Pik3ca Gene

PIK3CA is the acronym for phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha.

Phosphoinositide 3-kinases also known as PI-3-kinases (PI3K), are one of the most frequently dysregulated signaling pathways in human cancers and are associated with many cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. PIK3CA is an integral component of the PI3K signaling pathway.

PIK3CA has long been described as an oncogene. The kinase has two major hotspots for activating mutations, the 542/545 region of the helical domain and the 1047 region of the kinase domain. A pseudogene of this gene has been defined on chromosome 22.

Determination of the mutation status of the PIK3CA gene is important, among other things, in the treatment of patients with:

• Colorectal carcinoma (CRC)
• Breast carcinoma
• Lung carcinoma
• Acrolentiginous melanoma (ALM).

List of diseases with proven germ line and somatic mutations in the PIK3CA gene:

• Pathogenic germline mutation(s): Cowden syndrome
• Somatic mutation(s) causing the disease: CLOVE(S) syndrome
• Disease-causing somatic mutation(s): Hemihyperplasia-multiple lipomatosis syndrome
• Somatic mutation(s) causing the disease: Hemimegalencephaly
• Disease-causing somatic mutation(s): Hepatocellular carcinoma, adult
• Disease-causing somatic mutation(s): Macrodactyly of the fingers, unilateral
• Disease-causing somatic mutation(s): macrodactyly of the toes, unilateral hemihyperplasia-multiple lipomatosis syndrome
• Disease-causing somatic mutation(s): Segmental-progressive large growth syndrome with fibroadipose hyperplasia

The mutation frequency of PIK3CA is approximately 30% in breast carcinoma, 10-30% in colorectal carcinoma and 1-3% in lung carcinoma . In non-small cell lung cancer(NSCLC), PIK3CA mutations can occur together with mutations in the EGFR gene.

Under consumption of ATP, phosphatidylinositiol, phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate are phosphorylated to produce PIP3 (phosphatidylinositol-3,4,5-trisphosphates). PIP3 plays a key role in the activation of signalling cascades involved in cell growth, survival, proliferation, motility and morphology.

PIK3CA inhibitors for solid tumours are currently still in clinical development.

1. Brazil DP et al (2001) Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci 26:657-64.
2. Fruman DA (2004) Towards an understanding of isoform specificity in phosphoinositide 3-kinase signalling in lymphocytes. Biochem Soc Trans 32:315-9.
3. Geering B et al. (2007) Regulation of class IA PI3Ks: is there a role for monomeric PI3K subunits? Biochem Soc Trans 35:199-203.
4. Haugh AM et al (2018) Distinct Patterns of Acral Melanoma Based on Site and Relative Sun Exposure. J Invest Dermatol 138:384-393.
5. Jhawer et al (2008): PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res. 68:1953-1961.
6. Janku F (2017): Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: From laboratory to patients. Cancer Treat Rev. 59:93-101.
7. Kalinsky K et al (2009): PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res. 15:5049-5059.
8. Kim D et al (2002) Akt: versatile mediator of cell survival and beyond. J Biochem Mol Biol 35:106-15.
9. Koyasu S (2003) The role of PI3K in immune cells. Nat Immunol 4: 313-9.
10. Luo J et al (2003) Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4:257-62.
11. Sarah EM et al (2012) Molecular pathways: targeting phosphoinositide 3-kinase p110-Delta in chronic lymphocytic leukemia. Clinical Cancer Research DOI: 10.1158/1078-0432.CCR-11-1402.