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Human Molecular Genetics, 2002, Vol. 11, No. 11 1327-1332
© 2002 Oxford University Press

CGH-targeted linkage analysis reveals a possible BRCA1 modifier locus on chromosome 5q

Katherine L. Nathanson1,2, Yin Y. Shugart5, Romaica Omaruddin1, Csilla Szabo6, David Goldgar6, Timothy R. Rebbeck3 and Barbara L. Weber1,2,4,*

1Department of Medicine, 2Abramson Family Cancer Research Institute, 3Department of Biostatistics and Epidemiology, 4Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, 5Epidemiology Department, Bloomberg of School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA and 6International Agency for Research on Cancer, 69372 Lyon Cedex 08, France

Received February 2, 2002; Accepted March 15, 2002

Women with germline mutations in BRCA1 have a greatly elevated risk of breast and ovarian cancer. However, considerable variation in the degree of breast cancer risk associated with a BRCA1 mutation has been observed, suggesting that modifiers of BRCA1 penetrance may exist. We hypothesized that the modifier genes might be located in regions of allelic imbalance in the tumors of BRCA1 mutation carriers, as have been reported on chromosomes 4p, 4q and 5q. In order to determine whether novel genetic modifiers of BRCA1-associated breast cancer penetrance in these regions exist, we used non-parametric linkage analysis methods to determine whether allele sharing of chromosomes 4p, 4q and 5q was observed preferentially within BRCA1 mutation families in women with BRCA1 mutations and breast cancer. No significant linkage on chromosome 4p or 4q was observed associated with breast cancer risk in BRCA1 mutation carriers. However, we observed a significant linkage signal at D5S1471 on chromosome 5q (P=0.009) in all the families analyzed together. The significance of this observation increased in the subset of families with an average of breast cancer diagnosis less than 45 years (P=0.003). These results suggest the presence of one or more genes on chromosome 5q33–34 that modify breast cancer risk in BRCA1 mutation carriers. The approach described here may be utilized to identify penetrance modifiers in other autosomal dominant syndromes.

* To whom correspondence should be addressed at: 514 BRB 2/3, 421 Curie Blvd, University of Pennsylvania, Philadelphia, PA 19104, USA. Tel: +1 215 898 0247; Fax: +1 215 573 2486; Email: weberb{at}mail.med.upenn.edu


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