Correlation between the incidence of PIK3CA mutations in breast cancer and histopathological characteristics of the tumor

Česká verzia

Authors: A. Mendelová ^1,2; E. Jezková ^1,2; P. Zubor ¹; V. Holubeková ²; Z. Lasabová ²; L. Plank ³; J. Danko ¹
Authors place of work: Gynekologicko-pôrodnícka klinika JLF UK a UNM, Jesseniova lekárska fakulta, Martin, Univerzita Komenského, Bratislava, Slovenská republika, prednosta prof. MUDr. J. Danko, CSc. ¹; Ústav molekulovej biológie JLF UK a UNM, Jesseniova lekárska fakulta, Martin, Univerzita Komenského, Bratislava, Slovenská republika, prednosta doc. RNDr. Z. Lasabová, PhD. ²; Ústav patologickej anatómie JLF UK a UNM, Jesseniova lekárska fakulta, Martin, Univerzita Komenského, Bratislava, Slovenská republika, prednosta prof. MUDr. L. Plank, CSc. ³
Published in the journal: Ceska Gynekol 2014; 79(4): 283-288

Summary

Objective:
To determine the presence of mutations in exon 9 (encoding the helical domain) and exon 20 (encoding the kinase domain) of phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene in DNA obtained from paraffin embedded tissue from patients with carcinoma of the mammary gland and to correlate results with clinicopathological characteristics of cancer.

Design:
Prospective clinical study.

Setting:
Department of Molecular Biology, Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Commenius University, Martin, Slovak Republic.

Methods:
In set of 95 tissue samples from patients with breast cancer, mutations in exon 9 and 20 were analysed by sequencing. We also observed the associations between mutations and histopathological characteristics of tumor.

Results:
Overall, mutations were present in 25.3% (24/95) of PIK3CA gene, of this 14.7% (14/95) of mutations were located in exon 9 and 10.5% (10/95) of mutations were in exon 20. We detected three “hotspot” mutations, two were located in exon 9 (E542K, E545K) and the third mutation was found in exon 20 (H1047R). Mutations in exon 9 showed significant correlation with lower grade(p = 0.0074) and pN status without metastases(p = 0.0415). Mutations in exon 20 were associated with higher age of patient (p = 0.0249). The E545K mutation correlated with lower grade (p = 0.0013) and pN status (p = 0.0232) particularly; the H1047R mutation was significantly more frequent in lobular type of breast cancer (p = 0.0354).

Conclusion:
The PI3K signaling pathway plays a critical oncogenic role in the development of human breast cancer and the prevalence of its deregulation advocates its potential as a feasible therapeutic target. In our study we demonstrate a significant correlation between the presence of PIK3CA mutations and some clinicopathological characteristics of tumour. We have shown that the mutations in exon 9 of PIK3CA were associated with favourable prognostic factors.

Keywords:
“hotspot” mutation, PIK3CA, PI3K pathway, breast cancer

Zdroje

1. Barbareschi, M., Buttitta, F., Felicioni, L., et al. Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res, 2007, 13, p. 6064–6069.

2. Cantley, LC. The phosphoinositide 3-kinase pathway. Science, 2002, 296, p. 1655–1657.

3. Cathomas, G. PIK3CA in colorectal cancer. Frontiers in oncology, 2014, 4, p. 35.

4. Cizkova, M., Susini, A., Vacher, S., et al. PIK3CA mutation impact on survival in breast cancer patients and in ERα, PR and ERBB2-based subgoups. Breast Cancer Res, 2012, 14, p. 28–36.

5. Courtney, KD., Corcoran, RB., Engelman, JA. The PI3K pathway as drug target in human cancer. J Clin Oncol, 2010, 28, p. 1075–1083.

6. Di Nicolantorio, F., Arena, S., Tabarnero, J., et al. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest, 2010, 120, p. 2858–2866.

7. Ellis, MJ., Lin, L., Crowder, R., et al. Phosphatidyl-inositol-3-kinase aplha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer. Breast Cancer Res Treat, 2010, 119, p. 379–390.

8. Hlinkova, K. Molekulárne markery cielenej liečby u vybraných onkologických malignít. Onkológia (Bratislava), 2010, 5, 2, p. 64–69.

9. Huang, CH., Mandelker, D., Gabelli, SB., et al. Insights into the oncogenic effects of PIK3CA mutations from the structure of p110alpha/p85alpha. Cell Cycle, 2008, 7, p. 1151–1156.

10. Janku, F., Wheler, JJ., Westin, SN., et al. PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol, 2012, 30, 8, p. 778–782.

11. Juric, D., Baselga, J. Tumor genetic testing for patients selection in phase I clinical trials: The case of PI3K inhibitors. J Clin Oncol, 2012, 30, p. 765–766.

12. Kalinsky, K., Jacks, LM., Heguy, A., et al. PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res, 2009, 15, p. 5049–5059.

13. Kaplan, DR., Whitman, M., Schaffhausen, B., et al. Common elements in growth factor stimulation and oncogenic transormation: 85 kd phosphoprotein and phosphatidylinositol kinase activity. Cell, 1987, 50, p. 1021–1029.

14. Li, SY., Rong, M., Grieu, F., et al. PIK3CA mutations in breast cancer are associated with poor outcome. Breast Cancer Res Treat, 2006, 96, p. 91–95.

15. Loi, S., Haibe-Kains, B., Majjaj, S., et al. PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc Natl Acad Sci U S A, 2010, 107, p. 10208–10213.

16. López-Knowles, E., O´Toole, SA., McNeil, CM., et al. PI3K pathway activation breast cancer is associated with the basal-like phenotype and cancer-specific mortality. Int J Cancer, 2010, 126, p. 1121–1131.

17. Maruyama, N., Miyoshi, Y., Taguchi, T., et al. Clinicopathologic analysis of breast cancers with PIK3CA mutations in Japanese women. Clin Canccer Res, 2007, 13, p. 408–414.

18. Vivanco, I., Sawyers, CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer, 2002, 2, p. 489–501.

19. Wang, GM., Park, BH. The role of PIK3CA mutations as a predictor of outcomes and a therapeutic target. Curr Breast Cancer Rep, 2010, 2, p. 167–173.

20. Woodward, WA., Strom, EA., Tucker, SL., et al. Changes in the 2003 American Joint Committee on Cancer staging for breast cancer dramatically affect stage-specific survival. J Clin Oncol, 2003, 21, p. 3244–3248.

21. Wu, G., Xing, M., Mambo, E., et al. Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Res, 2005, 7, 5, p. 609–616.