Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1998 Jun;62(6):1381–1388. doi: 10.1086/301885

Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study.

S L Neuhausen 1, A K Godwin 1, R Gershoni-Baruch 1, E Schubert 1, J Garber 1, D Stoppa-Lyonnet 1, E Olah 1, B Csokay 1, O Serova 1, F Lalloo 1, A Osorio 1, M Stratton 1, K Offit 1, J Boyd 1, M A Caligo 1, R J Scott 1, A Schofield 1, E Teugels 1, M Schwab 1, L Cannon-Albright 1, T Bishop 1, D Easton 1, J Benitez 1, M C King 1, B A Ponder 1, B Weber 1, P Devilee 1, A Borg 1, S A Narod 1, D Goldgar 1
PMCID: PMC1377164  PMID: 9585613

Abstract

Several BRCA2 mutations are found to occur in geographically diverse breast and ovarian cancer families. To investigate both mutation origin and mutation-specific phenotypes due to BRCA2, we constructed a haplotype of 10 polymorphic short tandem-repeat (STR) markers flanking the BRCA2 locus, in a set of 111 breast or breast/ovarian cancer families selected for having one of nine recurrent BRCA2 mutations. Six of the individual mutations are estimated to have arisen 400-2,000 years ago. In particular, the 6174delT mutation, found in approximately 1% of individuals of Ashkenazi Jewish ancestry, was estimated to have arisen 29 generations ago (1-LOD support interval 22-38). This is substantially more recent than the estimated age of the BRCA1 185delAG mutation (46 generations), derived from our analogous study of BRCA1 mutations. In general, there was no evidence of multiple origins of identical BRCA2 mutations. Our study data were consistent with the previous report of a higher incidence of ovarian cancer in families with mutations in a 3.3-kb region of exon 11 (the ovarian cancer cluster region [OCCR]) (P=.10); but that higher incidence was not statistically significant. There was significant evidence that age at diagnosis of breast cancer varied by mutation (P<.001), although only 8% of the variance in age at diagnosis could be explained by the specific mutation, and there was no evidence of family-specific effects. When the age at diagnosis of the breast cancer cases was examined by OCCR, cases associated with mutations in the OCCR had a significantly older mean age at diagnosis than was seen in those outside this region (48 years vs. 42 years; P=.0005).

