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Low-penetrance susceptibility variants and postmenopausal oestrogen receptor positive breast cancer

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The risk of breast cancer (BC) in women is high and many factors including genetic factors increase the risk for the disease. It is revealed that the variations of low-penetrance susceptibility genes are important for carcinogenesis as they interact with the environmental and hereditary factors. Recently, the list of BC-associated common single nucleotide polymorphisms (SNPs) and chromosomal loci in low-penetrance susceptibility genes have been expanded in genomewide association studies. FGFR2, LSP1, MAP3K1, TGFB1, TOX3, 2q35 and 8q loci variations are some examples for these common SNPs. These SNPs and their association with BC risk was investigated in many different populations. Therefore in this study, we aimed to evaluate low-penetrance susceptibility SNPs; namely FGFR2 rs1219648, rs2981579, rs2981582; MAP3K1 rs889312; TOX3 rs3803662; LSP1 rs909116, rs3817198 and SLC4A7 rs4973768 together, for the first time in Turkish postmenopausal oestrogen receptor positive BC cases. Following the DNA isolation, multiplex PCR and matrix-assisted laser desorption/ionization mass spectrometry with time of flight measurement (MALDI-TOF) based SNP analysis were performed. MAP3K1 rs889312 SNP demonstrated the strongest association with BC risk among the other low penetrant SNPs, it was also associated with BC risk in a dominant model. Only in a ressesive model, TOX3 rs3803662 was associated with BC risk. In addition, rs4973768 CC and rs909116 CC genotypes are correlated with higher tumour size which is not reported in the literature as yet; on the other hand there are no associations between any of the other SNP genotypes and clinopathological parameters. In our opinion, MAP3K1 rs889312 may be a good BC susceptibility biomarker candidate for Turkish population.

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  1. Ahmed S., Thomas G., Ghoussaini M., Healey C. S., Humphreys M. K., Platte R. et al. 2009 Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat. Genet. 41, 585–590.

  2. Althuis M. D., Fergenbaum J. H., Garcia-Closas M., Brinton L. A., Madigan M. P. and Sherman M. E. 2004 Etiology of hormone receptor-defined breast cancer: a systematic review of the literature. Cancer Epidemiol. Biomarkers Prev. 13, 1558–1568.

  3. Antoniou A. C., Beesley J., McGuffog L., Sinilnikova O. M., Healey S., Neuhausen S. L. et al. 2010 Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction. Cancer Res. 70, 9742–9754.

  4. Barnholtz-Sloan J. S., Shetty P. B., Guan X., Nyante S. J., Luo J., Brennan D. J. et al. 2010 FGFR2 and other loci identified in genome-wide association studies are associated with breast cancer in African-American and younger women. Carcinogenesis 31, 1417–1423.

  5. Barrdahl M., Canzian F., Lindström S., Shui I., Black A., Hoover R. N. et al. 2015 Association of breast cancer risk loci with breast cancer survival. Int. J. Cancer 137, 2837–2845.

  6. Beuselinck B., Karadimou A., Lambrechts D., Claes B., Wolter P., Couchy G. et al. 2013 Single-nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib. Br. J. Cancer 108, 887–900.

  7. Camidge D. R., Berge E. M., Doebele R. C., Ballas M. S., Jahan T., Haigentz M. Jr et al. 2014 A phase II, open-label study of ramucirumab in combination with paclitaxel and carboplatin as first-line therapy in patients with stage IIIB/IV non-small-cell lung cancer. J. Thorac. Oncol. 9, 1532–1539.

  8. Campbell T. M., Castro M. A. A., de Santiago I., Fletcher M. N. C., Halim S., Prathalingam R. et al. 2016 FGFR2 risk SNPs confer breast cancer risk by augmenting oestrogen responsiveness. Carcinogenesis 37, 741–750.

  9. Chen M. B., Wu X. Y., Shen W., Wei M. X., Li C., Cai B. et al. 2011 Association between polymorphisms of trinucleotide repeat containing 9 gene and breast cancer risk: evidence from 62,005 subjects. Breast Cancer Res. Treat. 126, 177–183.

  10. Chen W., Zhong R., Ming J., Zou L., Zhu B., Lu X. et al. 2012 The SLC4A7 variant rs4973768 is associated with breast cancer risk: evidence from a case-control study and a meta-analysis. Breast Cancer Res. Treat. 136, 847–857.

