Skip to main content

Advertisement

SpringerLink
Log in

BRCA1/BRCA2 gene mutations/SNPs and BRCA1 haplotypes in early-onset breast cancer patients of Indian ethnicity

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

We examined BRCA1/2 mutations and single nucleotide polymorphisms (SNPs) for identification of BRCA1 haplotypes, in early-onset breast cancer patients and their relatives, sporadic breast cancer patients, and unrelated normal healthy females, of Indian ethnicity. Peripheral blood DNA was amplified by polymerase chain reaction, at BRCA1/2 coding exons and subject to nucleotide sequencing using ABI 3100 Genetic Analyzer. We observed BRCA1/BRCA2 mutations in 52 % early-onset breast cancer patients and in 57 % relatives. Deleterious mutations detected in early-onset patients and relatives were 187delAG, 632insT, 1052delT, Q759X, Q780X, R1203X, 5154delC, IVS14 + 1G > A, IVS17 + 1G > T, and 632insT in BRCA1 gene; and 4075delGT, 5076delAA, 6079delAGTT, and W3127X in BRCA2 gene. A high degree of penetrance of BRCA1/2 gene mutations was observed in the relatives. BRCA1/2 SNPs were identified in the Indian population, and association of BRCA1 haplotypes with breast cancer was investigated. A significantly increased frequency of the SNPs 203G/A, 3624A/G and 7470A/G SNPs in BRCA2 gene was observed in normal controls indicative of a protective effect of the SNPs. BRCA1 haplotype 2 was most frequently observed in our population. Our study indicates a high incidence of BRCA1/BRCA2 gene mutations in the Indian patients. The BRCA1/2 mutations and SNPs are detailed on our website http://relibrca.rellife.com.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM, editors. Globocan 2008 v1.2. In: Cancer incidence and mortality worldwide: IARC Cancer Base No.10 Internet. Lyon France: International Agency for Research in Cancer; 2010. Available from: http://globocan.iarc.fr/.

  2. Curado MP, Edwards B, Shin HR, Storm H, Ferlay J, Heanue M, Boyle P, editors. Cancer Incidence in Five Continents, No. 160. Volume IX. Lyon, France: IARC Scientific Publications; 2007. 896 pp.

  3. Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB, editors. In: Cancer incidence in five continents, No. 155. Volume VIII. Lyon, France: IARC Scientific Publications; 2002. 781 pp.

  4. National Cancer Registry Program. Consolidated report of the population based cancer registries. New Delhi: Indian Council of Medical Research; 2001.

    Google Scholar 

  5. Dumitrescu RG, Cotarla I. Understanding breast cancer risk—where do we stand in 2005? J Cell Mol Med. 2005;9:208–21.

    Article  PubMed  CAS  Google Scholar 

  6. Olopade OI, Grushko TA, Nanda R, Huo D. Advances in breast cancer: pathways to personalized medicine. Clin Cancer Res. 2008;14:7988–99.

    Article  PubMed  CAS  Google Scholar 

  7. Eeles RA. Future possibilities in the prevention of breast cancer intervention strategies in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res. 2000;2:283–90.

    Article  PubMed  CAS  Google Scholar 

  8. Breast Cancer Information Core (BIC) Database—NHGRI: research server: http://research.nhgri.nih.gov/bic/.

  9. Fodor FH, Weston A, Bleiweiss IJ, McCurdy LD, Walsh MM, Tartter PI, Brower ST, Eng CM. Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients. Am J Hum Genet. 1998;63:45–51.

    Article  PubMed  CAS  Google Scholar 

  10. Roa BB, Boyd AA, Volcik K, Richards CS. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet. 1996;14:185–7.

    Article  PubMed  CAS  Google Scholar 

  11. Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, Timmerman MM, Brody LC, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997;336:1401–8.

    Article  PubMed  CAS  Google Scholar 

  12. Johannesdottir G, Gudmundsson J, Bergthorsson JT, Arason A, Agnarsson BA, Eiriksdottir G, Johannsson OT, Borg A, et al. High prevalence of the 999del5 mutation in Icelandic breast and ovarian cancer patients. Cancer Res. 1996;56:3663–5.

    PubMed  CAS  Google Scholar 

  13. Thorlacius S, Sigurdsson S, Bjarnadottir H, Olafsdottir G, Jonasson JG, Tryggvadottir L, Tulinius H, Eyfjörd JE. Study of a single BRCA2 mutation with high carrier frequency in a small population. Am J Hum Genet. 1997;60:1079–84.

