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. 1995 Oct;72(4):805–812. doi: 10.1038/bjc.1995.417

The genetics of breast and ovarian cancer.

D Ford 1, D F Easton 1
PMCID: PMC2034018  PMID: 7547224

Abstract

A number of genes are known to be involved in inherited susceptibility to breast and/or ovarian cancer. In the context of high-risk families the most important genes are BRCA1 on chromosome 17q, which is associated with a high penetrance of both breast and ovarian cancer, and BRCA2 on chromosome 13q, which causes a high risk of breast cancer but a lower risk of ovarian cancer. Other high-risk cancer genes that confer increased risks of breast or ovarian cancer in addition to other cancers include the hereditary non-polyposis colorectal cancer genes and the TP53 gene, which causes breast cancer as part of the Li-Fraumeni syndrome. The predisposing mutations in these genes are relatively rare in the population. More common genes which are associated with an increased, but lower, risk of breast cancer are the ataxiatelangiectasia gene and the HRAS1 gene. This paper reviews recent progress in mapping and cloning of these susceptibility genes, and provides estimates of the cancer risks associated with each gene and the frequency of predisposing mutations.

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Selected References

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  1. Aaltonen L. A., Sankila R., Mecklin J. P., Järvinen H., Pukkala E., Peltomäki P., de la Chapelle A. A novel approach to estimate the proportion of hereditary nonpolyposis colorectal cancer of total colorectal cancer burden. Cancer Detect Prev. 1994;18(1):57–63. [PubMed] [Google Scholar]
  2. Bishop D. T., Cannon-Albright L., McLellan T., Gardner E. J., Skolnick M. H. Segregation and linkage analysis of nine Utah breast cancer pedigrees. Genet Epidemiol. 1988;5(3):151–169. doi: 10.1002/gepi.1370050303. [DOI] [PubMed] [Google Scholar]
  3. Bodmer W., Bishop T., Karran P. Genetic steps in colorectal cancer. Nat Genet. 1994 Mar;6(3):217–219. doi: 10.1038/ng0394-217. [DOI] [PubMed] [Google Scholar]
  4. Børresen A. L., Andersen T. I., Garber J., Barbier-Piraux N., Thorlacius S., Eyfjörd J., Ottestad L., Smith-Sørensen B., Hovig E., Malkin D. Screening for germ line TP53 mutations in breast cancer patients. Cancer Res. 1992 Jun 1;52(11):3234–3236. [PubMed] [Google Scholar]
  5. Børresen A. L., Andersen T. I., Tretli S., Heiberg A., Møller P. Breast cancer and other cancers in Norwegian families with ataxia-telangiectasia. Genes Chromosomes Cancer. 1990 Nov;2(4):339–340. doi: 10.1002/gcc.2870020412. [DOI] [PubMed] [Google Scholar]
  6. Capon D. J., Chen E. Y., Levinson A. D., Seeburg P. H., Goeddel D. V. Complete nucleotide sequences of the T24 human bladder carcinoma oncogene and its normal homologue. Nature. 1983 Mar 3;302(5903):33–37. doi: 10.1038/302033a0. [DOI] [PubMed] [Google Scholar]
  7. Claus E. B., Risch N. J., Thompson W. D. Age at onset as an indicator of familial risk of breast cancer. Am J Epidemiol. 1990 Jun;131(6):961–972. doi: 10.1093/oxfordjournals.aje.a115616. [DOI] [PubMed] [Google Scholar]
  8. Claus E. B., Risch N. J., Thompson W. D. Using age of onset to distinguish between subforms of breast cancer. Ann Hum Genet. 1990 May;54(Pt 2):169–177. doi: 10.1111/j.1469-1809.1990.tb00373.x. [DOI] [PubMed] [Google Scholar]
