Single nucleotide polymorphisms: the role of breast cancer development and clinical perspective

Background. Breast cancer (BC) is the most prevalent cancer in women worldwide. Genetic susceptibility to BC is heterogeneous including mutations with medium to high penetrance and single nucleotide polymorphisms (SNPs) with low penetrance. Precise assessment of genetic risk would allow to personalize the programs of prevention and treatment of BC and to reduce mortality.

Objective. We aimed to determine the frequencies of single nucleotide polymorphisms rs2981582 (FGFR2), rs3817198 (LSP1), rs889312 (5q11), rs13281615 (8q24), rs13387042 (2q35), rs3803662 (16q12) in unselected group of BC patients and healthy women in Russian population, to reveal possible associations of these polymorphisms with BC development.

Subjects and methods. An unselected group of 963 patients with BC and control group of 591 healthy female blood donors were examined. Whole peripheral blood samples were used to extract genomic DNA. Real-time polymerase chain reaction with melting curves analysis was performed for SNP genotyping.

Results: Minor allele frequencies were as follows: 41.6±1.1% and 36.2±1.1% for rs2981582 (FGFR2), 35.3±1.1% and 34.3±1.1% for rs3817198 (LSP1), 39.3±1.1% and 43.7±1.1% for rs13387042 (2q35), 27.7±1.0% and 27.8±1.0% for rs889312 (5q11), 46.2±1.1% and 44.7±1.1% for rs13281615 (8q24), 35.7±1.1% and 29.9±1.1% for rs3803662 (16q12) in group of BC patients and group of healthy women respectively. The obtained ORs for BC were 1.26 (95% CI, 1.11–1.41; p=0.003) for rs2981582, OR=0.84 (95% CI, 0.69–0.98; p=0.02) for rs13387042 and OR=1.30 (95% CI, 1.14–1.45; p=0.002) for rs3803662.

Conclusion: We confirmed the associations of previously identified SNPs rs2981582 (FGFR2), rs13387042 (2q35) and rs3803662 (16q12) with BC in Russian population.

1. Davydov M.I., Axel E.M. Statistics of malignant tumors in Russia and CIS in 2012. Moscow, 2014 – p. 226.

2. van der Groep P., van der Wall E., van Diest P. J. Pathology of hereditary breast cancer // Cell. Oncol. (Dordr.). – 2011.– V. 34.– P. 71–88.

3. Lynch H. T., Snyder C., Lynch J. Hereditary breast cancer: practical pursuit for clinical translation // Ann. Surg. Oncol. – 2012.– V. 19.– P. 1723–1731.

4. Ripperger T., Gadzicki D., Meindl A., Schlegelberger B. Breast cancer susceptibility: current knowledge and implications for genetic counselling // Eur. J. Hum. Genet. – 2009. – V. 17.– P. 722–731.

5. Ferla R., Cal V., Cascio S., et al. FoundermutationsinBRCA1 andBRCA2 genes // Ann. Oncol. – 2007.– V. 18.– P. 93–98.

6. 6. Chen S., Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance // J. Clin. Oncol. – 2007. – V. 25.– P. 1329–1333.

7. Antoniou A., Pharoah P. D., Narod S., et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies // Am. J. Hum. Genet. – 2003.– V. 72.– P. 1117–1130.

8. Ford D., Easton D. F., Bishop D. T., et al. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium // Lancet. – 1994.– V. 343. – P. 692–695.

9. Ford D., Easton D. F., Stratton M., et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium // Am. J. Hum. Genet. – 1998.– V. 62.– P. 676–689.

10. Apostolou P., Fostira F. Hereditary breast cancer: the era of new susceptibilit y genes // Biomed. Res. Int. – 2013.– V. 2013. –747318.

11. Gadzicki D., Evans D. G., Harris H., et al. Genetic testing for familial/hereditary breast cancercomparison of guidelines and recommendations from the UK, France, the Netherlands and Germany // J. Community. Genet. – 2011.– V. 2.– P. 53–69.

12. National Comprehensive Cancer Network. Clinical practice guidelines in oncology genetic/familal high-risk assessment: breast and ovarian. V ersion 1. 2012.

13. Gronwald J., Tung N., Foulkes W. D., et al. Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update // Int. J. Cancer. – 2006.– V. 118.– P. 2281–2284.

14. Domchek S. M., Friebel T. M., Singer C. F., et al. Association of risk-reducing surger y in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality // JAMA. – 2010.– V. 304.– P. 967–975.

15. Maxwell K. N., Nathanson K. L. Common breast cancer risk variants in the post-COGS era: a comprehensive review // BreastCancer Res. – 2013.– V. 15.– P. 212.

16. Filippini S. E., Vega A. Breast cancergenes: beyond BRCA1 and BRCA2 // Front Biosci. (Landmark Ed.). – 2013.– V. 18.– P. 1358–1372.

