Abstract
Mutations in the BRCA1 and BRCA2 genes profoundly increase the risk of developing breast and/or ovarian cancer among women. To explore the contribution of BRCA1 and BRCA2 mutations in the development of hereditary breast cancer among Indian women, we carried out mutation analysis of the BRCA1 and BRCA2 genes in 61 breast or ovarian cancer patients from south India with a positive family history of breast and/or ovarian cancer. Mutation analysis was carried out using conformation-sensitive gel electrophoresis (CSGE) followed by sequencing. Mutations were identified in 17 patients (28.0%); 15 (24.6%) had BRCA1 mutations and two (3.28%) had BRCA2 mutations. While no specific association between BRCA1 or BRCA2 mutations with cancer type was seen, mutations were more often seen in families with ovarian cancer. While 40% (4/10) and 30.8% (4/12) of families with ovarian or breast and ovarian cancer had mutations, only 23.1% (9/39) of families with breast cancer carried mutations in the BRCA1 and BRCA2 genes. In addition, while BRCA1 mutations were found in all age groups, BRCA2 mutations were found only in the age group of ≤40 years. Of the BRCA1 mutations, there were three novel mutations (295delCA; 4213T→A; 5267T→G) and three mutations that have been reported earlier. Interestingly, 185delAG, a BRCA1 mutation which occurs at a very high frequency in Ashkenazi Jews, was found at a frequency of 16.4% (10/61). There was one novel mutation (4866insT) and one reported mutation in BRCA2. Thus, our study emphasizes the importance of mutation screening in familial breast and/or ovarian cancers, and the potential implications of these findings in genetic counselling and preventive therapy.
Similar content being viewed by others
References
Antoniou A, Pharoah P D, Narod S, Risch H A, Eyfjord J E, Hopper J L, Loman N, Olsson H, et al. 2003 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. 72 1117–1130
Brose M S, Rebbeck T R, Calzone K A, Stopfer J E, Nathanson K L and Weber B L 2002 Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program; J. Natl. Cancer Inst. 94 1365–1372
Easton D F, Bishop D T, Ford D and Crockford G P 1993 Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium; Am. J. Hum. Genet. 52 678–701
Emery J, Lucassen A and Murphy M 2001 Common hereditary cancers and implications for primary care; Lancet 358 56–63
Ganguly A, Leahy K, Marshall A M, Dhulipala R, Godmilow L and Ganguly T 1997 Genetic testing for breast cancer susceptibility: frequency of BRCA1 and BRCA2 mutations; Genet. Test. 1 85–90
Ganguly A, Rock M J and Prockop D J 1993 Conformation-sensitive gel electrophoresis for rapid detection of single-base differences in double-stranded PCR products and DNA fragments: evidence for solvent-induced bends in DNA heteroduplexes; Proc. Natl. Acad. Sci. USA 90 10325–10329
Gayther S A, Russell P, Harrington P, Antoniou A C, Easton D F and Ponder B A 1999 The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: no evidence for other ovarian cancer-susceptibility genes; Am. J. Hum. Genet. 65 1021–1029
Grzybowska E, Siemińska M, Zientek H, Kalinowska E, Michalska J, Utracka-Hutka B, Rogozińska-Szczepka J and Kaźmierczak-Maciejewska M 2002 Germline mutations in the BRCA1 gene predisposing to breast and ovarian cancers in Upper Silesia population; Acta Biochim. Pol. 49 351–356
Güran S, Ozet A, Dede M, Gille J J and Yenen M C 2005 Hereditary breast cancer syndromes in a Turkish population. Results of molecular germline analysis; Cancer Genet. Cytogenet. 160 164–168
Hall J M, Lee M K, Newman B, Morrow J E, Anderson L A, Huey B and King M C 1990 Linkage of early-onset familial breast cancer to chromosome 17q21; Science 250 1684–1689
Hedau S, Jain N, Husain S A, Mandal A K, Ray G, Shahid M, Kant R, Gupta V, Shukla N K, Deo S S and Das B C 2004 Novel germline mutations in breast cancer susceptibility genes BRCA1, BRCA2 and p53 gene in breast cancer patients from India; Breast Cancer Res. Treat. 88 177–186
Ikeda N, Miyoshi Y, Yoneda K, Shiba E, Sekihara Y, Kinoshita M and Noguchi S 2001 Frequency of BRCA1 and BRCA2 germline mutations in Japanese breast cancer families; Int. J. Cancer 91 83–98
Indian Council of Medical Research National Cancer Registry Programme (NCRP) 2001 Consolidated report of population based cancer registries, 1990–1996 Available at: http://icmr.nic.in/ncrp/ncrp_p/cancer_p_based.htm
Indian Council of Medical Research National Cancer Registry Programme (NCRP) 2006 Consolidated report of population based cancer registries, 2001–2004 Available at: http://icmr.nic.in/ncrp/report_pop_2001-04/cancer_p_based.htm
King M C, Marks J H and Mandell J B 2003 Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2; Science 302 643–646
Krainer M, Silva-Arrieta S, FitzGerald M G, Shimada A, Ishioka C, Kanamaru R, MacDonald D J, Unsal H, et al. 1997 Differential contributions of BRCA1 and BRCA2 to early-onset breast cancer; N. Engl. J. Med. 336 1416–1421