  9. Claus E. B., Risch N., Thompson W. D. Genetic analysis of breast cancer in the cancer and steroid hormone study. Am J Hum Genet. 1991 Feb;48(2):232–242. [PMC free article] [PubMed] [Google Scholar]
  10. Collins N., McManus R., Wooster R., Mangion J., Seal S., Lakhani S. R., Ormiston W., Daly P. A., Ford D., Easton D. F. Consistent loss of the wild type allele in breast cancers from a family linked to the BRCA2 gene on chromosome 13q12-13. Oncogene. 1995 Apr 20;10(8):1673–1675. [PubMed] [Google Scholar]
  11. Cornelis R. S., Devilee P., van Vliet M., Kuipers-Dijkshoorn N., Kersenmaeker A., Bardoel A., Khan P. M., Cornelisse C. J. Allele loss patterns on chromosome 17q in 109 breast carcinomas indicate at least two distinct target regions. Oncogene. 1993 Mar;8(3):781–785. [PubMed] [Google Scholar]
  12. 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]
  13. Easton D. F. Cancer risks in A-T heterozygotes. Int J Radiat Biol. 1994 Dec;66(6 Suppl):S177–S182. doi: 10.1080/09553009414552011. [DOI] [PubMed] [Google Scholar]
  14. Easton D. F., Ford D., Bishop D. T. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet. 1995 Jan;56(1):265–271. [PMC free article] [PubMed] [Google Scholar]
  15. Eeles R. A. Predictive testing for germline mutations in the p53 gene: are all the questions answered? Eur J Cancer. 1993;29A(10):1361–1365. doi: 10.1016/0959-8049(93)90001-v. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Gatti R. A., Berkel I., Boder E., Braedt G., Charmley P., Concannon P., Ersoy F., Foroud T., Jaspers N. G., Lange K. Localization of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature. 1988 Dec 8;336(6199):577–580. doi: 10.1038/336577a0. [DOI] [PubMed] [Google Scholar]
  18. Goldgar D. E., Easton D. F., Cannon-Albright L. A., Skolnick M. H. Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. J Natl Cancer Inst. 1994 Nov 2;86(21):1600–1608. doi: 10.1093/jnci/86.21.1600. [DOI] [PubMed] [Google Scholar]
  19. Goldgar D. E., Fields P., Lewis C. M., Tran T. D., Cannon-Albright L. A., Ward J. H., Swensen J., Skolnick M. H. A large kindred with 17q-linked breast and ovarian cancer: genetic, phenotypic, and genealogical analysis. J Natl Cancer Inst. 1994 Feb 2;86(3):200–209. doi: 10.1093/jnci/86.3.200. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Houlston R. S., Collins A., Slack J., Campbell S., Collins W. P., Whitehead M. I., Morton N. E. Genetic epidemiology of ovarian cancer: segregation analysis. Ann Hum Genet. 1991 Oct;55(Pt 4):291–299. doi: 10.1111/j.1469-1809.1991.tb00856.x. [DOI] [PubMed] [Google Scholar]
  22. Huang H. J., Yee J. K., Shew J. Y., Chen P. L., Bookstein R., Friedmann T., Lee E. Y., Lee W. H. Suppression of the neoplastic phenotype by replacement of the RB gene in human cancer cells. Science. 1988 Dec 16;242(4885):1563–1566. doi: 10.1126/science.3201247. [DOI] [PubMed] [Google Scholar]
  23. Jacobs I. J., Smith S. A., Wiseman R. W., Futreal P. A., Harrington T., Osborne R. J., Leech V., Molyneux A., Berchuck A., Ponder B. A. A deletion unit on chromosome 17q in epithelial ovarian tumors distal to the familial breast/ovarian cancer locus. Cancer Res. 1993 Mar 15;53(6):1218–1221. [PubMed] [Google Scholar]
