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PIK3CA

Thursday 9 September 2004

Definition: PI3K subunit p110alpha (PIK3CA) is a subunit of PI3Ks. The phosphatidylinositol 3-kinases (PI3Ks) are known regulators of cellular growth and proliferation.

Phosphoinositide-3-kinase catalytic alpha polypeptide (PIK3CA) encodes the p110α subunit of the mitogenic signaling protein phosphoinositide 3-kinase (PI3K).

PIK3CA mutations in the helical binding domain and the catalytic subunit of the protein have been associated with tumorigenesis and treatment resistance in various malignancies.

The impact of PIK3CA mutations on the efficacy of targeted therapies such as erlotinib and crizotinib is unknown.

Pathology

PI3KCA is one of the most commonly mutated oncogenes in human cancer.

- somatic mutations in PIK3CA gene (kinase domain ++) in:

- PIK3CA mutations in the helical domain (in exon 9) and in the kinase domain (exon 20) cause tumor formation by different means.

- colorectal carcinoma

  • PIK3CA kinase domain mutation identifies a subgroup of stage III colon cancer patients with poor prognosis. (21830111)
  • PIK3CA mutation in exon 20 is a negative prognostic factor in stage III colon cancer patients. Moreover, this negative effect is not present in stage I and II patients. (21830111)

- mammary carcinomas (breast cancer) (21830111)

  • The PI3K-Akt cascade is a key signaling pathway involved in cell proliferation, survival, and growth.
  • Activating PIK3CA mutations have been reported in breast carcinoma (BC).
  • PIK3CA mutations are significantly associated with ER+ in HER2-negative cases. (21830111)
  • A higher frequency of PIK3CA mutations is present in lobular carcinoma compared with ductal carcinoma (50% vs. 35%). (21830111)
  • There is no association between the survival and PIK3CA mutational status. (21830111)
  • In hereditary BC, PIK3CA mutations are found only in the BRCA2 group.
  • The PIK3CA mutation seems to characterize the luminal-type BC, in both sporadic and BRCA2 mutated forms, and is absent in the basal-type BC, in both the sporadic and BRCA1 mutated forms. (21830111)

- pulmonary adenocarcinoma

  • PIK3CA mutations occur in lung adenocarcinomas, usually concurrently with EGFR, KRAS, and ALK.

- PIK3CA-mutated mammary carcinoma

  • PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer. (25559818)
  • PIK3CA mutations were identified in 23% of HER2-positive breast tumors, and these mutations were associated with poorer outcome in all of the treatment arms. (25559818)
  • Activating mutations in PIK3CA predicted poor pathologic complete response (pCR) in patients with HER2-positive breast cancer treated with neoadjuvant therapies that target HER2. (25559818)
  • Consequently, the combination of anti-HER2 agents and PI3K inhibitors is being investigated.
  • PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer. (2519975)

PIK3CA

References

- Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma-rationale for comprehensive mutation profiling. Chaft JE, Arcila ME, Paik PK, Lau C, Riely GJ, Pietanza MC, Zakowski MF, Rusch V, Sima CS, Ladanyi M, Kris MG. Mol Cancer Ther. 2012 Feb;11(2):485-91. doi : 10.1158/1535-7163.MCT-11-0692 PMID: 22135231

References

- Mutations of the PIK3CA gene in diffuse large B cell lymphoma. Baohua Y, Xiaoyan Z, Tiecheng Z, Tao Q, Daren S. Diagn Mol Pathol. 2008 Sep;17(3):159-65. PMID: 18382359

- PIK3CA kinase domain mutation identifies a subgroup of stage III colon cancer patients with poor prognosis. Fariña Sarasqueta A, Zeestraten EC, van Wezel T, van Lijnschoten G, van Eijk R, Dekker JW, Kuppen PJ, Goossens-Beumer IJ, Lemmens VE, van de Velde CJ, Rutten HJ, Morreau H, van den Brule AJ. Cell Oncol (Dordr). 2011 Dec;34(6):523-31. PMID: 21830111

- PIK3CA in breast carcinoma: a mutational analysis of sporadic and hereditary cases. Michelucci A, Di Cristofano C, Lami A, Collecchi P, Caligo A, Decarli N, Leopizzi M, Aretini P, Bertacca G, Porta RP, Ricci S, Della Rocca C, Stanta G, Bevilacqua G, Cavazzana A. Diagn Mol Pathol. 2009 Dec;18(4):200-5. PMID: 19861897

- Lopez-Knowles E, Hernandez S, Malats N, Kogevinas M, Lloreta J, Carrato A, Tardon A, Serra C, Real FX. PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors. Cancer Res. 2006 Aug 1;66(15):7401-4. PMID: 16885334

- Samuels Y, Diaz LA Jr, Schmidt-Kittler O, Cummins JM, Delong L, Cheong I, Rago C, Huso DL, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell. 2005 Jun;7(6):561-73. PMID: 15950905