  11. Chen Y., Shi C. and Guo Q. 2016 TNRC9 rs12443621 and FGFR2 rs2981582 polymorphisms and breast cancer risk. World J. Surg. Oncol. 14, 50.

  12. Cowper-Sal lari R., Zhang X., Wright J. B., Bailey S. D, Cole M. D, Eeckhoute J. et al. 2012 Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression. Nat. Genet. 44, 1191–1198.

  13. Cui F., Wu D., Wang W., He X. and Wang M. 2016 Variants of FGFR2 and their associations with breast cancer risk: a HUGE systematic review and meta-analysis. Breast Cancer Res. Treat. 155, 313–335.

  14. Deng N., Zhou H., Fan H. and Yuan Y. 2017 Single nucleotide polymorphisms and cancer susceptibility. Oncotarget 8, 110635–110649.

  15. Deng Z., Shi X., Liu Q., Wang Z., Feng T., Jin T. et al. 2016 Meta-analysis of TNRC9 rs3803662 polymorphism and breast cancer risk. Int. J. Clin. Exp. Med. 9, 6228–6236.

  16. Dunning A. M., Healey C. S., Baynes C., Maia A. T., Scollen S., Vega A. et al. 2009 Association of ESR1 gene tagging SNPs with breast cancer risk. Hum. Mol. Genet. 18, 1131–1139.

  17. Easton D. F., Pooley K. A., Dunning A. M., Pharoah P. D., Thompson D., Ballinger D. G. et al. 2007 Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093.

  18. Garcia-Closas M., Hall P., Nevanlinna H., Pooley K., Morrison J., Richesson D. A. et al. 2008 Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genet. 4, e1000054.

  19. Gates M. A., Tworoger S. S., Terry K. L., De Vivo I., Hunter D. J., Hankinson S. E. et al. 2009 Breast cancer susceptibility alleles and ovarian cancer risk in 2 study populations. Int. J. Cancer 124, 729–733.

  20. Guo J., Sueta A., Nakamura K., Yoshimoto N., Baba M., Ishida N. et al. 2017 Genetic and environmental factors and serum hormones, and risk of estrogen receptor-positive breast cancer in pre- and postmenopausal Japanese women. Oncotarget 8, 65759–65769.

  21. Han W., Woo J. H., Yu J. H., Lee M. J., Moon H. G., Kang D. et al. 2011 Common genetic variants associated with breast cancer in Korean women and differential susceptibility according to intrinsic subtype. Cancer Epidemiol. Biomarkers Prev. 20, 793–798.

  22. Han Y. J., Zhang J., Zheng Y., Huo D. and Olopade O. I. 2016 Genetic and epigenetic regulation of TOX3 expression in breast cancer. PLoS One 11, e0165559.

  23. Hu P., Huang Q., Li Z., Wu X., Ouyang Q., Chen J. et al. 2014 Silencing MAP3K1 expression through RNA interference enhances paclitaxel-induced cell cycle arrest in human breast cancer cells. Mol. Biol. Rep. 41, 19–24.

  24. Huijts P. E., Vreeswijk M. P., Kroeze-Jansema K. H., Jacobi C. E., Seynaeve C., Krol-Warmerdam E. M. et al. 2007 Clinical correlates of low-risk variants in FGFR2, TNRC9, MAP3K1, LSP1 and 8q24 in a Dutch cohort of incident breast cancer cases. Breast Cancer Res. 9, R78.

  25. Hunter D. J., Kraft P., Jacobs K. B., Cox D. G., Yeager M., Hankinson S. E. et al. 2007 A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat. Genet. 39, 870–874.

  26. Joshi A. D., Lindström S., Hüsing A., Barrdahl M., VanderWeele T. J., Campa D. et al. 2014 Additive interactions between susceptibility single-nucleotide polymorphisms identified in genome-wide association studies and breast cancer risk factors in the Breast and Prostate Cancer Cohort Consortium. Am. J. Epidemiol. 180, 1018–1027.

  27. Khazaei Z., Mosavi Jarrahi A., Momenabadi V., Ghorat F., Adineh H. A., Sohrabivafa M. et al. 2019 Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide stomach cancers and their relationship with the human development index (HDI). World Cancer Res. J. 6, e1257.

  28. Kuchenbaecker K. B., Neuhausen S. L., Robson M., Barrowdale D., McGuffog L., Mulligan A. M. et al. 2014 Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res. 16, 3416.