Kumar B V, Lakhotia S, Ankathil R, Madhavan J, Jayaprakash P G, Nair M K and Somasundaram K 2002 Germline BRCA1 mutation analysis in Indian breast/ovarian cancer families; Cancer Biol. Ther. 1 18–21
Lakhotia S and Somasundaram K 2003 Conformation-sensitive gel electrophoresis for detecting BRCA1 mutations; Methods Mol. Biol. 223 403–412
Levy-Lahad E and Friedman E 2007 Cancer risks among BRCA1 and BRCA2 mutation carriers; Br. J. Cancer 96 11–15
Levy-Lahad E, Catane R, Eisenberg S, Kaufman B, Hornreich G, Lishinsky E, Shohat M, Weber B L, et al. 1997 Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families; Am. J. Hum. Genet. 60 1059–1067
Liebens F P, Carly B, Pastijn A and Rozenberg S 2007 Management of BRCA1/2 associated breast cancer: a systematic qualitative review of the state of knowledge in 2006; Eur. J. Cancer 43 238–257
Mehdipour P, Hosseini-Asl S, Savabi-E A, Habibi L, Alvandi E and Atri M 2006 Low frequency of 185delAG founder mutation of BRCA1 gene in Iranian breast cancer patients; J. Cancer Molecules 2 123–127
Miki Y, Swensen J, Shattuck-Eidens D, Futreal P A, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, et al. 1994 A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1; Science 266 66–71
Mullineaux L G, Castellano T M, Shaw J, Axell L, Wood M E, Diab S, Klein C, Sitarik M, et al. 2003 Identification of germline 185delAG BRCA1 mutations in non-Jewish Americans of Spanish ancestry from the San Luis Valley, Colorado; Cancer 98 597–602
Narod S A and Foulkes W D 2004 BRCA1 and BRCA2: 1994 and beyond; Nat. Rev. Cancer 4 665–676
Parkin D M W S, Ferlay J, Teppo L and Thomas D B (eds) 2002 Cancer incidence in five continents, volume VIII (Lyon, France: IARC)
Phelan C M, Kwan E, Jack E, Li S, Morgan C, Aubé J, Hanna D and Narod S A 2002 A low frequency of non-founder BRCA1 mutations in Ashkenazi Jewish breast-ovarian cancer families; Hum. Mutat. 20 352–357
Rajkumar T, Soumittra N, Nancy N K, Swaminathan R, Sridevi V and Shanta V 2003 BRCA1, BRCA2 and CHEK2 (1100 del C) germline mutations in hereditary breast and ovarian cancer families in South India; Asian Pac. J. Cancer Prev. 4 203–208
Rashid M U, Zaidi A, Torres D, Sultan F, Benner A, Naqvi B, Shakoori A R, Seidel-Renkert A, et al. 2006 Prevalence of BRCA1 and BRCA2 mutations in Pakistani breast and ovarian cancer patients; Int. J. Cancer 119 2832–2839
Saxena S, Chakraborty A, Kaushal M, Kotwal S, Bhatanager D, Mohil R S, Chintamani C, Aggarwal A K, et al. 2006 Contribution of germline BRCA1 and BRCA2 sequence alterations to breast cancer in Northern India; BMC Med. Genet. 7 75
Saxena S, Szabo C I, Chopin S, Barjhoux L, Sinilnikova O, Lenoir G, Goldgar D E and Bhatanager D 2002 BRCA1 and BRCA2 in Indian breast cancer patients; Hum. Mutat. 20 473–474
Shih H A, Couch F J, Nathanson K L, Blackwood M A, Rebbeck T R, Armstrong K A, Calzone K, Stopfer J, et al. 2002 BRCA1 and BRCA2 mutation frequency in women evaluated in a breast cancer risk evaluation clinic; J. Clin. Oncol. 20 994–999
Somasundaram K 2003 Breast cancer gene 1 (BRCA1): role in cell cycle regulation and DNA repair-perhaps through transcription; J. Cell Biochem. 88 1084–1091
Struewing J P, Abeliovich D, Peretz T, Avishai N, Kaback M M, Collins F S and Brody L C 1995 The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals; Nat. Genet. 11 198–200
Valarmathi M T, Agarwal A, Deo S S, Shukla N K and Das S N 2003 BRCA1 germline mutations in Indian familial breast cancer; Hum. Mutat. 21 98–99
Valarmathi M T, Sawhney M, Deo S S, Shukla N K and Das S N 2004 Novel germline mutations in the BRCA1 and BRCA2 genes in Indian breast and breast-ovarian cancer families; Hum. Mutat. 23 205
Weitzel J N, Lagos V, Blazer K R, Nelson R, Ricker C, Herzog J, McGuire C and Neuhausen S 2005 Prevalence of BRCA mutations and founder effect in high-risk Hispanic families; Cancer Epidemiol. Biomarkers Prev. 14 1666–1671
Williams C J, Rock M, Considine E, McCarron S, Gow P, Ladda R, McLain D, Michels V M, et al. 1995 Three new point mutations in type II procollagen (COL2A1) and identification of a fourth family with the COL2A1 Arg519→Cys base substitution using conformation sensitive gel electrophoresis; Hum. Mol. Genet. 4 309–312
Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C and Micklem G 1995 Identification of the breast cancer susceptibility gene BRCA2; Nature (London) 378 789–792
Wooster R and Weber B L 2003 Breast and ovarian cancer; N. Engl. J. Med. 348 2339–2347
Zhi X, Szabo C, Chopin S, Suter N, Wang Q S, Ostrander E A, Sinilnikova O M, Lenoir G M, Goldgar D and Shi Y R 2002 BRCA1 and BRCA2 sequence variants in Chinese breast cancer families; Hum. Mutat. 20 474
Author information
Authors and Affiliations
Corresponding author
Additional information
Contributed equally
Rights and permissions
About this article
Cite this article
Vaidyanathan, K., Lakhotia, S., Ravishankar, H.M. et al. 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 34, 415–422 (2009). https://doi.org/10.1007/s12038-009-0048-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12038-009-0048-9