BRCA1 alterations are associated with endometriosis, but BRCA2 alterations show no detectable endometriosis risk: a study in Indian population

Purpose To investigate the role of genetic variations and expression alterations of BRCA1 and BRCA2 genes in the pathophysiology of endometriosis.

A genetic association study was conducted in 573 endometriosis cases and 490 controls of Indian origin. We genotyped 13 selected promoter SNPs of BRCA1 gene and 2 selected promoter SNPs of BRCA2 gene by PCR-sequencing analysis. In addition, to better understand genetic contributions to the pathophysiology of endometriosis, the expression pattern of BRCA1 & 2 was analyzed in the eutopic endometria of endometriosis cases and controls by western-blot and immunohistochemical analysis.

Our results revealed significant association between BRCA1 rs71361504 (−/GTT) SNP and endometriosis risk in Indian women (P < 0.0001), while the remaining SNPs of both BRCA1 & 2 genes showed no difference between cases and controls. Western-blot and immunohistochemical analysis revealed significantly decreased BRCA1 expression levels in eutopic endometria of patients compared with controls (P < 0.05). Furthermore, nuclear BRCA1 was frequently lost compared with cytoplasmic BRCA1 in eutopic endometria of patients. Expression of BRCA2 did not differ between patients and controls.

BRCA1 rs71361504 SNP may modify the endometriosis risk in Indian women. In addition, decreased expression of BRCA1 may play an important role in the pathophysiology of endometriosis. The analysis of BRCA1 genetic variants and/or expression might help to identify patients at high risk for disease outcome. Similar content being viewed by others

Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364:1789–99. Spuijbroek MD, Dunselman GA, Menheere PP, Evers JL. Early endometriosis invades the extracellular matrix. Fertil Steril. 1992;58:929–33. Govatati S, Kodati VL, Deenadayal M, Chakravarty B, Shivaji S, Bhanoori M. Mutations in the PTEN tumor suppressor gene and risk of endometriosis: a case–control study. Hum Reprod. 2014;29:324–36. Govatati S, Deenadayal M, Shivaji S, Bhanoori M. Mitochondrial displacement loop alterations are associated with endometriosis. Fertil Steril. 2013;99:1980–6. Govatati S, Deenadayal M, Shivaji S, Bhanoori M. Mitochondrial NADH:ubiquinone oxidoreductase alterations are associated with endometriosis. Mitochondrion. 2013;13:782–90. Govatati S, Tangudu NK, Deenadayal M, Chakravarty B, Shivaji S, Bhanoori M. Association of E-cadherin single nucleotide polymorphisms with the increased risk of Endometriosis in Indian women. Mol Hum Reprod. 2012;18:280–7. Govatati S, Chakravarty B, Deenadayal M, Kodati VL, Latha M, Shivaji S, et al. p53 and risk of endometriosis in Indian women. Genet Test Mol Biomarkers. 2012;16:865–73. Govatati S, Tipirisetti TR, Perugu S, Kodati VL, Deenadayal M, Vishnupriya S, et al. Mitochondrial genome variations in advanced stage endometriosis: A study in South Indian population. PLoS ONE. 2012;7:e40668. Bhanoori M, Kameshwari DB, Zondervan KT, Deenadayal M, Kennedy S, Shivaji S. The endothelial nitric oxide synthase Glu298Asp polymorphism is not a risk factor for endometriosis in south Indian women. Eur J Obstet Gynecol R B. 2008;139:53–8. Bhanoori M, Deenadayal M, Kennedy S, Shivaji S. The G2964A 3′-untranslated region polymorphism of the signal transducer and activator of transcription 6 gene is associated with endometriosis in South Indian women. Hum Reprod. 2007;22:1026–30. Bhanoori M, Arvind Babu K, Pavankumar Reddy NG, Lakshmi Rao K, Zondervan K, Deenadayal M, et al. The vascular endothelial growth factor (VEGF) +405G > C 5′-untranslated region polymorphism and increased risk of endometriosis in South Indian women: a case control study. Hum Reprod. 2005;20:1844–9. Bhanoori M, Babu KA, Deenadayal M, Kennedy S, Shivaji S. The interleukin-6-174G/C promoter polymorphism is not associated with endometriosis in South Indian women. J Soc Gynecol Investig. 2005;12:365–9. Tempfer CB, Simoni M, Destenaves B, Fauser BCJM. Functional genetic polymorphisms and female reproductive disorders: Part II—endometriosis. Hum Reprod Update. 2009;15:97–118. Sowter HM, Ashworth A. BRCA1 and BRCA2 as ovarian cancer susceptibility genes. Carcinogenesis. 2005;26:1651–6. Couch FJ, Weber BL. Mutations and polymorphisms in the familial early-onset breast cancer (BRCA1) gene. Breast Cancer Information Core. Hum Mutat. 1996;8:8–18. Shattuck-Eidens D, McClure M, Simard J, Labrie F, Narod S, Couch F, et al. A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. Implications for presymptomatic testing and screening. JAMA. 1995;273:535–41. Goumenou AG, Vassiliadis S, Matalliotakis IM, Koumantakis EG, Lembessis P, Koutsilieris M. Mutation analysis of BrCA1, BrCA2, and p53 versus soluble HLA class I and class II in a case of familial endometriosis. Fertil Steril. 2003;79:445–8. Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev. 2012;12:68–78. Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 2000;14:927–39. Wang C, Horiuchi A, Imai T, Ohira S, Itoh K, Nikaido T, et al. Expression of BRCA1 protein in benign, borderline, and malignant epithelial ovarian neoplasms and its relationship to methylation and allelic loss of the BRCA1 gene. J Pathol. 2004;202:215–23. Rauh-Adelmann C, Lau KM, Sabeti N, Long JP, Mok SC, Ho SM. Altered expression of BRCA1, BRCA2, and a newly identified BRCA2 exon 12 deletion variant in malignant human ovarian, prostate, and breast cancer cell lines. Mol Carcinog. 2000;28:236–46. Russell PA, Pharoah PD, De Foy K, Ramus SJ, Symmonds I, Wilson A, et al. Frequent loss of BRCA1 mRNA and protein expression in sporadic ovarian cancers. Int J Cancer. 2000;87:317–21. BieÁche I, NogueÁs C, Lidereau R. Overexpression of BRCA2 gene in sporadic breast tumours. Oncogene. 1999;18:5232–8. Thompson ME, Jensen RA, Obermiller PS, Page DL, Holt JT. Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet. 1995;9:444–50. Reich D, Thangaraj K, Patterson N, Price AL, Singh L. Reconstructing Indian population history. Nature. 2009;461:489–94. Revised American Society for Reproductive Medicine classification of endometriosis. Fertil Steril. 1997;67:817–21. Zondervan KT, Cardon LR, Kennedy SH. What makes a good case–control study? Design issues for complex genetic traits such as endometriosis. Hum Reprod. 2002;17:1415–23. Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Fertil Steril. 1950;1:3–25. Tumu VR, Govatati S, Guruvaiah P, Deenadayal M, Shivaji S, Bhanoori M. An interleukin-6 gene promoter polymorphism is associated with polycystic ovary syndrome in South Indian women. J Assist Reprod Genet. 2013;30:1541–6. Maravic LR, Raduloviae S. Breast cancer susceptibility gene 1 - BRCA 1. Arch Oncol. 2000;8:21–3. Wilson CA, Ramos L, Villasenor MR, Anders KH, Press MF, Clarke K, et al. Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas. Nat Genet. 1999;21:236–40. Jarvis EM, Kirk JA, Clarke CL. Loss of nuclear BRCA1 expression in breast cancers is associated with a highly proliferative tumor phenotype. Cancer Genet Cytogenet. 1998;101:109–15. Yang Q, Sakurai T, Mori I, Yoshimura G, Nakamura M, Nakamura Y, et al. Prognostic significance of BRCA1 expression in Japanese sporadic breast carcinomas. Cancer. 2001;92:54–60. Jensen RA, Thompson ME, Jetton TL, Szabo CI, van der Meer R, Helou B, et al. BRCA1 is secreted and exhibits properties of a granin. Nat Genet. 1996;12:303–8. Chen Y, Chen CF, Riley DJ, Allred DC, Chen PL, Von Hoff D, et al. Aberrant subcellular localization of BRCA1 in breast cancer. Science. 1995;270:789–91. Thakur S, Le H, Carroll B, Farid LM, Couch F, Wilson R, et al. Disparate localization of BRCA1 and an alternate splice form, gamma BRCA1. Proc Am Assoc Cancer Res. 1996;37:188. Rajan JV, Wang M, Marquis ST, Chodosh LA. Brca2 is coordinately regulated with Brca1 during proliferation and differentiation in mammary epithelial cells. Proc Natl Acad Sci U S A. 1996;93:13078–83. Vaughn JP, Cirisano FD, Huper G, Berchuck A, Futreal PA, Marks JR, et al. Cell cycle control of BRCA2. Cancer Res. 1996;56:4590–4. Acknowledgments We are most grateful to all the patients who participated in the present study. Dr. Suresh Govatati would like to thank Council of Scientific and Industrial Research (CSIR), India for JRF (NET) and SRF (NET). Conflict of interest The authors declare that they have no conflict of interest. Funding This study was supported by grants from the Science & Engineering Research Board (SERB), India (Lr No: SR/FT/LS-188/2009) to M.B. Author information Authors and Affiliations Corresponding author Additional information Capsule BRCA1 alterations may modify the endometriosis risk in Indian women. The analysis of BRCA1 genetic variants and/or expression might help to identify patients at high risk for disease outcome. Electronic supplementary material Below is the link to the electronic supplementary material. Supplemental Table 1 (download DOC ) (DOC 41 kb) Supplemental Table 2 (download DOC ) (DOC 42 kb) Rights and permissions About this article Cite this article Govatati, S., Challa, K., Reddy, S.B. et al. BRCA1 alterations are associated with endometriosis, but BRCA2 alterations show no detectable endometriosis risk: a study in Indian population. J Assist Reprod Genet 32, 277–285 (2015). https://doi.org/10.1007/s10815-014-0379-9 Received: Accepted: Published: Issue date: DOI: https://doi.org/10.1007/s10815-014-0379-9