  24. Jolly K. W., Malkin D., Douglass E. C., Brown T. F., Sinclair A. E., Look A. T. Splice-site mutation of the p53 gene in a family with hereditary breast-ovarian cancer. Oncogene. 1994 Jan;9(1):97–102. [PubMed] [Google Scholar]
  25. 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]
  26. Kho C. J., Zarbl H. Fte-1, a v-fos transformation effector gene, encodes the mammalian homologue of a yeast gene involved in protein import into mitochondria. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2200–2204. doi: 10.1073/pnas.89.6.2200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Knudson A. G., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. doi: 10.1073/pnas.68.4.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Krontiris T. G. Detection of cancer predisposition by hypervariable region analysis. Birth Defects Orig Artic Ser. 1990;26(1):129–140. [PubMed] [Google Scholar]
  29. Krontiris T. G., Devlin B., Karp D. D., Robert N. J., Risch N. An association between the risk of cancer and mutations in the HRAS1 minisatellite locus. N Engl J Med. 1993 Aug 19;329(8):517–523. doi: 10.1056/NEJM199308193290801. [DOI] [PubMed] [Google Scholar]
  30. Krontiris T. G., DiMartino N. A., Colb M., Mitcheson H. D., Parkinson D. R. Human restriction fragment length polymorphisms and cancer risk assessment. J Cell Biochem. 1986;30(4):319–329. doi: 10.1002/jcb.240300405. [DOI] [PubMed] [Google Scholar]
  31. Li F. P., Fraumeni J. F., Jr, Mulvihill J. J., Blattner W. A., Dreyfus M. G., Tucker M. A., Miller R. W. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988 Sep 15;48(18):5358–5362. [PubMed] [Google Scholar]
  32. Lobaccaro J. M., Lumbroso S., Belon C., Galtier-Dereure F., Bringer J., Lesimple T., Namer M., Cutuli B. F., Pujol H., Sultan C. Androgen receptor gene mutation in male breast cancer. Hum Mol Genet. 1993 Nov;2(11):1799–1802. doi: 10.1093/hmg/2.11.1799. [DOI] [PubMed] [Google Scholar]
  33. Lynch H. T., Krush A. J., Lemon H. M., Kaplan A. R., Condit P. T., Bottomley R. H. Tumor variation in families with breast cancer. JAMA. 1972 Dec 25;222(13):1631–1635. [PubMed] [Google Scholar]
  34. Malkin D., Li F. P., Strong L. C., Fraumeni J. F., Jr, Nelson C. E., Kim D. H., Kassel J., Gryka M. A., Bischoff F. Z., Tainsky M. A. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990 Nov 30;250(4985):1233–1238. doi: 10.1126/science.1978757. [DOI] [PubMed] [Google Scholar]
  35. McKinnon P. J. Ataxia-telangiectasia: an inherited disorder of ionizing-radiation sensitivity in man. Progress in the elucidation of the underlying biochemical defect. Hum Genet. 1987 Mar;75(3):197–208. doi: 10.1007/BF00281059. [DOI] [PubMed] [Google Scholar]
  36. Merajver S. D., Pham T. M., Caduff R. F., Chen M., Poy E. L., Cooney K. A., Weber B. L., Collins F. S., Johnston C., Frank T. S. Somatic mutations in the BRCA1 gene in sporadic ovarian tumours. Nat Genet. 1995 Apr;9(4):439–443. doi: 10.1038/ng0495-439. [DOI] [PubMed] [Google Scholar]
  37. 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]
  38. Narod S. A. Genetics of breast and ovarian cancer. Br Med Bull. 1994 Jul;50(3):656–676. doi: 10.1093/oxfordjournals.bmb.a072915. [DOI] [PubMed] [Google Scholar]
  39. Nicolaides N. C., Papadopoulos N., Liu B., Wei Y. F., Carter K. C., Ruben S. M., Rosen C. A., Haseltine W. A., Fleischmann R. D., Fraser C. M. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature. 1994 Sep 1;371(6492):75–80. doi: 10.1038/371075a0. [DOI] [PubMed] [Google Scholar]