    PubMed  CAS  Google Scholar 

  14. Hedau S, Jain N, Husain SA, Mandal AK, Ray G, Shahid M, Kant R, Gupta V, et al. Novel germline mutations in breast cancer susceptibility genes BRCA1, BRCA2 and p53 gene in breast cancer patients from India. Breast Cancer Res Treat. 2004;88:177–86.

    Article  PubMed  CAS  Google Scholar 

  15. Kumar BV, Lakhotia S, Ankhatil R, Madhavan J, Jayaprakash PG, Nair MK, Somasundaram K. Germline BRCA1 mutation analysis in Indian breast/ovarian cancer families. Cancer Biol Ther. 2002;1:18–21.

    PubMed  CAS  Google Scholar 

  16. Saxena S, Szabo CI, Chopin S, Barjhoux L, Sinilnikova O, Lenoir G, Goldgar DE, Bhatanager D. BRCA1 and BRCA2 in Indian breast cancer patients. Hum Mutat. 2002;20:473–4.

    Article  PubMed  Google Scholar 

  17. Saxena S, Chakraborthy A, Kauhsal M, Kotwal S, Bhatanager D, Mohil R, Chintamani C, Aggarwal AK, et al. Contribution of germline BRCA1 and BRCA2 sequence alterations to breast cancer in northern India. BMC Med Genet. 2006;7:75.

    Article  PubMed  Google Scholar 

  18. Valarmathi MT, Sawhney M, Deo SSV, Shukla NK, Das SN. Novel germline mutations in the BRCA1 and BRCA2 genes in Indian breast-ovarian cancer families. Hum Mutat. 2004;23:205.

    Article  PubMed  Google Scholar 

  19. Vaidyanathan K, Lakhotia S, Ravishankar HM, Tabassum U, Mukherjee G, Somasundaram K. BRCA1 and BRCA2 germline mutation analysis among Indian women from south India: identification of four novel mutations and high-frequency occurrence of 185delAG mutation. J Biosci. 2009;34:415–22.

    Article  PubMed  CAS  Google Scholar 

  20. Rajkumar T, Soumittra N, Nancy NK, Swaminathan R, Sridevi V, Shanta V. BRCA1, BRCA2 and CHEK2 (1100 del C) germline mutations in hereditary breast and ovarian cancer families in South India. Asian Pac J Cancer Prev. 2003;4:203–8.

    PubMed  Google Scholar 

  21. Frank TS, Deffenbaugh AM, Reid JE, Hulick M, Ward BE, Lingenfelter B, Gumpper KL, Scholl T, et al. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol. 2002;20:1480–90.

    Article  PubMed  CAS  Google Scholar 

  22. Judkins T, Hendrickson BC, Deffenbaugh AM, Eliason K, Leclair B, Norton MJ, Ward BE, Pruss D, et al. Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations. Cancer Res. 2005;65:10096–103.

    Article  PubMed  CAS  Google Scholar 

  23. Abeliovich D, Kaduri L, Lerer I, Weinberg N, Amir G, Sagi M, Zlotogora J, Heching N, et al. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60 % of ovarian cancer and 30 % of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet. 1997;60:505–14.

    PubMed  CAS  Google Scholar 

  24. Thorlacius S, Sigurdsson S, Bjarnadottir H, Olafsdottir G, Jonasson JG, Tryggvadottir L, Tulinius H, Eyfjörd JE. Study of a single BRCA2 mutation with high carrier frequency in a small population. Am J Hum Genet. 1997;60:1079–84.

    PubMed  CAS  Google Scholar 

  25. Loman N, Johannsson O, Kristoffersson U, Olsson H, Borg A. Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J Natl Cancer Inst. 2001;93:1215–23.

    Article  PubMed  CAS  Google Scholar 

  26. Malone KE, Daling JR, Neal C, Suter NM, O’Brien C, Cushing-Haugen K, Jonasdottir TJ, Thompson JD, et al. Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases. Cancer. 2000;88:1393–402.

    Article  PubMed  CAS  Google Scholar 

  27. Shih HA, Couch FJ, Nathason KL, Blackwood MA, Rebbeck TR, Armstrong KA, Calzone K, Stopfer J, et al. BRCA1 and BRCA2 mutations frequency in women evaluated in a breast cancer risk evaluation clinic. J Clin Oncol. 2002;20:994–9.

    Article  PubMed  CAS  Google Scholar 

  28. Shih HA, Nathanson KL, Seal S, Blackwood MA, Rebbeck TR, Armstrong KA, Weber BL. BRCA1 and BRCA2 mutations in breast cancer families with multiple primary cancers. Clin Cancer Res. 2000;6:4259–64.

