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.

Familial adenomatous polyposis (FAP) is a disease with autosomal-dominant inheritance that predisposes to carcinoma of the colorectum, stomach, duodenum, and thyroid. There is increasing evidence that germline variants in APC (E1317Q) predispose to the development of multiple colorectal adenomas and carcinoma.

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. 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.

FGFR3 has been found to be mutated in up to 64% of cases of bladder cancer; FGFR3 mutations tend to be exclusive of RAS mutations ,TP53 overexpression, TP53 mutation, but not PIK3CA mutations. However, subsets of cases with co-mutations have been described. FGFR3 mutations (including Y373C) are believed to lead to constitutive activation of the receptor and activation of the RAS-MAPK pathway. FGFR3 mutations are often seen in non-muscle invasive bladder cancers and tend to correlate with low stage and grade; however FGFR3 mutations have also been described in muscle-invasive bladder cancer. Targeted therapies with FGFR3 inhibitors have been explored in patients with bladder cancer.

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.

Somatic mutations in PIK3CA are seen in approximately 2% of papillary thyroid carcinoma, poorly differentiated carcinoma, anaplastic carcinoma. Somatic mutations of PIK3CA have been described particularly in advanced and dedifferentiating thyroid tumors. Their prevalence varies from 16 to 23% in anaplastic thyroid carcinomas. They are less frequent in papillary and follicular thyroid carcinomas and the prevalence in medullary thyroid carcinomas remains unknown. Although inhibitors of the PI3K/AKT/mTOR pathway have shown efficacy against thyroid cancer in pre-clinical models, their success in clinical trials remains to be determined.

PTEN is a tumor suppressor gene, located on chromosome 10q23. It encodes a lipid and protein phosphatase that negatively regulates the PI3K/AKT/mTOR pathway. Cancer-associated alterations in this gene often result in loss of PTEN protein and upregulation of the PI3K/AKT/mTOR pathway. Germline mutations of PTEN lead to inherited hamartoma and Cowden syndrome while somatic mutations are also known to occur in multiple malignancies. PTEN alterations are rare and not well characterized in parathyroid tumors. One study reported loss of heterozygosity of PTEN in 7 of 14 parathyroid carcinomas. PTEN p.G165R variant is a reported pathogenic variant that causes glycine to arginine substitution at codon 165 affecting NH2-terminal phosphatase domain. This variant has been reported previously in endometrial and CNS tumors in COSMIC data base. Functional studies demonstrate that individuals harboring this variant have decreased levels of the functional PTEN protein when compared to wild type controls. However, its clinical significance remains to be fully elucidated.

Pancreatic ductal adenocarcinoma (PDAC) is initiated by oncogenic mutant KRAS, which has been shown to drive pancreatic neoplasia. More than 90% of pancreatic ductal adenocarcinoma samples have a KRAS mutation which may have prognostic, and (with ongoing trials assessing the efficacy of novel KRAS inhibitors) possibly therapeutic implications. However, targeting KRAS directly has been difficult in these tumors.

SMAD4 is a tumor suppressor gene and it encodes an intracellular mediator in the transforming growth factor β (TGF β) signal transduction pathway. The gene is inactivated in 40% of human gastric cancers by loss of heterozygosity, promoter hypermethylation, and somatic mutation. Prior sequencing studies have shown that SMAD4 is mutated in up to 8% of gastric cancers. SMAD4 p.R361H mutation occurs within the MH2 domain which is the SMAD-SMAD interaction and transcription activation domain of the protein. The loss of SMAD4, especially loss of nuclear SMAD4 expression, is involved in gastric cancer progression. Mutations at codon 361 have been previously reported in various tumor types. The exact clinical significance of this mutation in gastric cancers needs to be fully elucidated.

KRAS is a gene that encodes one of the several proteins in the epidermal growth factor receptor (EGFR) signaling pathway that is important in the development and progression of cancer. KRAS can harbor oncogenic mutations that yield a constitutively active protein. KRAS mutations are found in approximately 2-3% of esophageal cancers. In colorectal cancers, mutations in the KRAS gene may indicate poor prognosis and poor drug responses against anti-EGFR therapies. However, prognostic and predictive implications of KRAS mutations in esophageal cancers need to be fully elucidated. Results should be interpreted in conjunction with other laboratory and clinical findings.

