Short Review/Commentary

PIK3CA Gene Mutations in Major Gynecologic Cancers

Akram Husain RS and Ramakrishnan V*
Genetics Lab, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, India

*Corresponding author: Ramakrishnan V, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Health City, Kelambakkam-603 103, Tamil Nadu, India

Published: 28 Sep, 2016
Cite this article as: Akram Husain RS, Ramakrishnan V. PIK3CA Gene Mutations in Major Gynecologic Cancers. Clin Oncol. 2016; 1: 1110.

Short Review/Commentary

Gynecologic malignancies posses’ major threat in women, leading to cancer in their reproductive organs, there are five main types including cervical, ovarian, uterine, vaginal and vulvar [1]. Traditionally, cancers have been viewed as diseases that are caused by the accumulation of genetic mutations, epigenetic alterations and environmental risk factors [2]. The development of sequencing era lead to identification of candidate genes, oncogenes, tumor suppressor genes which are directly associated with the disease [3]. These gynecological cancers account for 5.1 million new cancer cases among women every year globally. Out of these five malignancies cervical and ovarian cancers are more common affecting women from 30 years and above with high incidence rates [4]. In brief, cervical cancer defined as the malignant neoplasm arising from cells originating in the cervix and the cancer in any one of the ovaries are termed as ovarian cancer. Comparative Genomic Hybridization (CGH) studies have documented the amplification of 3q region in various tumor types, which found PIK3CA at 3q26 encoding the p110a catalytic subunit of phosphatidylinositol (PI) 3-kinase as an oncogene in cervical [5] and ovarian cancer [6]. This review focuses on the reported genetic mutations occurring in Phosphatidylinositol-4, 5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) oncogene of cervical and ovarian cancer respectively.
PIK3CA gene spanning 20 exons encodes for protein of 1068 amino acids, 9th and 20th exons are considered as mutational hot spots harboring more somatic mutations playing significant roles in various stages of cancers [7]. (Figure1) explains the chromosomal locations, exon structure, location of reported mutations at their corresponding genomic positions and the protein domains. The p110α subunit consists of five domains namely: ABD (adaptor-binding domain, RBD (Rasbinding domain), C2 domain, helical and kinase domains. The PI3K-AKT signaling pathway mainly involve in the regulation of various biological processes including cell propagation, progression and survival [8]. Abnormal activation of this pathway has been observed in various types of gynecologic cancers, causing aberrant cell-cycle progression, altered adhesion, apoptosis inhibition, motility and angiogenesis indicating the significance of PI3K pathway in carcinogenesis [9].
In cervical cancer, recent study in 2015 published from Chinese population with 771 cervical cancer patients screened for PIK3CA gene documented 13.6% subject’s harbored non-synonymous mutations from the 9th and 20th exons in which most of them are found to be pathogenic [10]. A study comprising 114 cervical cancer samples from Italy revealed 11% of mutations in this gene in different stages of cervical malignancy [11]. Similar study with 255 cancer patients from Sweden and China were analyzed exon 1, 9, 20 of PIK3CA gene in cervical carcinomas identified 8.15% of somatic mutations suggesting that genetic alterations of this oncogene are late events during the process of carcinogenesis [12]. The functional consequence of these mutations leads to over expression of mutant PIK3CA proteins causing the cellular transformation with phosphorylation of proteins in the AKT signaling pathway [13].
The effects of PIK3CA gene mutations in ovarian cancer were same as the cervical malignancies with higher percentage of variations in exon 9, 20 comprising the helical and kinase domains [14]. A study published in 2005 with 198 cancer patients from USA revealed 12% of mutations signifying the oncogenic role of PIK3CA gene and its pathway in ovarian cancers [15]. Similar study, comprising 182 ovarian cancer subjects from Australia documented with mutational frequency of 6%, these mutations played major role in pathogenesis of this disease. The presence of hotspot regions strongly elucidate that mutant protein may be associated with higher kinase activity and oncogenic properties [16]. In-spite of several confounding factors such as sample source, collection, preservation methods, geographical variations, ethnic background, DNA isolation, PCR methods also have an impact on mutation detection. Despite these limitations, the high frequencies of PIK3CA gene mutations have an impact on clinical applications for cancer diagnosis, prognosis of disease followed by therapeutic measures.

Figure 1

Another alt text

Figure 1
Exon structure of PIK3CA gene with reported mutations and their protein domains.


  1. Mishra K. Gynaecological malignancies from palliative care perspective. Indian journal of palliative care. 2011; 17: 45-50.
  2. You JS, Jones PA. Cancer genetics and epigenetics: two sides of the same coin? Cancer cell. 2012; 22: 9-20.
  3. Osborne C, Wilson P, Tripathy D. Oncogenes and tumor suppressor genes in breast cancer: potential diagnostic and therapeutic applications. The oncologist. 2004; 9: 361-377.
  4. Cui B, Zheng B, Zhang X, Stendahl U, Andersson S, Wallin KL. Mutation of PIK3CA: possible risk factor for cervical carcinogenesis in older women. Int J oncol. 2009; 34: 409-420.
  5. Ma YY, Wei SJ, Lin YC, Lung JC, Chang TC, Whang-Peng J, et al. PIK3CA as an oncogene in cervical cancer. Oncogene. 2000; 19: 2739-2744.
  6. Lockwood WW, Coe BP, Williams AC, MacAulay C, Lam WL. Whole genome tiling path array CGH analysis of segmental copy number alterations in cervical cancer cell lines. Int J Cancer. 2007; 120: 436-443.
  7. Ojesina AI, Lichtenstein L, Freeman SS, Pedamallu CS, Imaz-Rosshandler I, Pugh TJ, et al. Landscape of genomic alterations in cervical carcinomas. Nature. 2014; 506: 371-375.
  8. Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002; 296: 1655-1657.
  9. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase–AKT pathway in human cancer. Nature Reviews Cancer. 2002; 2: 489-501.
  10. Xiang L, Jiang W, Li J, Shen X, Yang W, Yang G, et al. PIK3CA mutation analysis in Chinese patients with surgically resected cervical cancer. Sci Rep. 2015; 5: 14035.
  11. Tornesello ML, Annunziata C, Buonaguro L, Losito S, Greggi S, Buonaguro FM. TP53 and PIK3CA gene mutations in adenocarcinoma, squamous cell carcinoma and high-grade intraepithelial neoplasia of the cervix. J Trans Med. 2014; 12: 225.
  12. Bertelsen BI, Steine SJ, Sandvei R, Molven A, Laerum OD. Molecular analysis of the PI3K‐AKT pathway in uterine cervical neoplasia: Frequent PIK3CA amplification and AKT phosphorylation. Int J Cancer. 2006; 118: 1877-1883.
  13. Karakas B, Bachman KE, Park BH. Mutation of the PIK3CA oncogene in human cancers. Br J Cancer. 2006; 94: 455-459.
  14. Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS, et al. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer research. 2004; 64: 7678-7681.
  15. Levine DA, Bogomolniy F, Yee CJ, Lash A, Barakat RR, Borgen PI, et al. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clinical Cancer Research. 2005; 11: 2875-2878.
  16. Zardavas D, Phillips WA, Loi S. PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data. Breast Cancer Res. 2014; 16: 201.