CGH-targeted linkage analysis reveals a possible BRCA1 modifier locus on chromosome 5q.
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.
Nathanson
Katherine L
KL
Department of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Shugart
Yin Y
YY
Omaruddin
Romaica
R
Szabo
Csilla
C
Goldgar
David
D
Rebbeck
Timothy R
TR
Weber
Barbara L
BL
D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D002874:Chromosome Mapping; D002894:Chromosomes, Human, Pair 4; D002895:Chromosomes, Human, Pair 5; D005260:Female; D018390:Gene Targeting; D005819:Genetic Markers; D006801:Humans; D008875:Middle Aged; D009693:Nucleic Acid Hybridization
D019313:BRCA1 Protein; D005819:Genetic Markers