PIK3CA is the the p110 catalytic subunit-alpha of phosphatidylinositol 3 kinase. Activating mutations of PIK3CA occur in various types. PIK3CA mutations have been reported in approximately 8% of cases of diffuse large B cell lymphoma and are typically mutually exclusive of PTEN loss in that tumor type. PIK3CA mutations are very rare in chronic lymphocytic leukemia and believed to be absent in acute myeloid leukemia and myelodysplastic syndromes. PIK3CA mutations are potentially targetable in some settings and pathway inhibitors are currently under investigation .

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 80% of the identified mutations found within three hotspot: E542K, E545K, and H1047R. PIK3CA mutations are often found in hormone receptor positive breast cancer and have been associated with resistance to anti-EGFR therapy in some studies but not in others.

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/).

PTEN is a lipid and protein phosphatase that negatively regulates the PI3K/AKT/mTOR pathway. PTEN has been reported to show nonsense and frameshift mutations in approximately 10% of adult T cell ALL patients. PTEN mutations may occur together with large deletions of PTEN which are not detected by this assay. PTEN abnormalities are thought to be more frequent in NOTCH1/FBXW7 unmutated T-ALL and appear to be mutually exclusive of NRAS/KRAS mutations in T-ALL. PTEN alterations are associated with reduced or absent protein expression and may be associated with a poor prognosis in adult T cell ALL, but not pediatric T-ALL, according to some studies. PTEN alterations appear to be infrequent among myeloid malignancies.

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.

PIK3CA mutations activate the PI3K-PTEN-AKT pathway which is downstream from both the EGFR and the RAS-RAF-MAPK pathways. PIK3CA mutations are present in ~5% of cutaneous melanomas. PIK3CA M1043I is a known oncogenic hotspot mutation. M1043I confers a gain of function on the protein as indicated by in increased activation of downstream signaling and and transformation in cell culture. Clinical trials targeting PI3K/Akt/mTor pathway inhibitors are available for patients with PIK3CA mutated tumors.

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 5% of renal cell carcinomas. 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.

This gene is a known cancer gene.

This gene is a known cancer gene.

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.