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

PIK3CA mutations activate the PI3K-PTEN-AKT pathway which is downstream from both the EGFR and 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). Activating mutations in PIK3CA are found in a wide variety of human cancers including up to 4% of prostate cancers. The role of PIK3CA mutations as prognosticators of outcome or predictors of therapeutic response awaits further evaluation. Clinical trials are available for patients with PIK3CA mutated tumors.

MET is a member of the receptor tyrosine kinase and proto-oncogene playing a major role in tumor development and metastasis. MET mutations have been reported in 1% of primary prostate cancers and up to 4.4% of metastatic prostate cancers. Studies have suggested that overexpression of c-MET and aberrant activation of the HGF/c-MET axis in prostate cancer is a relatively late event in tumor progression seen in advanced stages of the disease. MET E168D mutation is located in the SEMA domain containing the ligand binding site. The prognostic and predictive significance of MET mutations in prostate cancer is not clear and correlation with other clinical and laboratory findings is necessary.

CDC73 mutations have been previously reported in parathyroid tumors. However, it could be a germ line alteration.

The FGFR1 copy number gain is part of a large partial chrom 8 gain. The role of FGFR1 in prostate cancer is under study. FGRF1 amplification may be associated with sensitivity to pazopanib in some tumor types.

In colorectal cancer, EGFR gene amplification is associated with sensitivity EGFR-targeted therapies, such as Erbitux and Vectibix.

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.

IDH2 R172X mutations have been detected in 55-82% of sinonasal undifferentiated carcinomas (SNUC). These tumors may be amenable to IDH2-targeted therapies.

FBXW7 is a tumor suppressor gene that is mutated in several tumors including colorectal, liver, bladder and ovarian cancers. It is also mutated in endometrial, esophageal, and head and neck squamous cancers. FBXW7 is a tumor suppressor gene responsible for the degradation of several proto-oncogenes. mTOR is one of the substrates of FBXW7-mediated protein degradation, and loss of function of FBXW7 increases the levels of total and activated mTOR. FBXW7 R505G lies within the WD repeat 4 of the FBXW7 protein. R505G has been identified in the scientific literature, but has not been biochemically characterized and therefore, its effect on FBXW7 protein function is unknown. Preclinical data suggest that FBXW7 mutations may sensitize cells to mTOR inhibitors, however, the response to mTOR inhibitors and the clinicopathologic effects of FBXW7 R505G remains to be further elucidated.

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.

CDH1 on 16q22.1 encodes E-cadherin which functions in intercellular adhesion. E-cadherin is involved in transmitting chemical signals and controlling cell maturation and movement, and acts as a tumor suppressor. A lack of functional E-cadherin impairs cell adhesion and increases the likelihood of invasion and metastasis of tumor cells. CDH1 is altered by mutation or deletion in various cancers and loss of E-cadherin has been demonstrated in a variety of sporadic cancer types including breast cancer, gastric cancer, colorectal cancer, and esophageal cancer. Along with point mutations and loss of heterozygosity (LOH), epigenetic silencing by hypermethylation of the CDH1 promoter has been associated with the loss of E-cadherin gene expression during cancer progression. Individuals with a germline CDH1 mutation have an increased risk of developing diffuse gastric cancer and breast cancer. More than 100 different pathogenic germline mutations are distributed throughout the CDH1 gene including splice-site sequences and have been found to cause a familial cancer disorder called hereditary diffuse gastric cancer (HDGC). Somatic CDH1 alterations are also found in approximately 30% of all patients with gastric cancers, both diffuse and intestinal types. Genetic alterations of CDH1 have been identified in 4% of colorectal adenocarcinomas. CDH1 D400V lies within the Cadherin domain 3 of the Cdh1 protein (UniProt.org) and mutations in this locus has been reported previously.