  29. Ledwoń J. K., Hennig E. E., Maryan N., Goryca K., Nowakowska D., Niwińska A. et al. 2013 Common low-penetrance risk variants associated with breast cancer in Polish women. BMC Cancer 13, 510.

  30. Lei H. and Deng C. X. 2017 Fibroblast growth factor receptor 2 signaling in breast cancer. Int. J. Biol. Sci. 13,1163–1171.

  31. Lim U., Kocarnik J. M., Bush W. S., Matise T. C., Caberto C., Park S. L. et al. 2014 Pleiotropy of cancer susceptibility variants on the risk of non-Hodgkin lymphoma: the PAGE consortium. PLoS One 9, e89791.

  32. McGrath M., Lee I. M., Buring J., Hunter D. J. and De Vivo I. 2008 Novel breast cancer risk alleles and endometrial cancer risk. Int. J. Cancer 123, 2961–2964.

  33. Miles F. L., Rao J. Y., Eckhert C., Chang S. C., Pantuck A. and Zhang Z. F. 2015 Associations of immunity-related single nucleotide polymorphisms with overall survival among prostate cancer patients. Int. J. Clin. Exp. Med. 8, 11470–11476.

  34. Milne R. L., Gaudet M. M., Spurdle A. B., Fasching P. A., Couch F. J., Benítez J. et al. 2010 Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study. Breast Cancer Res. 12, R110.

  35. Moghaddam A. S., Roodgar M., Mansourpour H. and Jarrahi A. M. 2017 LSP1 gene rs3817198 polymorphism and breast cancer risk: a systematic review and meta-analysis study. Asian Pac. J. Cancer Biol. 1, 79–84.

  36. Nagrani R., Mhatre S., Rajaraman P., Chatterjee N., Akbari M. R., Boffetta P. et al. 2017 Association of genome-wide association study (GWAS) ıdentified snps and risk of breast cancer in an Indian population. Sci. Rep. 7, 40963.

  37. Nan H., Qureshi A. A., Hunter D. J. and Han J. 2009 Genetic variants in FGFR2 and FGFR4 genes and skin cancer risk in the Nurses’ Health Study. BMC Cancer 9, 172.

  38. Özgöz A., Samli H., Öztürk K. H., Orhan B., İçduygu F. M., Aktepe F. et al. 2013 An investigation of the effects of FGFR2 and B7-H4 polymorphisms in breast cancer. J. Cancer Res. Ther. 9, 370–375.

  39. Özmen V. 2014 Breast cancer in Turkey: clinical and histopathological characteristics (analysis of 13,240 patients). J. Breast Health 10, 98–105.

  40. Park S. L., Fesinmeyer M. D., Timofeeva M., Caberto C. P., Kocarnik J. M., Han Y. et al. 2014 Pleiotropic associations of risk variants identified for other cancers with lung cancer risk: the PAGE and TRICL consortia. J. Natl. Cancer Inst. 106, dju061.

  41. Quaye L., Tyrer J., Ramus S. J., Song H., Wozniak E., DiCioccio R. A. et al. 2009 Association between common germline genetic variation in 94 candidate genes or regions and risks of invasive epithelial ovarian cancer. PLoS One 4, e5983.

  42. Rebbeck T. R., DeMichele A., Tran T. V., Panossian S., Bunin G. R., Troxel A. B. et al. 2009 Hormone-dependent effects of FGFR2 and MAP3K1 in breast cancer susceptibility in a population- based sample of post-menopausal African-American and European-American women. Carcinogenesis 30, 269–274.

  43. Robbez-Masson L. J., Bödör C., Jones J. L., Hurst H. C., Fitzgibbon J., Hart I. R. et al. 2013 Functional analysis of a breast cancer-associated FGFR2 single nucleotide polymorphism using zinc finger mediated genome editing. PLoS One 8, e78839.

  44. Ruiz-Narváez E. A., Rosenberg L., Cozier Y. C., Cupples L. A., Adams-Campbell L. L., Palmer J. R. 2010 Polymorphisms in the TOX3/LOC643714 locus and risk of breast cancer in African- American women. Cancer Epidemiol. Biomarkers Prev. 19, 1320–1327.

  45. Shan J., Mahfoudh W., Dsouza S. P., Hassen E., Bouaouina N., Abdelhak S. et al. 2012 Genome-wide association studies (GWAS) breast cancer susceptibility loci in Arabs: susceptibility and prognostic implications in Tunisians. Breast Cancer Res. Treat. 135, 715–724.

  46. Slattery M. L., Lundgreen A. and Wolff R. K. 2012 MAP kinase genes and colon and rectal cancer. Carcinogenesis 33, 2398–2408.

  47. Song H., Ramus S. J., Kjaer S. K., DiCioccio R. A., Chenevix-Trench G., Pearce C. L. et al. 2009 Association between invasive ovarian cancer susceptibility and 11 best candidate SNPs from breast cancer genome-wide association study. Hum. Mol. Genet. 18, 2297–2304.

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

  49. Stacey S. N., Manolescu A., Sulem P., Thorlacius S., Gudjonsson S. A., Jonsson G. F. et al. 2008 Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat. Genet. 40, 703–706.

  50. Thanh N. T. N., Lan N. T. T., Phat P. T., Giang N. D. T. and Hue N. T. 2018 Two polymorphisms, rs2046210 and rs3803662, are associated with breast cancer risk in a Vietnamese case-control cohort. Genes Genet. Syst. 93, 101–109.

  51. Turnbull C., Ahmed S., Morrison J., Pernet D. and Renwick A. 2010 Genome-wide association study identifies five new breast cancer susceptibility loci. Nat. Genet. 42, 504–507.

  52. Turner N. and Grose R. 2010 Fibroblast growth factor signalling: from development to cancer. Nat. Rev. Cancer 10, 116–129.

  53. Türkyılmaz M., Hacıkamiloğlu E., Deniz E. B., Boztaş G, Dündar S. and Ergün A. K. et al. 2018 In Cancer statistics of Turkey 2015 (ed. İlter H. and B. Keskinkılıç), pp. 44. Directorate General of Public Health, The Ministry of Health, Ankara.

  54. Udler M. S., Ahmed S., Healey C. S., Meyer K., Struewing J., Maranian M. et al. 2010 Fine scale mapping of the breast cancer 16q12 locus. Hum. Mol. Genet. 19, 2507–2515.

  55. Wei X., Zhang E., Wang C., Gu D., Shen L., Wang M. et al. 2014 A MAP3k1 SNP predicts survival of gastric cancer in a Chinese population. PLoS One 9, e96083.

  56. Zhang L. and Long X. 2015 Association of three SNPs in TOX3 and breast cancer risk: Evidence from 97275 cases and 128686 controls. Sci. Rep. 5, 12773.

  57. Zhang X., Bailey S. D. and Lupien M. 2014 Laying a solid foundation for Manhattan–’setting the functional basis for the post- GWAS era’. Trends Genet. 30, 140–149.

  58. Zheng Q., Ye J., Wu H., Yu Q. and Cao J. 2014 Association between mitogen-activated protein kinase kinase kinase 1 polymorphisms and breast cancer susceptibility: a meta-analysis of 20 case-control studies. PLoS One 9, e90771.

  59. Zheng W., Cai Q., Signorello L. B., Long J., Hargreaves M. K. and Deming S. L. 2009 Evaluation of 11 breast cancer susceptibility loci in African-American women. Cancer Epidemiol. Biomarkers Prev. 18, 2761–2764.

  60. Zheng W., Wen W., Gao Y. T., Shyr Y., Zheng Y., Long J. et al. 2010 Genetic and clinical predictors for breast cancer risk assessment and stratification among Chinese women. J. Natl. Cancer Inst. 102, 972–981.

  61. Zhou L., Yao F., Luan H., Wang Y., Dong X., Zhou W. et al. 2012 Three novel functional polymorphisms in the promoter of FGFR2 gene and breast cancer risk: a HuGE review and meta-analysis. Breast Cancer Res. Treat. 136, 885–897.

  62. Zhu B., Wang J., Qin L., Wang L., Zheng Y., Zhang L. et al. 2018 FGFR2 gene polymorphism rs2981582 is associated with non-functioning pituitary adenomas in Chinese Han population: a case-control study. Biosci. Rep. 38, pii:BSR20181081.

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This study was supported by the Kastamonu University Scientific Research Projects Management Co-ordination Office with code Number KÜBAP-01/2013-02.

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Correspondence to Asuman Özgöz.

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Corresponding editor: H. A. Ranganath

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Özgöz, A., Mutlu İçduygu, F., Yükseltürk, A. et al. Low-penetrance susceptibility variants and postmenopausal oestrogen receptor positive breast cancer. J Genet 99, 15 (2020). https://doi.org/10.1007/s12041-019-1174-2

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  • low penetrance
  • susceptibility
  • polymorphism
  • breast cancer.