in East Asian patient cohorts. Mutations in KRAS are usually mutually exclusive with other oncogenic driver aberrations including EGFR, BRAF, HER2 mutations and ALK and ROS1 rearrangements. KRAS mutations in NSCLC most often occur in codons 12 or 13 and with a lower frequency in codon 61. KRAS Q22K mutation consists of a C to A transversion substituting lysine for glutamine. This KRAS variant, at codon 22, is exceedingly rare in lung cancers, and also only rarely been described in very few other cancers. Mutations at this site have also been reported as germline mutations in Noonan syndrome. The preclinical studies have shown that cell lines expressing the KRAS Q22K mutation possess high in vivo oncogenic potential, higher than that of wild-type KRAS. The prognostic as well as predictive role of this and other KRAS mutations continues to be studied. Although various attempts inhibiting KRAS have been made, there is no established therapy specific for this large patient subpopulation.

This GNAS mutation causes constitutive activation of the G-protein complex and activates adenylate cyclase to produce cyclic-AMP (cAMP) that can activate oncogenic pathways. The frequency of GNAS mutation in non-small cell carcinoma of the lung cases is relatively low (<5%) and its significance remains to be fully elucidated.

NKX2-1 is a lineage-specific transcription factor that is frequently focally amplified in lung adenocarcinoma (PMID 17982442). NKX2-1 amplification supports a diagnosis of lung adenocarcinoma, as this event occurs rarely in other tumor types, including in lung squamous or small-cell lung cancer. NKX2-1 has been proposed to be an oncogenic "survival factor" for lung adenocarcinomas (PMID 23763999) though studies have also demonstrated tumor suppressor effects for this gene (PMID 21471965). There is no known relationship between NKX2-1 amplification and drug sensitivity.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR tyrosine kinase inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. EGFR S768I (exon 20) occurs in 1–2% of EGFR mutant lung cancers and is often coincident with other EGFR mutations. EGFR S768I is reported to be sensitive to EGFR-TKIs. EGFR G724S (exon 18) is very rare and its significance is unknown.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. EGFR exon 19 in-frame insertions have been described in about 1% of EGFR-mutant lung cancers. They appear to be more common in nonsmoking women. These exon 19 insertions appear to be sensitizing mutations and have been shown to respond to TKIs in some studies.

The STK11 is a tumor suppressor gene located on chromosome 19p13.3. The encoded protein has serine-threonine kinase activity. Functionally, STK11 regulates cellular energy metabolism and cell polarity by activating AMP-activated protein kinase (AMPK) and other members of the AMPK family. Germline mutations in the STK11 gene are responsible for Peutz-Jeghers syndrome, an autosomal dominant disorder with variable clinical phenotype and increased risk of some cancers. Somatic mutations of STK11 gene are reported in several tumors including lung cancers. Studies have demonstrated STK11 inactivation is a common event and may be involved in the development of sporadic lung adenocarcinoma. Inactivation mutations of STK11 are found in 30% of lung cancer cell lines and in 15% of primary lung adenocarcinomas. Clinical relevance of these alterations and impact on disease progression and patient survival needs to be fully elucidated.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. EGFR exon 18 mutations account for 3.6% of all the EGFR mutations in lung adenocarcinomas. Of these, G719 mutations account for the majority of them and are sensitive to anti-EGFR inhibitors. Exon 18 deletions are rare (<0.1%) and but they are potentially responsive to anti-EGFR TKIs in some small clinical case studies. Of note, they appeared to be more sensitive to second-generation TKIs, especially afatinib and neratinib, than to first- and third-generation TKIs based on in vitro experiments.

The anaplastic lymphoma kinase (ALK) has emerged as a potentially relevant biomarker and therapeutic target in a variety of solid and hematologic malignancies. It is a receptor tyrosine kinase (RTK) that is known to be activated either by point mutations or by chromosomal translocations. These genetic alterations act as oncogenic drivers and promote constitutive, ligand-independent activation of this RTK. Approximately 3-7% of non-small cell lung cancers (NSCLC) harbor ALK fusions/rearrangements. This fusion oncogene rearrangement is transforming both in vitro and in vivo and defines a distinct clinicopathologic subset of NSCLC that are highly sensitive to therapy with ALK-targeted inhibitors. While crizotinib is highly active in patients with ALK-positive NSCLC, patients have been shown to invariably develop resistance to this drug. In approximately one-third of resistant cases, tumors can acquire a secondary mutation within the ALK tyrosine kinase domain. ALK F1174 variant is a somatic mutation in the ALK kinase domain and has been detected in neuroblastomas. It has a transforming activity in vitro and in vivo, and may cause resistance to crizotinib as well as second generation ALK inhibitors such as ceritinib.

Germ line mutations of mutations in either TSC1 or TSC2 are found in 75-90% of cases of tuberous sclerosis complex (TSC), an autosomal dominant tumor syndrome associated with variable clinical phenotype including several hamrtomas and benign tumors. In addition, somatic alterations in these genes may occur in some tumor types. TSC1 and TSC2 both are tumor suppressor genes and their inactivation occurs by a classical two-hit mechanism. TSC1 is located on chromosome 9q34 and encodes hamartin. TSC2 is located on chromosome 16p13 and encodes tuberin. Hamartin and tuberin interact with and regulate a variety of proteins. These are negative regulators of the mTOR pathway, which is important for cell proliferation and frequently found activated in tumors. Mutation or deletion of TSC1 or TSC2 is found in 9-16 % of urothelial bladder tumors and up to 3% of clear cell renal cell carcinomas. More than 50% of bladder tumors of all grades and stages show LOH for markers on chromosome 9 and the TSC1 locus at 9q34 is a common critical region of deletion. Therefore, mTOR inhibitors have been identified as potential therapies for TSC1-mutated bladder cancers in some studies. LOH for the TSC1 or TSC2 locus has been described in 22% of 86 human lung cancer specimens. However, TSC1/2 sequence alterations are infrequent in lung and other epithelial malignancies.

