PIK3CA – hereditary breast carcinoma

PIK3CA has been implicated as a germline predisposition gene in unselected cohorts of breast cancer patients. In a study of 133 Sub-Saharan African breast cancer probands, pathogenic germline PIK3CA variants were identified in 61/133 individuals (45.9%) ([PMID:35731312]). The most frequent change was an atypical hotspot c.1634A>C, and frameshift variants such as c.1658_1659del (p.Ser553ThrfsTer20) were observed in four carriers ([PMID:35731312]). No familial segregation data were provided, and inheritance patterns remain to be clarified.

Functional assays across multiple models demonstrate that recurrent PIK3CA hotspot mutations drive oncogenic gain-of-function. In MCF-10A mammary epithelial cells, E545K and H1047R variants hyperactivate PI3K/AKT signaling, promote growth factor-independent proliferation, anchorage-independent growth, and confer resistance to apoptosis and chemotherapeutics ([PMID:16322248]). These data concordantly support a dominant-acting mechanism via enhanced lipid kinase activity and downstream pathway activation.

References

• Journal of Clinical Oncology • 2022 • Germline mutation spectrum of breast cancer predisposition genes in Sub-Saharan African patients PMID:35731312
• Cancer Research • 2005 • Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells PMID:16322248

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