17. Buisson R., Dion-C t A.M., Coulombe Y., et al. Cooperation ofbreast cancerproteins PALB2 and piccolo BRCA2 in stimulating homologous recombination // Nat. Struct. Mol. Biol. – 2010. – V. 17.– P. 1247–1254.

18. Antoniou A. C., Pharoah P. D., McMullan G., et al. A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes // Br. J. Cancer. – 2002.– V. 86. – P. 76–83.

19. Wang W. Y., Barratt B. J., Clayton D. G., Todd J. A. Genome-wide association studies: theoretical and practical concerns // Nat. Rev. Genet. – 2005.– V. 6.– P. 109–118.

20. 20. Easton D. F., Pooley K. A., Dunning A. M., et al. Genome-wide association study identifies novel breast cancer susceptibility loci // Nature. – 2007.– V. 447.– P. 1087–1093.

21. Stacey S. N., Manolescu A., Sulem P., et al. Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer // Nat. Genet. – 2007.– V. 39. – P. 865–869.

22. Peng S., L B., Ruan W., et al. Genetic polymorphisms and breast cancer risk: evidence from meta-analyses, pooled analyses, and genome-wide association studies // Breast Cancer Res Treat. – 2011.– V. 127.– P. 309–324.

23. Baynes C., Healey C. S., Pooley K. A., et al. Commonvariants in the ATM, BRCA1, BRCA2, CHEK2 and TP53 cancer susceptibilit y genes are unlikely to increase breast cancer risk // Breast Cancer Res. – 2007.– V. 9.– R27.

24. Smith A., Moran A., Boyd M. C., et al.Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening // J. Med. Genet. – 2007.– V. 44.– P. 10–15.

25. Antoniou A. C., Easton D. F. Models of genetic susceptibility to breast cancer // Oncogene. – 2006.– V. 25.– P. 5898–5905.

26. Antoniou A. C., Sinilnikova O. M., McGuffog L., et al. Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers //Hum. Molec. Genet. – 2009. – V. 4442–4456.

27. Antoniou A. C., Spurdle A. B., Sinilnikova O. M., et al., CIMBA. Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers // Am. J. Hum. Genet. – 2008.– V. 82.– P. 937–948.

28. Antoniou A. C., Beesley J., McGuffog L., et al. Common breast cancer susceptibilit y alleles and the risk of breast cancer for BRC A1 and BRCA2 mutation carriers: implications for risk prediction // Cancer Res. – 2010.– V. 70.– P. 9742– 9754.

29. Chenevix-Trench G., Milne R. L., Antoniou A. C.et al. An international initiative to identif y genetic modifiers of cancer risk in BRC A1 and BRCA2 mutation carriers: the Consortium of Investigators of Modifiers of BRCA1and BRCA2 (CIMBA) // Breast Cancer Res. – 2007.– V. 9.– P. 104.

30. Hunter D. J., Kraft P., Jacobs K. B., et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer // Nat. Genet. – 2007.– V. 39.– P. 870–874.

31. Garcia-Closas M., Hall P., Nevanlinna H., et al. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics //PLoS Genet. – 2008. 4 (4): e1000054.

32. Boyarskikh U. A., Zarubina N. A., Biltueva J. A., et al. Association of FGFR2 gene polymorphisms with the risk of breast cancer in population of W est Siberia // Eur. J. Hum. Genet. – 2009.– V. 17. – P. 1688–1691.

33. Farakhdinova A.R. Molecular and genetic investigation of breast cancer. Diss. Ufa. 2012.

34. Michailidou K., Hall P., Gonzalez-Neira A, et al. Large-scale genotyping identifies 41 new loci associated with breast cancer risk // Nat. Genet. – 2013.– V. 15.– P. 353–361.

35. Gail M. H., Benichou J. Validationstudies on a model for breast cancer risk //J. Natl. Cancer Inst. – 1994.– V. 86.– P. 573–575.

36. Gail M. H., Costantino J. P., Bryant J., et al. Weighing the risks and benefits of tamo xifen treatment for preventing breast cancer // J. Natl. Cancer Inst. –1999.– V. 91.– P. 1829–1846.

37. Wacholder S., Hartge P., Prentice R., et al. Performance of Common Genetic Variants in Breast-Cancer Risk Models // N. Engl. J. Med. – 2010.– V. 362.– P. 986–993.

38. Sueta A., Ito H., Kawase T., et al. A genetic risk predictor for breast cancer using a combination of low-penetrance polymorphisms in a Japanese population // Breast Cancer Res. T reat. – 2012. – V. 132.– P. 711–721.

39. Wang X., Oldani M. J., Zhao X. et al. A review of cancer risk prediction models with genetic variants // Cancer Inform. – 2014.– V. 13 (Suppl 2). – P. 19–28.

40. Sawyer S., Mitchell G., McKinley J., et al. A role for common genomic variants in the assessment of familial breast cancer // J. Clin.Oncol. – 2012. – V. 30.– P. 4330–4336.