Germ line mutations of mutations in either TSC1 or TSC2 are found in 75-90% of cases of tuberous sclerosis complex (TSC), an autosomal dominant tumor syndrome associated with variable clinical phenotype including several hamrtomas and benign tumors. In addition, somatic alterations in these genes may occur in some tumor types. TSC1 and TSC2 both are tumor suppressor genes and their inactivation occurs by a classical two-hit mechanism. TSC1 is located on chromosome 9q34 and encodes hamartin. TSC2 is located on chromosome 16p13 and encodes tuberin. Hamartin and tuberin interact with and regulate a variety of proteins. These are negative regulators of the mTOR pathway, which is important for cell proliferation and frequently found activated in tumors. Mutation or deletion of TSC1 or TSC2 is found in 9-16 % of urothelial bladder tumors and up to 3% of clear cell renal cell carcinomas. More than 50% of bladder tumors of all grades and stages show LOH for markers on chromosome 9 and the TSC1 locus at 9q34 is a common critical region of deletion. Therefore, mTOR inhibitors have been identified as potential therapies for TSC1-mutated bladder cancers in some studies. LOH for the TSC1 or TSC2 locus has been described in 22% of 86 human lung cancer specimens. However, TSC1/2 sequence alterations are infrequent in lung and other epithelial malignancies.

IDH2 is a mitochondrial enzyme involved in citrate metabolism. Mutations at Arg140 and Arg172 of IDH2 are typically heterozygous and are considered gain-of-function mutations that lead to increased levels of 2-hydroxyglutarate believed to alter epigenetic regulation in various tumors, especially in myeloid neoplasms. The Arg140 mutation of IDH2 has not been reported previously in lung tumors. However, a few other IDH2 mutations have been described in non-small cell lung cancers (NSCLC) in a very small number of patients in the literature. The prognostic impact of IDH2 mutations in NSCLC remains uncertain at this time. Mutant IDH2 may provide a potential therapeutic target in some settings. Clinical correlation is recommended.

The PTPN11gene encodes SHP-2, a widely expressed cytoplasmic protein tyrosine phosphatase. SHP-2 is essential for activation of the RAS/MAPK signaling cascade. Most mutations are gain-of-function and result in prolonged ligand-dependent activation of the RAS/MAPK cascade. Germ-line PTPN11 mutations cause Noonan syndrome, a developmental disorder characterized by an increased risk of malignancies. Activating somatic mutations in PTPN11 have been documented in certain hematologic malignancies but they are infrequent in solid tumors. About 3% of all lung cancers harbor somatic mutations in PTPN11 gene but their prognostic and therapeutic significance remains to be fully elucidated. The utility of SHP2 inhibitors continues to be explored in some preclinical studies.

The cytoplasmic β-catenin protein is implicated as a cell-cell adhesion regulator coupled with cadherin and is considered as a member in the wingless/Wnt signal transduction pathway. Mutations in CTNNB1, the gene encoding β-catenin, tend to impact or even eliminate APC-dependent serine and threonine phosphorylation sites in exon 3, resulting in oncogenic stabilization of the protein. Increased protein within the nuclei serves as a transcriptional factor through binding to the Tcf/Lef family. Mutations in the β-catenin gene are uncommon in NSCLC occurring in about 1-4% of the cases. Nuclear accumulation of β-catenin was found to be associated with EGFR mutations, and β-catenin overexpression was associated with NSCLC cell line resistance to gefitinib. Wnt pathway inhibitors are in preclinical development or have entered early clinical trials. Because high β-catenin expression has been associated with good outcome rather than with poor outcome in NSCLC patients, it could potentially prove important to target specific downstream β-catenin functions rather than using agents that could directly suppress β-catenin levels through upstream targeting of the Wnt pathway.

Somatic mutations in BRAF have been found in 1--4% of all NSCLC most of which are adenocarcinomas. The G466V mutation results in an amino acid substitution within the kinase domain of BRAF. Unlike other mutant BRAF proteins, G466V shows decreased kinase activity. In preclinical studies, lung cancer cell lines with G466V mutation were sensitive to TKI dasatinib, presumably by induction of tumor cell senescence. However, therapeutic implications of BRAF inhibitors in patients with this mutation need to be fully elucidated. Drug: Trametinib

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. EGFR L747P (c.2239_2240 TT>CC) is a rare missense compound substitution mutation in the Exon 19 and has been reported to be resistant to some EGFR inhibitors.

The anaplastic lymphoma kinase (ALK) has emerged as a potentially relevant biomarker and therapeutic target in a variety of solid and hematologic malignancies. It is a receptor tyrosine kinase (RTK) that is known to be activated either by point mutations or by chromosomal translocations. These genetic alterations act as oncogenic drivers, promoting constitutive, ligand-independent activation of this RTK. Approximately 3-7% of non-small cell lung cancers (NSCLC) harbor ALK fusions/rearrangements. ALK fusion oncogenes are transforming both in vitro and in vivo, defining a distinct clinicopathologic subset of NSCLC that are highly sensitive to therapy with ALK-targeted inhibitors. While crizotinib (ALK/MET TKI) is highly active in patients with ALK-positive NSCLC, patients have been shown to invariably develop resistance to this drug. In approximately one-third of resistant cases, tumors can acquire a secondary mutation within the ALK tyrosine kinase domain. L1196 is present in the gatekeeper position at the bottom of the ATP-binding pocket of the protein. Gatekeeper genetic alterations seem to confer TKI resistance in oncogenic tyrosine kinases. L1196M mutant confers high-level resistance to crizotinib, but has been shown to be sensitive to ceretinib.

