Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
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Phosphatidylinositol 3-kinase (PI3KCA) Oncogene Mutation Analysis and Gene Expression Profiling in Primary Breast Cancer Patients

  • Kandula, Mahesh (Department of Biotechnology, Krisani Biosciences Private Limited) ;
  • Chennaboina, Kalyan Kumar (Department of Biotechnology, Krisani Biosciences Private Limited) ;
  • Ammi Raju, Y.S. (Department of Biotechnology, Krisani Biosciences Private Limited) ;
  • Raju, Suryanarayana (Nizams Institute of Medical Sciences)
  • Published : 2013.09.30
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Abstract

Background: The phosphatidylinositol 3-kinase (PI3K) pathway plays a significant role in apoptosis, cellular proliferation and motility. The aim of the present study was to analyze mutations and gene expression profiles of the PI3KCA gene to determine any role in breast carcinomas. Materials and Methods: We analyzed 38 breast cancers for mutations in the two PIK3CA hotspots in exons 9 and 20 by direct sequencing of DNA obtained from biopsy samples. We have also analyzed expression of the PI3KCA gene in 38 breast carcinoma tumor and corresponding control tissue samples at the mRNA level by RT-PCR. The Fisher's exact test ($2{\times}2$ only) was performed using MedCalc software for to examine associations with mRNA levels. Results: In the present study a total of 13 cases demonstrated somatic mutations. In 9/13 cases 1633 G>A (E545K) were found in exon 9, whereas in exon 20, 4/13 cases had 3140A>G mutation. Our combined analysis showed PI3KCA mutations present in 34% of human breast cancer patients. In our study, we have also clearly found significantly higher expression in breast cancer tissues in comparison with control tissues (p=0.001). Conclusions: PIK3CA mutation is an emerging tumor marker that, in the future, might be used in the process of choosing a treatment. The detection of PI3KCA mutation might have important clinical implications for diagnosis, progression and therapy.

Keywords

References

  1. Areumnuri K, Jung EL, Seung SL, et al (2005). Coexistent mutations of KRAS and PIK3CA affect the efficacy of NVP-BEZ235, a dual PI3K/MTOR inhibitor, in regulating the PI3K/MTOR pathway in colorectal cancer. Int J Cancer, 133, 984-96.
  2. Bachman KE, Argani P, Samuels Y, et al (2004). The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther, 3, 772-5. https://doi.org/10.4161/cbt.3.8.994
  3. Barbareschi MB, Felicioni L, Cotrupi S, et al (2007). Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res, 13, 6064-9. https://doi.org/10.1158/1078-0432.CCR-07-0266
  4. Campbell IG, Russell SE, Choong DY, et al (2004). Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res, 64, 7678-81. https://doi.org/10.1158/0008-5472.CAN-04-2933
  5. Cizkova M, Dujaric ME, Lehmann C, et al (2013). Outcome impact of PIK3CA mutations in HER2-positive breast cancer patients treated with trastuzumab. Br J Cancer, 108, 1807-9. https://doi.org/10.1038/bjc.2013.164
  6. Cooper L, Melinda S, Maria G, et al (2013). Clinical and pathologic characteristics of patients with PI3K-mutant breast cancers. J Clin Oncol, 31, 26.
  7. Dupont Jensen J, Laenkholm AV, Knoop A, et al (2011). PIK3CA mutations may be discordant between primary and corresponding metastatic disease in breast cancer. Clin Cancer Res, 4, 667-77.
  8. Ihle NT, Lemos R Jr, Wipf P, et al (2009). Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. Cancer Res, 69, 143-50. https://doi.org/10.1158/0008-5472.CAN-07-6656
  9. Kalinsky K, Jacks LM, Heguy A, et al (2009). PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res, 16, 5049-59.
  10. Kang S, Bader AG, Vogt PK, et al (2005). Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci, 102, 802-7. https://doi.org/10.1073/pnas.0408864102
  11. Lai YL, Mau BL, Cheng WH, et al (2008). PIK3CA exon 20 mutation is independently associated with a poor prognosis in breast cancer patients. Ann Surg Oncol, 4, 1064-9.
  12. Lee JW, Soung YH, Kim SY, et al (2005). PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene, 24, 1477-80. https://doi.org/10.1038/sj.onc.1208304
  13. Levine DA, Bogomolniy F, Yee CJ, et al (2005). Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res, 11, 2875-8. https://doi.org/10.1158/1078-0432.CCR-04-2142
  14. Li SY, Rong M, Grieu F, et al (2006). PIK3CA mutations in breast cancer are associated with poor outcome. Breast Cancer Res Treat, 19, 1-5.
  15. Magdalena C, Aurélie S, Sophie V, et al (2012). PIK3CA mutation impact on survival in breast cancer patients and in ERa, PR and ERBB2-based subgroups. Breast Cancer Res, 14, 28.
  16. Maruyama N, Miyoshi Y, Taguchi T, et al (2007). Clinicopathologic analysis of breast cancers with PIK3CA mutations in Japanese women. Clin Cancer Res, 13, 408-14. https://doi.org/10.1158/1078-0432.CCR-06-0267
  17. Oda K, Okada J, Timmerman L, et al (2008). PIK3CA cooperates with other phosphatidylinositol 3'-kinase pathway mutations to effect oncogenic transformation. Cancer Res, 68, 8127-36. https://doi.org/10.1158/0008-5472.CAN-08-0755
  18. Saal LH, Holm K, Maurer M, et al (2005). PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res, 65, 2554-9. https://doi.org/10.1158/0008-5472-CAN-04-3913
  19. Samuels Y, Diaz J, Schmidt-Kittler O, et al (2005). Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell, 7, 561-73. https://doi.org/10.1016/j.ccr.2005.05.014
  20. Samuels Y, Ericson K (2006). Oncogenic PI3K and its role in cancer. Curr Opin Oncol, 1, 77-82.
  21. Samuels Y, Waldman T (2010). Oncogenic mutations of PIK3CA in human cancers. Curr Top Microbiol Immunol, 347, 21-41.
  22. Samuels Y, Wang Z, Bardelli A (2004). High frequency of mutations of the PIK3CA gene in human cancers. Science, 304, 554. https://doi.org/10.1126/science.1096502
  23. Sherene L, Benjamin HK, Samira MF, et al (2010). PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. PNAS, 107, 22. https://doi.org/10.1073/pnas.0908453107
  24. Sherene L, Stefan M, Jose B, et al (2013). PIK3CA genotype and a PIK3CA mutation-related gene signature and response to everolimus and letrozole in estrogen receptor positive breast cancer. J Clin Oncol, 9, 8127-36 .
  25. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, et al (2008). An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res, 15, 6084-91.
  26. Vivanco I, Sawyers CL (2002). The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer, 2, 489-501. https://doi.org/10.1038/nrc839
  27. Zhao L, Vogt PK (2008). Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc Natl Acad Sci USA, 105, 2652-7. https://doi.org/10.1073/pnas.0712169105

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