The Mesenchymal Epithelial Transition (MET) proto-oncogene encodes the MET receptor tyrosine kinase, also called c-MET or hepatocyte growth factor (HGF) receptor. MET is a ubiquitously expressed cell surface receptor that leads to the activation of several downstream intracellular pathways which promote cellular growth and proliferation, motility, migration and angiogenesis. Dysregulation of MET via gene amplification, germline or somatic mutations or receptor overexpression has been observed in a variety of epithelial cancers, including breast prostate cancer, non-small cell lung cancer, renal papillary carcinoma, hepatocellular and gastric carcinomas. Genetic alterations in MET have been identified in 0.4% of thyroid carcinomas. The prognostic and predictive significance of MET mutations in thyroid cancer is not clear and correlation with other clinical and laboratory findings is necessary. M362T has been identified in the scientific literature, but has not been biochemically characterized and therefore, its effect on protein function is unknown. This variant is reported as a benign/likely benign germline variant in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/93565).

BRAF is part of the mitogen-activated protein kinase (MAPK) signaling pathway and V600E is an activating mutation of BRAF. The BRAF V600E mutation has been reported in 45% of patients with papillary thyroid carcinoma, which comprise 80 % of all thyroid cancers. Presence of a BRAF p.Val600Glu (V600E) mutation is highly specific for papillary thyroid carcinoma and is only rarely associated with the follicular variant PTC, other thyroid neoplasms, or nodular goiters. Anaplastic thyroid carcinomas are rare, highly aggressive, undifferentiated tumors that comprise 1% to 2% of all thyroid cancers in the United States. Well-differentiated papillary thyroid cancer, in which BRAF V600 mutations are an early and common driver mutation, precedes or coexists with approximately 50% of anaplastic thyroid carcinomas. Between 20% and 50% of anaplastic thyroid carcinomas harbor activating BRAF V600 mutations, with unknown prognostic significance. The possible prognostic impact of BRAF V600E mutations in carcinoma of the thyroid continues to be studied.

Mutations of the ESR1 gene have been increasingly recognized as an important mechanism of endocrine therapy resistance, with a prevalence that ranges from 11 to 39%. The majority of these mutations are located within the ligand-binding domain, especially codon 537 and 538, and result in an estrogen-independent constitutive activation of the ER and, therefore, resistance to estrogen deprivation therapy such as aromatase inhibition.

KRAS is a gene that encodes one of the several proteins in the epidermal growth factor receptor (EGFR) signaling pathway that is important in the development and progression of cancer. KRAS can harbor oncogenic mutations that yield a constitutively active protein. Such mutations are found in approximately 30% to 50% of metastatic colorectal tumors and are common in other tumor types. Mutations in the KRAS gene may indicate poor prognosis and poor drug response with therapies targeted to EGFR. The absence of a KRAS mutation predicts a greater likelihood of response to EGFR-targeted therapies and improved survival with such treatment. The relevant KRAS mutation is in one of five codons (12 13, 61, 117 or 146). The presence of KRAS mutations in codon 12, 13 or 61 is associated with a high likelihood of resistance to therapies targeting EGFR. In addition, mutations at codons 117 and 146 may also be associated with reduced response to EGFR-targeted therapies. Results should be interpreted in conjunction with other laboratory and clinical findings. Drug resistance: Panitumumab Cetuximab

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.

Approximately half of all prostate cancers harbor recurrent gene fusions involving ETS transcription factors. The most common gene rearrangement is the fusion of the 5' untranslated region of TMPRSS2 (an androgen-regulated gene) and ERG (a member of ETS transcription factor family). TMPRSS2:ERG fusion is cancer-specific and results in ERG protein overexpression. ERG fusion is associated with adverse clinicopathologic predictors, metastases, and disease-specific death in non-PSA screened populations. In a cohort of active surveillance patients, it is correlated with increased tumor volume and higher Gleason grade. The effect of ERG fusions on aggressive features or outcome following radical prostatectomy is less clear and needs further elucidation.