Variation in BRCA1 Cancer Risks by Mutation Position

Variation in BRCA1 Cancer Risks by Mutation Position1

Deborah Thompson,
Douglas Easton2 and
the Breast Cancer Linkage Consortium3

Cancer Research Campaign Genetic Epidemiology Unit, Strangeways Research Laboratories, University of Cambridge, Cambridge CB1 8RN, United Kingdom

Abstract

Previous studies have reported variation in BRCA1 breast and ovarian cancer risks with mutation position, suggesting that mutations toward the 3′ end of the gene are associated with lower ovarian cancer risks. We evaluated the evidence for genotype-phenotype correlations in 356 families with protein-truncating BRCA1 mutations. In contrast to previous reports, the ovarian:breast cancer ratio associated with mutations in a central region of the gene (nucleotides 2401–4190) was significantly higher than for other mutations [odds ratio, 1.70 (P = 0.017) compared with nucleotides 1–2400; odds ratio, 1.89 (P = 0.02) compared with nucleotides 4191–end]. The risks of breast and ovarian cancer conferred by mutations in different regions of the gene were estimated separately by conditional maximum likelihood. According to the best fitting model, the breast cancer risk associated with mutations in the central region was found to be significantly lower than for other mutations (relative risk, 0.71; 95% confidence interval, 0.58–0.86; P = 0.0002), whereas the ovarian cancer risk associated with mutations 3′ to nucleotide 4191 was significantly reduced relative to the rest of the gene (relative risk, 0.81; 95% confidence interval, 0.66–1.00; P = 0.044). The cancer risks associated with missense mutations in the RING domain in exon 5 appear to be similar to those associated with protein-truncating mutations toward the 3′ end of BRCA1, based on nine additional families.

Footnotes

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵1 The coordination and analysis of this study were supported by the Cancer Research Campaign and by a Concerted Action from the European Union. Data collection was supported by the Cancer Research Campaign, the Imperial Cancer Research Fund, The Swedish Cancer Society, Foundation de France, Biomed2 BMH4-CT96-1133, SAF 96/0192, the Nordic Cancer Union, The Cancer Society and Cancer Registry of Finland, the Canadian Breast Cancer Research Initiative, NIH Grant RO1 CA77415 (to S. L. Neuhausen), American Cancer Society Grant 35 RPG-99-181-01-CCE (to S. L. Neuhausen), and the Utah Cancer Registry (supported by NCI Grant NO1-CN-67000, with additional support from the Utah State Department of Health and the University of Utah).
↵2 To whom requests for reprints should be addressed, at CRC Genetic Epidemiology Unit, Strangeways Research Laboratory, Worts Causeway, Cambridge, CB1 8RN, United Kingdom. Phone: (44) 1223 740160/740157; Fax: (44) 1223 740159; E-mail: douglas{at}srl.cam.ac.uk
↵3 Consortium members who contributed families are listed fully at the end of the report.
↵4 Online Mendelian Inheritance in Man (OMIM). http://www.ncbi.nlm.nih.gov [for inherited breast cancer type 1 (MM 113705)].
↵5 The abbreviations used are: BIC, Breast Cancer Information Core; PT, protein truncating; MS, missense; CRC, Cancer Research Campaign; OR, odds ratio; RR, relative risk; CI, confidence interval; OCCR, ovarian cancer cluster region.
↵6 http://www.nchgr.nih.gov/Intramural_research/Lab-transfer/Bic.
- Accepted January 17, 1902.
- Received June 15, 1901.
- Revision received December 7, 1901.