The anaplastic lymphoma kinase (ALK) has emerged as a potentially relevant biomarker and therapeutic target in a variety of solid and hematologic malignancies. It is a receptor tyrosine kinase (RTK) that is known to be activated either by point mutations or by chromosomal translocations. These genetic alterations act as oncogenic drivers, promoting constitutive, ligand-independent activation of this RTK. Approximately 3-7% of non-small cell lung cancers (NSCLC) harbor ALK fusions/rearrangements. ALK fusion oncogenes are transforming both in vitro and in vivo, defining a distinct clinicopathologic subset of NSCLC that are highly sensitive to therapy with ALK-targeted inhibitors. While crizotinib (ALK/MET TKI) is highly active in patients with ALK-positive NSCLC, patients have been shown to invariably develop resistance to this drug. In approximately one-third of resistant cases, tumors can acquire a secondary mutation within the ALK tyrosine kinase domain. ALK G1202R is postulated to be in the solvent-exposed region abutting the crizotinib-binding site, likely diminishing the binding affinity of crizotinib and other ALK inhibitors to the mutant ALK. G1202R has been shown to cause resistance to crizotinib as well as second generation ALK inhibitors (ceritinib, alectinib).

AKT1 mutations have been reported in a variety of tumor types such as endometrial, lung, breast, colorectal, ovarian, and prostate cancers. The mutations are mutually exclusive from PIK3CA mutations. Increased expression and activation of AKT1 observed in many cancers is caused by a variety of different mechanisms including genomic alterations of AKT1, PIK3CA, PTEN, RAS family members, or growth factor receptors. Gain-of-function alterations of AKT1 can lead to neoplastic transformation in model systems, and is a potential target for therapeutic strategies. The E17K variant is by far the most frequent AKT1 mutation reported, implicating it as an important tumor promoting event.

FGFR3 is one of 4 high affinity tyrosine kinase receptors for the fibroblast growth factor family of ligands. On ligand stimulation, FGFR3 undergoes dimerization and tyrosine autophosphorylation, resulting in cell proliferation or differentiation, , through the mitogen-activated protein kinase (MAPK) and phospholipase Cg signal transduction pathways. Some FGFR3 mutations are believed to result in ligand-independent activation of the receptor. However, FGFR3 F384L mutation is not associated with activation of FGFR and, in NIH-3T3 cells, it was demonstrated to be devoid of any transforming activity. In some cases, the possibility of FGFR3 variants being of germline origin, cannot be excluded. The FGFR3 F384L mutation has been reported as a benign/likely benign germline variant in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/134404/). Clinical correlation is recommended.

FGFR1 amplification is associated with poor survival in patients with resected squamous cell lung cancer. FGRF1 amplification may be associated with sensitivity to the multitargeted tyrosine kinase inhibitor pazopanib.

The ALK gene encodes a receptor tyrosine kinase that is recurrently altered by chromosomal rearrangements in multiple malignancies, and the prevalence of oncogenic ALK fusions in lung adenocarcinoma is approximately 5%. The EML4-ALK fusion is known to be oncogenic. Crizotinib is a tyrosine kinase inhibitor that is FDA approved for treatment of ALK-fusion positive lung non-small lung carcinoma.

CRKL (Crk-like protein) is a substrate of the BCR-ABL tyrosine kinase, and plays a role in fibroblast transformation by BCR-ABL. It is potentially oncogenic. In lung adenocarcinomas, CRKL amplification may be associated with resistance to anti-EGFR therapy.

This gene encodes a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. Amplification of ERBB3 and/or overexpression of its protein have been reported in numerous cancers, including prostate, bladder, non small cell lung cancer, endometrial cancer and breast tumors. Several ERBB3 inhibitors are under various clinical trials against different types of solid tumors, including non small cell lung cancer, breast cancer, ovarian cancer and gastric cancer.

The protein of CCND1 (Cyclin D 1) belongs to the highly conserved cyclin family, functioning as regulators of CDK kinases. This cyclin forms a complex with and functions as a regulatory subunit of CDK4 or CDK6, whose activity is required for cell cycle G1/S transition. This protein has been shown to interact with tumor suppressor protein Rb and the expression of this gene is regulated positively by Rb. Amplification of this gene, which alters cell cycle progression, are observed frequently in a variety of tumors. Cyclin D1 and the mechanisms it regulates have the potential to be a therapeutic target for cancer drugs, including inhibition of Cyclin D1, induction of Cyclin D1 degradation, and inhibition of Cyclin D1/CDK 4/6 complex.

Activation of FGFR protein family can lead to the activation of RAS-MAPK and PI3K-AKT pathways. Amplification of FGFR2 has been observed in lung adenocarcinoma, lung squamous cell carcinoma, endometrial carcinoma, urothelial carcinoma, germ cell tumor and breast cancers. Anti-FGFR2 agents are actively under multiple clinical trials against many types of solid tumor, including lung squamous cell carcinoma, gastric cancer, endometrial cancer, and cholangiocarcinoma. Germeline mutations in FGFR2 are also associated with multiple craniosynostosis syndromes.

KIT, also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117, is a growth factor receptor of the tyrosine kinase subclass III family, normally expressed in a variety of tissue types. Signaling through CD117 plays a role in cell survival, proliferation, and differentiation. Altered forms of this receptor may be associated with some types of cancers. Somatic mutations of KIT in lung adenocarcinoma are relatively rare, reported up to 3.3% of the cases. The predictive and prognostic significance of KIT mutations in lung adenocarcinomas needs further elucidation. Results should be interpreted in conjunction with other laboratory and clinical findings.

IDH1 is an enzyme localized to the cytoplasm and peroxisomes and involved in citrate metabolism. IDH-mutant tumors have aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in several malignancies including AML, central nervous system and biliary tract. Strikingly, IDH1 mutations were rarely detected in the other solid tumor types. IDH1 mutations have been reported in 1-2% of lung adenocarcinomas. The clinical significance of this mutation with regards to response to anti-IDH1 therapy in lung cancer is unknown. Results should be interpreted in conjunction with other laboratory and clinical findings.