    PubMed  CAS  Google Scholar 

  29. Abkevich V, Zharkikh A, Deffenbaugh AM, Frank D, Chen Y, Shattuck D, Skolnick MH, Gutin A, et al. Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. J Med Genet. 2004;41:492–507.

    Article  PubMed  CAS  Google Scholar 

  30. Shattuck-Eidens D, Oliphant A, McClure M, McBride C, Gupte J, Rubano T, Pruss D, Tavtigian SV, et al. BRCA1 sequence analysis in women at high risk for susceptibility mutations risk factor analysis and implications for genetic testing. JAMA. 1997;278:1242–50.

    Article  PubMed  CAS  Google Scholar 

  31. Lee MS, Green R, Marsillac SM, Coquelle N, Williams RS, Yeung T, Foo D, Hau DD, et al. Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. Cancer Res. 2010;70:4880–90.

    Article  PubMed  CAS  Google Scholar 

  32. Ruffner H, Joazeiro CAP, Hemmati D, Hunter T, Verma IM. Cancer-predisposing mutations within the RING domain of BRCA1: loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity. PNAS USA. 2001;98:5134–9.

    Article  PubMed  CAS  Google Scholar 

  33. Dunning AM, Chiano M, Smith NR, Dearden J, Gore M, Oakes S, Wilson C, Stratton M, et al. Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population. Hum Mol Genet. 1997;6:285–9.

    Article  PubMed  CAS  Google Scholar 

  34. Durocher F, Shattuck-Eidens D, McClure M, Labrie F, Skolnick MH, Goldgar DE, Simard J. Comparison of BRCA1 polymorphisms, rare sequence variants and/or missense mutations in unaffected and breast/ovarian cancer populations. Hum Mol Genet. 1996;5:835–42.

    Article  PubMed  CAS  Google Scholar 

  35. Friedman LS, Ostermeyer EA, Szabo CI, Dowd P, Lynch ED, Rowell SE, King MC. Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nat Genet. 1994;8:399–404.

    Article  PubMed  CAS  Google Scholar 

  36. De Silva W, Karunanayake EH, Tennekoon KH, Allen M, Amarasinghe I, Angunawala P, Ziard MH. Novel sequence variants and a high frequency of recurrent polymorphisms in BRCA1 gene in Sri Lankan breast cancer patients and at risk individuals. BMC Cancer. 2008;8:214.

    Article  PubMed  Google Scholar 

  37. Toh GT, Kang P, Lee SSW, Lee DSC, Lee SY, Selamat S, Mohd Taib NA, Yoon SY, et al. BRCA1 and BRCA2 germline mutations in Malaysian women with early-onset breast cancer without a family history. PLoS One. 2008;3:e2024.

    Article  PubMed  Google Scholar 

  38. Merajver SD, Pham TM, Caduff RF, Chen M, Poy EL, Cooney KA, Weber BL, Collins FS, et al. Somatic mutations in the BRCA1 gene in sporadic ovarian tumours. Nat Genet. 1995;9:439–43.

    Article  PubMed  CAS  Google Scholar 

  39. Maurice A, Evans DG, Shenton A, Ashcroft L, Baildam A, Barr L, Byrne G, Bundred N, et al. Screening younger women with a family history of breast cancer—does early detection improve outcome? Eur J Cancer. 2006;42:1385–90.

    Article  PubMed  CAS  Google Scholar 

  40. Houssami N, Ciatto S, Martinelli F, Bonardi R, Duffy SW. Early detection of second breast cancers improves prognosis in breast cancer survivors. Ann Oncol. 2009;20:1505–10.

    Article  PubMed  CAS  Google Scholar 

  41. http://relibrca.rellife.com.

Download references

Acknowledgments

The authors gratefully acknowledge Dr.Vinay Deshmane, Onco-Surgeon, P.D. Hinduja Hospital and Medical Research Centre, Mumbai, for providing sporadic breast cancer samples. The authors acknowledge Reliance Life Sciences Pvt. Ltd., Mumbai, for financial support of the project.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Molecular Medicine, Dhirubhai Ambani Life Sciences Centre, Reliance Life Sciences Pvt. Ltd., Thane Belapur Road, Rabale, Navi Mumbai, 400701, India

    Abida Juwle & Dhananjaya Saranath

Authors
  1. Abida Juwle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dhananjaya Saranath
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dhananjaya Saranath.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Juwle, A., Saranath, D. BRCA1/BRCA2 gene mutations/SNPs and BRCA1 haplotypes in early-onset breast cancer patients of Indian ethnicity. Med Oncol 29, 3272–3281 (2012). https://doi.org/10.1007/s12032-012-0294-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12032-012-0294-9

Keywords

Search

Navigation