  40. Nishisho I., Nakamura Y., Miyoshi Y., Miki Y., Ando H., Horii A., Koyama K., Utsunomiya J., Baba S., Hedge P. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science. 1991 Aug 9;253(5020):665–669. doi: 10.1126/science.1651563. [DOI] [PubMed] [Google Scholar]
  41. Papadopoulos N., Nicolaides N. C., Wei Y. F., Ruben S. M., Carter K. C., Rosen C. A., Haseltine W. A., Fleischmann R. D., Fraser C. M., Adams M. D. Mutation of a mutL homolog in hereditary colon cancer. Science. 1994 Mar 18;263(5153):1625–1629. doi: 10.1126/science.8128251. [DOI] [PubMed] [Google Scholar]
  42. Parazzini F., Franceschi S., La Vecchia C., Fasoli M. The epidemiology of ovarian cancer. Gynecol Oncol. 1991 Oct;43(1):9–23. doi: 10.1016/0090-8258(91)90003-n. [DOI] [PubMed] [Google Scholar]
  43. Pippard E. C., Hall A. J., Barker D. J., Bridges B. A. Cancer in homozygotes and heterozygotes of ataxia-telangiectasia and xeroderma pigmentosum in Britain. Cancer Res. 1988 May 15;48(10):2929–2932. [PubMed] [Google Scholar]
  44. Rosnet O., Stephenson D., Mattei M. G., Marchetto S., Shibuya M., Chapman V. M., Birnbaum D. Close physical linkage of the FLT1 and FLT3 genes on chromosome 13 in man and chromosome 5 in mouse. Oncogene. 1993 Jan;8(1):173–179. [PubMed] [Google Scholar]
  45. Schildkraut J. M., Risch N., Thompson W. D. Evaluating genetic association among ovarian, breast, and endometrial cancer: evidence for a breast/ovarian cancer relationship. Am J Hum Genet. 1989 Oct;45(4):521–529. [PMC free article] [PubMed] [Google Scholar]
  46. Sidransky D., Tokino T., Helzlsouer K., Zehnbauer B., Rausch G., Shelton B., Prestigiacomo L., Vogelstein B., Davidson N. Inherited p53 gene mutations in breast cancer. Cancer Res. 1992 May 15;52(10):2984–2986. [PubMed] [Google Scholar]
  47. 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]
  48. Steichen-Gersdorf E., Gallion H. H., Ford D., Girodet C., Easton D. F., DiCioccio R. A., Evans G., Ponder M. A., Pye C., Mazoyer S. Familial site-specific ovarian cancer is linked to BRCA1 on 17q12-21. Am J Hum Genet. 1994 Nov;55(5):870–875. [PMC free article] [PubMed] [Google Scholar]
  49. 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]
  50. Swift M., Morrell D., Massey R. B., Chase C. L. Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med. 1991 Dec 26;325(26):1831–1836. doi: 10.1056/NEJM199112263252602. [DOI] [PubMed] [Google Scholar]
  51. Swift M., Reitnauer P. J., Morrell D., Chase C. L. Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med. 1987 May 21;316(21):1289–1294. doi: 10.1056/NEJM198705213162101. [DOI] [PubMed] [Google Scholar]
  52. Watson P., Lynch H. T. Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer. 1993 Feb 1;71(3):677–685. doi: 10.1002/1097-0142(19930201)71:3<677::aid-cncr2820710305>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  53. Wooster R., Mangion J., Eeles R., Smith S., Dowsett M., Averill D., Barrett-Lee P., Easton D. F., Ponder B. A., Stratton M. R. A germline mutation in the androgen receptor gene in two brothers with breast cancer and Reifenstein syndrome. Nat Genet. 1992 Oct;2(2):132–134. doi: 10.1038/ng1092-132. [DOI] [PubMed] [Google Scholar]

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