ERBB2 encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. ERBB2 mutations have been reported in ~2-3% of lung adenocarcinomas. The majority of ERBB2 mutations are in-frame insertions in exon 20, which encodes part of the kinase domain; however, point mutations (L755S and G776C) have also been identified. Lung adenocarcinomas with ERBB2 mutations are mutually exclusive with EGFR, KRAS, ALK alterations and these variants are more frequent in patients who are never-smokers. Mutations in ERRB2 do not have an independent prognostic value in lung adenocarcinoma, according to a recent study. In vitro analyses have shown that ERBB2 L755P and L755S mutations are associated with constitutive kinase activation and resistance to lapatinib treatment. The predictive significance of ERBB2 mutations in lung adenocarcinomas needs further elucidation. Recommend correlation with other clinical and laboratory findings.

Somatic mutations in BRAF have been found in up to 10% of all NSCLC, more common in adenocarcinomas. D594 is a highly conserved residue within the kinase domain of BRAF and mutation of this residue appears to result in kinase inactivation. In vitro study has shown that kinase-dead BRAF forms a constitutive complex with CRAF in the presence of activated RAS leading to MEK and ERK signaling. The predictive and prognostic significance of this mutation needs further study. Clinical correlation is recommended.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR tyrosine kinase inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. EGFR S768I (exon 20) occurs in 1–2% of EGFR mutant lung cancers and is often coincident with other EGFR mutations. S768I and V769L have previously been identified in the same NSCLC tumors. There are conflicting data regarding the sensitivity to EGFR-TKIs of tumors harboring S768I and V769L mutations. Correlation with other clinical and laboratory findings is necessary.

Erlotinib Afatinib Gefitinib

This gene is a known cancer gene. ARID1A/BAF250A subunit of the SWI/SNF (BAF) chromatin remodeling complex has emerged as recurrently mutated in a broad array of tumor types and a potential tumor suppressor. There is evidence indicating that ARID1A-mutated cancers may be subjected to therapeutic intervention.

Somatic mutations in TP53 are frequent in human cancer. Germline TP53 mutations cause of Li-Fraumeni syndrome, which is associated with a range of early-onset cancers. The types and positions of TP53 mutations are diverse. TP53 mutations may be potential prognostic and predictive markers in some tumor types, as well as targets for pharmacological intervention in some clinical settings. The IARC TP53 Database (http://www-p53.iarc.fr/) is a useful resource which catalogues TP53 mutations found in cancer.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. EGFR K757M has been reported as a rare variant lung adenocarcinoma, but the significance remains to be elucidated.

FGFR1 is a receptor tyrosine kinase activated upon binding of the FGF ligand, which activates RAS-MAPK and PI3K-AKT pathways. Altered function of FGFR1 in cancer may lead to increased cell proliferation and decreased apoptosis. The most common alteration of FGFR1 in lung adenocarcinoma is amplification and point mutations are rare (1% of cases). FGFR1 T141R does not lie within any known functional domains of the FGFR1 protein. T141R has been identified in sequencing studies, but has not been biochemically characterized and therefore, its effect on protein function is unknown. T141R has been reported as a somatic mutation in one case of lung adenocarcinoma in the literature. The clinicopathologic significance of FGFR1 T141R remains to be further elucidated.

Proto-oncogene tyrosine-protein kinase receptor RET, activates the MAPK pathway for cell proliferation and the PI3K/AKT pathway for cell survival. Certain inherited mutations in the RET proto-oncogene predispose individuals to the multiple endocrine neoplasia type 2 (MEN 2) cancer syndromes including MEN 2A and 2B, and familial medullary thyroid carcinoma. Somatic mutations in RET are rare in squamous cell carcinoma of the lung and are found in 2-3% of cases. RET E623K lies within the extracellular domain of the RET protein, but has not been characterized and therefore its effect on RET protein function is unknown. RET E623K has been reported as a benign germline mutation in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/24906/). These results should be interpreted in the clinical context.

Afatinib Erlotinib Gefitinib

Afatinib Erlotinib Gefitinib

Sensitive to: Afatinib Erlotinib Gefitinib

Afatinib Erlotinib Gefitinib AP32788

Afatinib Erlotinib Gefitinib

Vemurafenib Dabrafenib Dabrafenib + Trametinib

Vemurafenib Dabrafenib Dabrafenib + Trametinib

Crizotinib

Vemurafenib Dabrafenib Dabrafenib + Trametinib Vemurafenib + Cobimetinib Vemurafenib + Panitumumab Encorafenib + Binimetinib + Cetuximab Radiation + Trametinib + Fluorouracil

Afatinib Erlotinib Gefitinib

Somatic mutations in BRAF have been found in 1-4% of all NSCLC most of which are adenocarcinomas. The G466R mutation results in an amino acid substitution within the kinase domain of BRAF. Unlike other mutant BRAF proteins, G466R shows decreased kinase activity, however, it also causes paradoxically activation Erk signaling in cell culture Therapeutic implications of BRAF inhibitors in patients with this mutation need to be fully elucidated.

The STK11 is a tumor suppressor gene located on chromosome 19p13.3. The encoded protein has serine--threonine kinase activity. Functionally, STK11 regulates cellular energy metabolism and cell polarity by activating AMP-activated protein kinase (AMPK) and other members of the AMPK family. Germline mutations in the STK11 gene are responsible for Peutz--Jeghers syndrome, an autosomal dominant disorder with variable clinical phenotype and increased risk of some cancers. Somatic mutations of STK11 gene are reported in several tumors including lung cancers. Studies have demonstrated STK11 inactivation is a common event and may be involved in the development of sporadic lung adenocarcinoma. Inactivation mutations of STK11 are found in 15% of primary lung adenocarcinomas and 33% of large cell neuroendocrine carcinomas of the lung. Clinical relevance of these alterations and impact on disease progression and patient survival needs to be fully elucidated.

The PTPN11gene encodes SHP-2, a widely expressed cytoplasmic protein tyrosine phosphatase. SHP-2 is essential for activation of the RAS/MAPK signaling cascade. Most mutations are gain-of-function and result in prolonged ligand-dependent activation of the RAS/MAPK cascade. Germ-line PTPN11 mutations cause Noonan syndrome, a developmental disorder characterized by an increased risk of malignancies. Activating somatic mutations in PTPN11 have been documented in certain hematologic malignancies but they are infrequent in solid tumors. About 3% of all lung cancers harbor somatic mutations in PTPN11 gene but their prognostic and therapeutic significance remains to be fully elucidated. The PTPN11 V497L variant identified in this case has not been characterized in the literature and therefore its effect on protein function is unknown. This variant is best classified as a variant of uncertain significance. The utility of SHP2 inhibitors continues to be explored in some preclinical studies.