Full Text

The Full Text of this article is available as a PDF (299.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abeliovich D., Kaduri L., Lerer I., Weinberg N., Amir G., Sagi M., Zlotogora J., Heching N., Peretz T. 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 Mar;60(3):505–514. [PMC free article] [PubMed] [Google Scholar]
  2. Bar-Sade R. B., Theodor L., Gak E., Kruglikova A., Hirsch-Yechezkel G., Modan B., Kuperstein G., Seligsohn U., Rechavi G., Friedman E. Could the 185delAG BRCA1 mutation be an ancient Jewish mutation? Eur J Hum Genet. 1997 Nov-Dec;5(6):413–416. [PubMed] [Google Scholar]
  3. Couch F. J., Rommens J. M., Neuhausen S. L., Bélanger C., Dumont M., Abel K., Bell R., Berry S., Bogden R., Cannon-Albright L. Generation of an integrated transcription map of the BRCA2 region on chromosome 13q12-q13. Genomics. 1996 Aug 15;36(1):86–99. doi: 10.1006/geno.1996.0428. [DOI] [PubMed] [Google Scholar]
  4. Dib C., Fauré S., Fizames C., Samson D., Drouot N., Vignal A., Millasseau P., Marc S., Hazan J., Seboun E. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature. 1996 Mar 14;380(6570):152–154. doi: 10.1038/380152a0. [DOI] [PubMed] [Google Scholar]
  5. Gayther S. A., Mangion J., Russell P., Seal S., Barfoot R., Ponder B. A., Stratton M. R., Easton D. Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet. 1997 Jan;15(1):103–105. doi: 10.1038/ng0197-103. [DOI] [PubMed] [Google Scholar]
  6. Håkansson S., Johannsson O., Johansson U., Sellberg G., Loman N., Gerdes A. M., Holmberg E., Dahl N., Pandis N., Kristoffersson U. Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer. Am J Hum Genet. 1997 May;60(5):1068–1078. [PMC free article] [PubMed] [Google Scholar]
  7. Miki Y., Swensen J., Shattuck-Eidens D., Futreal P. A., Harshman K., Tavtigian S., Liu Q., Cochran C., Bennett L. M., Ding W. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994 Oct 7;266(5182):66–71. doi: 10.1126/science.7545954. [DOI] [PubMed] [Google Scholar]
  8. Neuhausen S. L., Mazoyer S., Friedman L., Stratton M., Offit K., Caligo A., Tomlinson G., Cannon-Albright L., Bishop T., Kelsell D. Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study. Am J Hum Genet. 1996 Feb;58(2):271–280. [PMC free article] [PubMed] [Google Scholar]
  9. Neuhausen S., Gilewski T., Norton L., Tran T., McGuire P., Swensen J., Hampel H., Borgen P., Brown K., Skolnick M. Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nat Genet. 1996 May;13(1):126–128. doi: 10.1038/ng0596-126. [DOI] [PubMed] [Google Scholar]
  10. Oddoux C., Struewing J. P., Clayton C. M., Neuhausen S., Brody L. C., Kaback M., Haas B., Norton L., Borgen P., Jhanwar S. The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet. 1996 Oct;14(2):188–190. doi: 10.1038/ng1096-188. [DOI] [PubMed] [Google Scholar]
  11. Offit K., Gilewski T., McGuire P., Schluger A., Hampel H., Brown K., Swensen J., Neuhausen S., Skolnick M., Norton L. Germline BRCA1 185delAG mutations in Jewish women with breast cancer. Lancet. 1996 Jun 15;347(9016):1643–1645. doi: 10.1016/s0140-6736(96)91484-1. [DOI] [PubMed] [Google Scholar]
  12. Roa B. B., Boyd A. A., Volcik K., Richards C. S. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet. 1996 Oct;14(2):185–187. doi: 10.1038/ng1096-185. [DOI] [PubMed] [Google Scholar]
  13. Sher C., Sharabini-Gargir L., Shohat M. Breast cancer and BRCA1 mutations. N Engl J Med. 1996 May 2;334(18):1199–1200. [PubMed] [Google Scholar]
  14. Struewing J. P., Abeliovich D., Peretz T., Avishai N., Kaback M. M., Collins F. S., Brody L. C. The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet. 1995 Oct;11(2):198–200. doi: 10.1038/ng1095-198. [DOI] [PubMed] [Google Scholar]
  15. Struewing J. P., Hartge P., Wacholder S., Baker S. M., Berlin M., McAdams M., Timmerman M. M., Brody L. C., Tucker M. A. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997 May 15;336(20):1401–1408. doi: 10.1056/NEJM199705153362001. [DOI] [PubMed] [Google Scholar]
  16. Szabo C. I., King M. C. Population genetics of BRCA1 and BRCA2. Am J Hum Genet. 1997 May;60(5):1013–1020. [PMC free article] [PubMed] [Google Scholar]
  17. Tavtigian S. V., Simard J., Rommens J., Couch F., Shattuck-Eidens D., Neuhausen S., Merajver S., Thorlacius S., Offit K., Stoppa-Lyonnet D. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet. 1996 Mar;12(3):333–337. doi: 10.1038/ng0396-333. [DOI] [PubMed] [Google Scholar]
  18. Tonin P., Weber B., Offit K., Couch F., Rebbeck T. R., Neuhausen S., Godwin A. K., Daly M., Wagner-Costalos J., Berman D. Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families. Nat Med. 1996 Nov;2(11):1179–1183. doi: 10.1038/nm1196-1179. [DOI] [PubMed] [Google Scholar]
  19. Wooster R., Bignell G., Lancaster J., Swift S., Seal S., Mangion J., Collins N., Gregory S., Gumbs C., Micklem G. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995 Dec 21;378(6559):789–792. doi: 10.1038/378789a0. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES