Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1995 Jul;57(1):1–7.

Detection of eight BRCA1 mutations in 10 breast/ovarian cancer families, including 1 family with male breast cancer.

J P Struewing 1, L C Brody 1, M R Erdos 1, R G Kase 1, T R Giambarresi 1, S A Smith 1, F S Collins 1, M A Tucker 1
PMCID: PMC1801253  PMID: 7611277

Abstract

Genetic epidemiological evidence suggests that mutations in BRCA1 may be responsible for approximately one half of early onset familial breast cancer and the majority of familial breast/ovarian cancer. The recent cloning of BRCA1 allows for the direct detection of mutations, but the feasibility of presymptomatic screening for cancer susceptibility is unknown. We analyzed genomic DNA from one affected individual from each of 24 families with at least three cases of ovarian or breast cancer, using SSCP assays. Variant SSCP bands were subcloned and sequenced. Allele-specific oligonucleotide hybridization was used to verify sequence changes and to screen DNA from control individuals. Six frameshift and two missense mutations were detected in 10 different families. A frameshift mutation was detected in a male proband affected with both breast and prostate cancer. A 40-bp deletion was detected in a patient who developed intra-abdominal carcinomatosis 1 year after prophylactic oophorectomy. Mutations were detected throughout the gene, and only one was detected in more than a single family. These results provide further evidence that inherited breast and ovarian cancer can occur as a consequence of a wide array of BRCA1 mutations. These results suggests that development of a screening test for BRCA1 mutations will be technically challenging. The finding of a mutation in a family with male breast cancer, not previously thought to be related to BRCA1, also illustrates the potential difficulties of genetic counseling for individuals known to carry mutations.

Full text

PDF
1

Images in this article

5Figure 1
on p.5

Selected References

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

  1. Beaudet A. L., Tsui L. C. A suggested nomenclature for designating mutations. Hum Mutat. 1993;2(4):245–248. doi: 10.1002/humu.1380020402. [DOI] [PubMed] [Google Scholar]
  2. Biesecker B. B., Boehnke M., Calzone K., Markel D. S., Garber J. E., Collins F. S., Weber B. L. Genetic counseling for families with inherited susceptibility to breast and ovarian cancer. JAMA. 1993 Apr 21;269(15):1970–1974. [PubMed] [Google Scholar]
  3. Castilla L. H., Couch F. J., Erdos M. R., Hoskins K. F., Calzone K., Garber J. E., Boyd J., Lubin M. B., Deshano M. L., Brody L. C. Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer. Nat Genet. 1994 Dec;8(4):387–391. doi: 10.1038/ng1294-387. [DOI] [PubMed] [Google Scholar]
  4. Easton D. F., Bishop D. T., Ford D., Crockford G. P. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1993 Apr;52(4):678–701. [PMC free article] [PubMed] [Google Scholar]
  5. Ford D., Easton D. F., Bishop D. T., Narod S. A., Goldgar D. E. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet. 1994 Mar 19;343(8899):692–695. doi: 10.1016/s0140-6736(94)91578-4. [DOI] [PubMed] [Google Scholar]
  6. Fraumeni J. F., Jr, Grundy G. W., Creagan E. T., Everson R. B. Six families prone to ovarian cancer. Cancer. 1975 Aug;36(2):364–369. doi: 10.1002/1097-0142(197508)36:2<364::aid-cncr2820360211>3.0.co;2-c. [DOI] [PubMed] [Google Scholar]
  7. Friedman L. S., Ostermeyer E. A., Szabo C. I., Dowd P., Lynch E. D., Rowell S. E., King M. C. Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nat Genet. 1994 Dec;8(4):399–404. doi: 10.1038/ng1294-399. [DOI] [PubMed] [Google Scholar]
  8. Futreal P. A., Liu Q., Shattuck-Eidens D., Cochran C., Harshman K., Tavtigian S., Bennett L. M., Haugen-Strano A., Swensen J., Miki Y. BRCA1 mutations in primary breast and ovarian carcinomas. Science. 1994 Oct 7;266(5182):120–122. doi: 10.1126/science.7939630. [DOI] [PubMed] [Google Scholar]
  9. Hall J. M., Lee M. K., Newman B., Morrow J. E., Anderson L. A., Huey B., King M. C. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990 Dec 21;250(4988):1684–1689. doi: 10.1126/science.2270482. [DOI] [PubMed] [Google Scholar]
  10. Hoskins K. F., Stopfer J. E., Calzone K. A., Merajver S. D., Rebbeck T. R., Garber J. E., Weber B. L. Assessment and counseling for women with a family history of breast cancer. A guide for clinicians. JAMA. 1995 Feb 15;273(7):577–585. [PubMed] [Google Scholar]
  11. Hussussian C. J., Struewing J. P., Goldstein A. M., Higgins P. A., Ally D. S., Sheahan M. D., Clark W. H., Jr, Tucker M. A., Dracopoli N. C. Germline p16 mutations in familial melanoma. Nat Genet. 1994 Sep;8(1):15–21. doi: 10.1038/ng0994-15. [DOI] [PubMed] [Google Scholar]
  12. Kelsell D. P., Black D. M., Bishop D. T., Spurr N. K. Genetic analysis of the BRCA1 region in a large breast/ovarian family: refinement of the minimal region containing BRCA1. Hum Mol Genet. 1993 Nov;2(11):1823–1828. doi: 10.1093/hmg/2.11.1823. [DOI] [PubMed] [Google Scholar]
  13. Kelsey J. L., Horn-Ross P. L. Breast cancer: magnitude of the problem and descriptive epidemiology. Epidemiol Rev. 1993;15(1):7–16. doi: 10.1093/oxfordjournals.epirev.a036118. [DOI] [PubMed] [Google Scholar]
  14. Lamture J. B., Beattie K. L., Burke B. E., Eggers M. D., Ehrlich D. J., Fowler R., Hollis M. A., Kosicki B. B., Reich R. K., Smith S. R. Direct detection of nucleic acid hybridization on the surface of a charge coupled device. Nucleic Acids Res. 1994 Jun 11;22(11):2121–2125. doi: 10.1093/nar/22.11.2121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lathrop G. M., Lalouel J. M., Julier C., Ott J. Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am J Hum Genet. 1985 May;37(3):482–498. [PMC free article] [PubMed] [Google Scholar]
  16. Lerman C., Croyle R. Psychological issues in genetic testing for breast cancer susceptibility. Arch Intern Med. 1994 Mar 28;154(6):609–616. [PubMed] [Google Scholar]
  17. Li F. P., Rapoport A. H., Fraumeni J. F., Jr, Jensen R. D. Familial ovarian carcinoma. JAMA. 1970 Nov 23;214(8):1559–1561. [PubMed] [Google Scholar]
  18. 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]
  19. Narod S. A., Feunteun J., Lynch H. T., Watson P., Conway T., Lynch J., Lenoir G. M. Familial breast-ovarian cancer locus on chromosome 17q12-q23. Lancet. 1991 Jul 13;338(8759):82–83. doi: 10.1016/0140-6736(91)90076-2. [DOI] [PubMed] [Google Scholar]
  20. Pease A. C., Solas D., Sullivan E. J., Cronin M. T., Holmes C. P., Fodor S. P. Light-generated oligonucleotide arrays for rapid DNA sequence analysis. Proc Natl Acad Sci U S A. 1994 May 24;91(11):5022–5026. doi: 10.1073/pnas.91.11.5022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Powell S. M., Petersen G. M., Krush A. J., Booker S., Jen J., Giardiello F. M., Hamilton S. R., Vogelstein B., Kinzler K. W. Molecular diagnosis of familial adenomatous polyposis. N Engl J Med. 1993 Dec 30;329(27):1982–1987. doi: 10.1056/NEJM199312303292702. [DOI] [PubMed] [Google Scholar]
  22. Richards B., Skoletsky J., Shuber A. P., Balfour R., Stern R. C., Dorkin H. L., Parad R. B., Witt D., Klinger K. W. Multiplex PCR amplification from the CFTR gene using DNA prepared from buccal brushes/swabs. Hum Mol Genet. 1993 Feb;2(2):159–163. doi: 10.1093/hmg/2.2.159. [DOI] [PubMed] [Google Scholar]
  23. Rowell S., Newman B., Boyd J., King M. C. Inherited predisposition to breast and ovarian cancer. Am J Hum Genet. 1994 Nov;55(5):861–865. [PMC free article] [PubMed] [Google Scholar]
  24. Shattuck-Eidens D., McClure M., Simard J., Labrie F., Narod S., Couch F., Hoskins K., Weber B., Castilla L., Erdos M. A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. Implications for presymptomatic testing and screening. JAMA. 1995 Feb 15;273(7):535–541. [PubMed] [Google Scholar]
  25. Simard J., Tonin P., Durocher F., Morgan K., Rommens J., Gingras S., Samson C., Leblanc J. F., Bélanger C., Dion F. Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families. Nat Genet. 1994 Dec;8(4):392–398. doi: 10.1038/ng1294-392. [DOI] [PubMed] [Google Scholar]
  26. Smith S. A., DiCioccio R. A., Struewing J. P., Easton D. F., Gallion H. H., Albertsen H., Mazoyer S., Johansson B., Steichen-Gersdorf E., Stratton M. Localisation of the breast-ovarian cancer susceptibility gene (BRCA1) on 17q12-21 to an interval of < or = 1 cM. Genes Chromosomes Cancer. 1994 May;10(1):71–76. doi: 10.1002/gcc.2870100112. [DOI] [PubMed] [Google Scholar]
  27. Smith S. A., Easton D. F., Evans D. G., Ponder B. A. Allele losses in the region 17q12-21 in familial breast and ovarian cancer involve the wild-type chromosome. Nat Genet. 1992 Oct;2(2):128–131. doi: 10.1038/ng1092-128. [DOI] [PubMed] [Google Scholar]
  28. Stratton M. R., Ford D., Neuhasen S., Seal S., Wooster R., Friedman L. S., King M. C., Egilsson V., Devilee P., McManus R. Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q. Nat Genet. 1994 May;7(1):103–107. doi: 10.1038/ng0594-103. [DOI] [PubMed] [Google Scholar]
  29. Tobacman J. K., Greene M. H., Tucker M. A., Costa J., Kase R., Fraumeni J. F., Jr Intra-abdominal carcinomatosis after prophylactic oophorectomy in ovarian-cancer-prone families. Lancet. 1982 Oct 9;2(8302):795–797. doi: 10.1016/s0140-6736(82)92681-2. [DOI] [PubMed] [Google Scholar]
  30. Weber B. L. Susceptibility genes for breast cancer. N Engl J Med. 1994 Dec 1;331(22):1523–1524. doi: 10.1056/NEJM199412013312214. [DOI] [PubMed] [Google Scholar]
  31. Weissenbach J., Gyapay G., Dib C., Vignal A., Morissette J., Millasseau P., Vaysseix G., Lathrop M. A second-generation linkage map of the human genome. Nature. 1992 Oct 29;359(6398):794–801. doi: 10.1038/359794a0. [DOI] [PubMed] [Google Scholar]
  32. Wingo P. A., Tong T., Bolden S. Cancer statistics, 1995. CA Cancer J Clin. 1995 Jan-Feb;45(1):8–30. doi: 10.3322/canjclin.45.1.8. [DOI] [PubMed] [Google Scholar]
  33. Wooster R., Neuhausen S. L., Mangion J., Quirk Y., Ford D., Collins N., Nguyen K., Seal S., Tran T., Averill D. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994 Sep 30;265(5181):2088–2090. doi: 10.1126/science.8091231. [DOI] [PubMed] [Google Scholar]

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

RESOURCES