The PTPN11gene encodes SHP-2, a widely expressed cytoplasmic protein tyrosine phosphatase. SHP-2 is essential for activation of the RAS/MAPK signaling cascade. Most mutations are gain-of-function and result in prolonged ligand-dependent activation of the RAS/MAPK cascade. Germ-line PTPN11 mutations cause Noonan syndrome, a developmental disorder characterized by an increased risk of malignancies. Activating somatic mutations in PTPN11 have been documented in certain hematologic malignancies but they are infrequent in solid tumors. The G503V variant results in increased phosphatase activity compared to the wild-type protein in culture. About 3% of all lung cancers harbor somatic mutations in PTPN11 gene but their prognostic and therapeutic significance remains to be fully elucidated. The utility of SHP2 inhibitors continues to be explored in some preclinical studies.

NOTCH1 is a transmembrane receptor that plays a role in various cellular processes including cell fate determination, growth, and survival. NOTCH1 may be somatically mutated in a variety of cancers, and these mutations can be either gain- or loss-of-function mutations depending on the tumor type. Translocations and activating somatic mutations in NOTCH1 have been identified in T-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia. On the other hand, NOTCH1 loss-of-function somatic mutations are more common in solid tumors, namely squamous cell carcinomas, and occur as missense, frameshift or nonsense mutations. Somatic NOTCH1 mutations are rare in lung adenocarcinoma and are found in about 4% of cases. The NOTCH1 L2457V variant identified in this case has been reported as a benign germline finding in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/380420/). These results should be interpreted in the clinical context.

The cytoplasmic b-catenin protein is implicated as a cell-cell adhesion regulator coupled with cadherin and is considered as a member in the wingless/Wnt signal transduction pathway. Mutations in CTNNB1, the gene encoding b-catenin, tend to impact or even eliminate APC-dependent serine and threonine phosphorylation sites in exon 3, resulting in oncogenic stabilization of the protein. Mutations in the b-catenin gene are uncommon in NSCLC occurring in about 1-4% of the cases. This particular variant has not been described lung adenocarcinomas but is located in a hotspot, thus likely to be oncogenic. Clinical correlation is recommended.

FGFR3 amplification may be associated with response to the multitargeted tyrosine kinase inhibitor pazopanib.

B-RAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. Mutations of B-RAF have been described in up to 40-70% of Langerhans cell histiocytosis and approximately 50% of Erdheim-Chester disease. The hotspot for mutations in BRAF is at codon Val600 and these are activating mutations. The most common activating mutation is p.Val600Glu(V600E). Various B-Raf inhibitors(Vemurafenib, Dabrafenib) have been FDA approved for therapy for some tumor types in certain settings, and clinical trials for advanced BRAF V600 mutation-positive tumors using targeted therapy (often in combination with other therapy) may be available (clinical trials.gov).

NOTCH1 is a transmembrane receptor, which plays a role in cell fate determination, growth, and survival. Notch signaling has been demonstrated to play a role in lung development and lung carcinogenesis. Notch activity is counteracted by NUMB. Gain-of-function mutations of NOTCH1 have been identified in approximately 10% of patients with non-small cell lung carcinoma (NSCLC). In addition, loss-of-function mutations in NUMB that allow for increased NOTCH1 activity have been observed in approximately 30% of NSCLC patients. Studies have observed that increased NOTCH1 expression is associated with a poor prognosis in patients with lung adenocarcinoma. The NOTCH1 intronic deletion variant (NM_017617:g.139397792_139397795del) is located nine base pairs downstream of exon 27. While the variant is located in close proximity to an exon-intron junction, a potential effect on gene splicing is unknown. These results should be interpreted in the clinical context.

ATM is a member of the protein superfamily of phosphatidylinositol 3-kinase related serine/threonine kinases (PIKKs). ATM functions as a tumor suppressor that initiates DNA damage checkpoint signaling. Germline loss-of-function mutations in ATM have been identified in the autosomal recessive disorder Ataxia telangiectasia. Somatic mutations in ATM have been identified in lymphoid malignancies and a selection of solid tumors. ATM-mutant cancers are increasingly sensitive to DNA damaging agents due to deficits in DNA repair pathways, and ATM loss may result in better response to checkpoint inhibition in some cancers. Genetic alterations of ATM have been identified in approximately 10% of lung adenocarcinomas. One study predicted impaired ATM kinase activity in the setting of ATM R2691C mutation based on structural modeling; however, these results have not been validated biochemically. Of note, this variant is reported in ClinVar as a germline variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/133636/). Correlation with other clinical and lab findings is recommended.

BRAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. The hotspot for mutations in BRAF is at codon Val600 and these are activating mutations. The most common activating mutation is p.Val600Glu(V600E). Activating BRAF(V600E) (Val600Glu) mutations have been identified in approximately 1-2% of lung adenocarcinomas. Various BRAF inhibitors (Vemurafenib, Dabrafenib, and Trametinib) have been FDA approved for therapy for some tumor types in certain clinical settings. Of note, Dabrafenib and Trametinib are approved for metastatic non-small cell lung cancer (NSCLC) harboring BRAF V600E mutations.

KDR (kinase domain receptor), also known as VEGFR2 or Flk-1, is a tyrosine kinase receptor for vascular endothelial growth factor (VEGF) and plays a key role in angiogenesis. While KDR mutations are rare, amplification or protein overexpression have been reported in small proportion of a variety of solid tumors. Genetic alteration in KDR have been identified in 10% of lung adenocarcinomas. KDR (VEGFR2) R962H lies within the protein kinase domain of the KDR. This variant has not been biochemically characterized; however, mutations in this locus have been identified in various tumor types. Most therapies blocking KDR signaling target the angiogenesis pathway in general, such as bevacizumab, an antibody that targets VEGF-A. These results should be interpreted in the clinical context.

The catalytic subunit (p110a) of phosphatidylinositol-3-kinase (PI3K) is encoded by the PIK3CA gene and acts to activate several signaling cascades, including the well-characterized AKT-mTOR pathway that promotes cell survival, proliferation, growth and motility. PIK3CA is among the most commonly mutated genes in cancer and aberrant activation of PI3K is a transforming event. Somatic mutations in PIK3CA have been found in 1--3% of NSCLC and genetic alteration in PIK3CA have been identified in 7% of lung adenocarcinomas. These mutations typically occur within specific hotspot regions. PIK3CA mutations appear to be more common in squamous cell histology compared to adenocarcinoma and can occur with or without a history of smoking. PIK3CA mutations can co-occur with EGFR mutations and PIK3CA mutations have been detected in a small percentage (approximately 5%) of EGFR-mutated lung cancers with acquired resistance to EGFR TKI therapy. The PIK3CA H1047R mutation is known to be oncogenic.

KIT, also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117, is a growth factor receptor of the tyrosine kinase subclass III family, normally expressed in a variety of tissue types. Signaling through CD117 plays a role in cell survival, proliferation, and differentiation. Altered forms of this receptor may be associated with many types of cancers including hematopoietic malignancies, gastrointestinal stromal tumors, and various carcinomas and sarcomas. KIT G565V lies within the cytoplasmic domain of the Kit protein; this variant has been documented in the scientific literature (in melanoma). While its effect on Kit protein function is unknown, it is reported in ClinVar as likely benign germline variant (https://preview.ncbi.nlm.nih.gov/clinvar/variation/41600/).

The APC gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. APC promotes rapid degradation of beta-catenin and participates in Wnt signaling as a negative regulator. APC is also involved in other processes including cell migration, cell adhesion, transcriptional activation and apoptosis. Germline defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. Codon I1307 lies within a regulatory region of the APC protein mediated by ubiquitination. Germline APC I1307K is associated with increased colorectal cancer risk by making the gene unstable and prone to acquire mutations during normal cell division. The germline APC I1307K gene mutation is most commonly found in people of Ashkenazi Jewish descent. Therefore, routine colorectal screening is very important in these individuals. One study showed that males had significantly increased I1307K carrier prevalence in lung, urologic, pancreatic, and skin cancers. APC somatic mutations are found 4% of lung adenocarcinomas. The I1307K has not been reported as a somatic mutation in lung adenocarcinomas to date. The prognostic and therapeutic implications of somatic APC mutations in lung adenocarcinomas remain to be fully elucidated. Correlation with other clinical and lab findings is recommended.

The protein encoded by the RB1 gene is a negative regulator of the cell cycle and was the first tumor suppressor gene identified. The active, hypophosphorylated form of the protein binds transcription factor E2F1. Inactivation of RB1 and loss of RB1 tumor suppressor function has been identified in many early stage cancers. RB1 alterations are found in approximately 8% of non-small cell lung cancers. RB1 S576fs*34 results in early truncation of the RB1 protein and presumably loss of function. The predictive and prognostic significance of RB1 mutations in lung non-small cell carcinoma is undergoing further investigation. It has been suggested that patients with RB1-deficient tumors do not respond to cyclin-dependent kinase (CDK) inhibitors; however, the clinical implication of the loss of a single copy of RB1, as in this patient's case, remains to be fully elucidated. These results should be interpreted in the clinical context.

PTEN is a tumor suppressor gene, and loss of PTEN results in upregulation of the PI3K/ AKT pathway. Loss of PTEN is most commonly due to promoter hypermethylation, while homozygous deletion and nonsense mutations with loss of heterozygosity (LOH) may also occur. PTEN mutations may occur in multiple exons. Somatic mutations in PTEN have been found in 4--8% of non-small cell carcinomas (NSCLC) including adenocarcinomas and squamous cell carcinomas. In preclinical studies, PTEN loss is associated with decreased sensitivity of EGFR mutant lung tumors to EGFR TKIs. Clinical trials assessing the efficacy of PI3K inhibitors in PTEN loss are being explored. This particular variant is known to be oncogenic. It has also been reported as pathogenic/likely pathogenic germline variant according to ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/376032/).

KIT, also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117, is a growth factor receptor of the tyrosine kinase subclass III family, normally expressed in a variety of tissue types. Signaling through CD117 plays a role in cell survival, proliferation, and differentiation. Altered forms of this receptor may be associated with some types of cancers. Somatic mutations of KIT in lung adenocarcinoma are relatively rare, reported up to 3.3% of the cases. The predictive and prognostic significance of KIT mutations in lung adenocarcinomas needs further elucidation. According to ClinVar, the clinical significance of this particular variant C844Y is unknown (https://preview.ncbi.nlm.nih.gov/clinvar/variation/409781/). Results should be interpreted in conjunction with other laboratory and clinical findings.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR exon19 deletions, exon 21 L858R and Exon 18 mutations correlate strongly with sensitivity to specific EGFR inhibitors, and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. Compound (dual) mutations in EGFR have been previously reported in lung adenocarcinoma and typically include a strong activating mutation combined with a weaker activating mutation. These cases appear to respond well to the EGFR targeted therapies. Mutations at E709 in exon 18 often occur together with other mutations in EGFR. This particular complex deletion insertion variant results in both the E709V and G719C in the protein, as well as a K713R variant, which also has been reported previously.

PTEN is a tumor suppressor gene, and loss of PTEN results in upregulation of the PI3K/ AKT pathway. Loss of PTEN is most commonly due to promoter hypermethylation, while homozygous deletion and nonsense mutations with loss of heterozygosity (LOH) may also occur. PTEN mutations may occur in multiple exons. Somatic mutations in PTEN have been found in 4--8% of non-small cell carcinomas (NSCLC) including adenocarcinomas and squamous cell carcinomas. This particular variant is likely to be oncogenic. In preclinical studies, PTEN loss is associated with decreased sensitivity of EGFR mutant lung tumors to EGFR TKIs. Clinical trials assessing the efficacy of PI3K inhibitors in PTEN loss are being explored.

The cytoplasmic b-catenin protein is implicated as a cell-cell adhesion regulator coupled with cadherin and is considered as a member in the wingless/Wnt signal transduction pathway. Mutations in CTNNB1, the gene encoding b-catenin, tend to impact or even eliminate APC-dependent serine and threonine phosphorylation sites in exon 3, resulting in oncogenic stabilization of the protein. Mutations in the b-catenin gene are uncommon in NSCLC occurring in about 1-4% of the cases. CTNNB1 S37C is a gain of function mutation, has been described in 0.3% of non-small cell lung carcinomas and is likely oncogenic. However, its prognostic and therapeutic significance remains to be fully elucidated.

ERBB4 is a member of the EGFR subfamily of receptor tyrosine kinases. Approximately 5.4% of non-small cell lung cancers harbor ERBB4 missense mutations (COSMIC). In addition, 5.2% of adenocarcinomas have mutations in the ERBB4 gene that encode an amino acid change in the receptor. Activating, potentially oncogenic ERBB4 mutations (in particular Y285C, D595V, D931Y, and K935I) have been identified. However, the functional effects of lung cancer associated ERBB4 mutations is largely unknown. ERBB4 P920H variant has been seen in one case of squamous cell carcinoma of the head and neck (cancer.sanger.ac.uk). However, further studies are warranted to assess the potential prognostic and therapeutic significance of this and other variants of ERBB4.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. EGFR R108K (C.323G>A) is a rare missense mutation in Exon 3. In a study of 1006 lung carcinomas, R108K mutation was found concomitantly with other EGFR mutations - most notably p.L858R (Illei et.al). However, its prognostic and therapeutic significance remains to be fully elucidated.

The catalytic subunit (p110a) of phosphatidylinositol-3-kinase (PI3K) is encoded by the PIK3CA gene and acts to activate several signaling cascades, including the well-characterized AKT-mTOR pathway that promotes cell survival, proliferation, growth and motility. PIK3CA is among the most commonly mutated genes in cancer and aberrant activation of PI3K is a transforming event. Somatic mutations in PIK3CA have been found in 1--3% of NSCLC and genetic alteration in PIK3CA have been identified in 7% of lung adenocarcinomas. These mutations typically occur within specific hotspot regions. PIK3CA mutations activate the PI3K-PTEN-AKT pathway which is downstream from both the EGFR and the RAS-RAF-MAPK pathways. The somatic mutations found thus far in PIK3CA are oncogenic, and the majority of them are clustered within exon 9 and 20 (helical and kinase domains), with three hotspots (E542K, E545K, and H1047R/L). PIK3CA mutations have been reported in 8-21% and 20-33% of head/neck and anal squamous cell carcinoma, respectively. PIK3CA mutations, especially ones involving the helical domain, in these types of squamous cell carcinoma are highly associated with HPV. The predictive and prognostic significance of PIK3CA mutations in squamous cell carcinoma is unclear and needs further elucidation. Clinical trials targeting PI3K/Akt/mTor pathway inhibitors are available for patients with PIK3CA mutated tumors.

CTNNB1 encodes the protein b-catenin, a transcriptional activator involved in the WNT signaling pathway. Somatic gain-of-function mutations in CTNNB1 result in aberrant accumulation of the b-catenin protein and are prevalent in a wide range of solid tumors, including endometrial carcinoma, ovarian carcinoma, hepatocellular carcinoma, and colorectal carcinoma, among others. Genetic alterations in CTNNB1 have been identified in 4% of non-small cell lung cancers. The CTNNB1 S437F mutation has been reported as pathogenic in lung adenocarcinoma, but no real progress has been made in targeting oncogenic mutant forms of CTNNB1 in lung cancer. However, CTNNB1 mutation-positive cancers are presumed to be resistant to pharmacologic inhibition of upstream components of the WNT pathway, instead requiring direct inhibition of b-catenin function. In one study pharmacological inhibition of b-catenin suppressed EGFR-L858R/T790M mutated lung tumor and genetic deletion of the b-catenin gene dramatically reduced lung tumor formation in transgenic mice, suggesting that b-catenin plays an essential role in lung tumorigenesis and that targeting the b-catenin pathway may provide novel strategies to prevent lung cancer development or overcome resistance to EGFR TKIs. These results should be interpreted in the clinical context.

PTEN is a tumor suppressor gene, and loss of PTEN results in upregulation of the PI3K/ AKT pathway. Loss of PTEN is most commonly due to promoter hypermethylation, while homozygous deletion and nonsense mutations with loss of heterozygosity (LOH) may also occur. PTEN mutations may occur in multiple exons. Somatic mutations in PTEN have been found in 4--8% of non-small cell carcinomas (NSCLC) including adenocarcinomas and squamous cell carcinomas. In preclinical studies, PTEN loss is associated with decreased sensitivity of EGFR mutant lung tumors to EGFR TKIs. Clinical trials assessing the efficacy of PI3K inhibitors in PTEN loss are being explored. This particular variant is known to be oncogenic.

Somatic mutations in BRAF have been found in 1-4% of all NSCLC most of which are adenocarcinomas and may be a potential therapeutic target in some settings. The BRAF V590I variant lies within the protein kinase domain of the Braf protein, has not been biochemically characterized, but results in similar cell proliferation and viability levels to wild-type Braf in culture (PMID: 29533785), and therefore is predicted to have no effect on Braf protein function, but its oncogenic potential has not been characterized. Clinical correlation is recommended.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR tyrosine kinase inhibitors (TKIs, eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. Exon 20 mutations are more commonly associated with resistance to tyrosine kinase inhibitors (TKIs), but may respond to third generation TKI (eg, osimertinib). This EGFR variant (G796S) lies within the tyrosine kinase domain and has been reported in rare cases of lung adenocarcinomas, squamous cell carcinoma of head and neck and prostate adenocarcinoma. In silico studies suggest G796S mutation may confer resistance to TKIs. However, additional studies are needed to further elucidate the oncogenicity of the mutation and therapeutic implications of this rare variant.

IDH1 is an enzyme localized to the cytoplasm and peroxisomes and involved in citrate metabolism. IDH-mutant tumors have aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in several malignancies including AML, central nervous system and biliary tract. Strikingly, IDH1 mutations were rarely detected in the other solid tumor types. While IDH1 mutations have been reported in 1-2% of lung adenocarcinomas, the clinical significance of this mutation with regards to response to anti-IDH1 therapy in lung cancer is unknown. This specific IDH1 p.PR119Q has been identified in numerous reports, but it has not been biochemically characterized and its effect on protein function is unknown. Results should be interpreted in conjunction with other laboratory and clinical findings.

CDKN2A gene functions as an important tumour suppressor in various human malignancies and somatic mutations in this gene are present in various tumor types, including, lung adenocarcinoma, squamous cell carcinoma of the larynx, clear cell sarcoma, head and neck cancer, melanoma and esophageal cancer, among other cancer types. Majority of the CDKN2A mutations span exon 2 and result in loss or decreased binding to CDK4/6 leading to uncontrolled cell growth through inactivation of Rb and p53 pathways. This particular variant G67C is considered to be likely pathogenic based on the known pathogenicity of G67R/S. Multiple preclinical and clinical studies are ongoing for CDKN2A deficient tumors in multiple tumor types.

Somatic mutations of CDKN2A are present in various tumor types, including, squamous cell carcinoma of the lung, clear cell sarcoma, head and neck cancer, melanoma and esophageal cancer. Majority of the CDKN2A mutations span exon 2 and result in loss or decreased binding to CDK4/6 leading to uncontrolled cell growth through inactivation of Rb and p53 pathways. The D84V mutant is predicted to confer loss of function to the CDKN2A protein as demonstrated by an inability to bind and inhibit the cyclin-dependent kinases CDK4 and CDK6. Multiple preclinical and clinical studies are ongoing for CDKN2A deficient tumors in multiple tumor types.

Smoothened (SMO) is a co-receptor involved in the Hedgehog (Hh) signaling. Constitutive or aberrant activation of the Hh pathway leading to tumorigenesis is seen in many cancers with SMO activating mutations identified in basal cell carcinoma and medulloblastoma. Several Hh signaling pathway inhibitors, such as vismodegib and sonidegib, have been recently developed for cancer treatment. Germline or somatic SMO mutations have not been previously characterized in NSCLC; however, in a recent report a germline SMO P641A mutation in a patient with refractory NSCLC responded to vismodegib therapy for several months. The functional effect of SMO V404M is conflicting as it demonstrated activity similar to the normal protein in culture in one study, but resulted in near complete loss of Hh pathway signaling in another study, and therefore, its effect on SMO protein function is unknown. Clinical correlation is recommended.

The Von Hippel-Lindau (vHL) gene encodes a protein that is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. The VHL gene may be altered as a somatic (acquired) alteration and/or as a germline alteration associated with a rare autosomal dominant inherited cancer syndrome predisposing to a variety of malignant and benign tumors including clear cell renal cell carcinoma (ccRCC). Alterations in VHL have been reported in less than 1% of lung adenocarcinomas. The VHL p.G144* has been reported in multiple renal cell carcinomas as a somatic alteration. According to ClinVar, the VHL p.G144* is also reported as a pathogenic germline variant (https://www.ncbi.nlm.nih.gov/clinvar/variation/223208/). These results should be interpreted in the clinicopathologic context and appropriate germline genetic workup may be considered if clinically indicated.

PTEN is a tumor suppressor gene, and loss of PTEN results in upregulation of the PI3K/ AKT pathway. Loss of PTEN is most commonly due to promoter hypermethylation, while homozygous deletion and nonsense mutations with loss of heterozygosity (LOH) may also occur. PTEN mutations may occur in multiple exons. Somatic mutations in PTEN have been found in 4-8% of non-small cell carcinomas (NSCLC) including adenocarcinomas and squamous cell carcinomas. In preclinical studies, PTEN loss is associated with decreased sensitivity of EGFR mutant lung tumors to EGFR TKIs. Clinical trials assessing the efficacy of PI3K inhibitors in PTEN loss are being explored. The PTENI101T has been observed in a variety of cancer types, most frequently gliomas, and has been predicted to be pathogenic. However, one study identified the PTEN I101T variant in 1 out of 172 patients with germline PTEN mutations.

The APC gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. APC promotes rapid degradation of beta-catenin and participates in Wnt signaling as a negative regulator. Germline defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Somatic mutations in APC have been reported in 4% of lung adenocarcinomas, the prognostic and therapeutic implications of which remain to be fully elucidated. APC K1454E lies within the beta-catenin binding and down-regulation region of the Apc protein. K1454E suppresses beta-catenin mediated transcription at a level similar to wild-type Apc in a cell culture assay and therefore, is predicted to have no effect on Apc protein function. This variant has also been reported as a germline variant in prior studies and reported in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/RCV000200964/) as likely benign.

Somatic mutations in BRAF have been found in up to 10% of all NSCLC, more common in adenocarcinomas. D594 is a highly conserved residue within the kinase domain of BRAF and mutation of this residue appears to result in kinase inactivation. In vitro study has shown that kinase-dead BRAF forms a constitutive complex with CRAF in the presence of activated RAS leading to MEK and ERK signaling.While clinical trials targeting BRAF-mutant NSCLC have mostly focused on patients with V600E-mutant disease, in vitro studies suggests potential sensitivity to targeted agents in cell lines with inactivating BRAF non-V600 mutations. However, established clinical activity of targeted BRAF and MEK inhibition in patients with these mutations has yet to be fully elucidated and further study is warranted. Clinical correlation is recommended.