Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families : Results of an international study

Several BRCA1 mutations have now been found to occur in geographically diverse breast and ovarian cancer families. To investigate mutation origin and mutation-specific phenotypes due to BRCA1, we constructed a haplotype of nine polymorphic markers within or immediately flanking the BRCA1 locus in a...

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Veröffentlicht in:American journal of human genetics 1996-02, Vol.58 (2), p.271-280
Hauptverfasser: NEUHAUSEN, S. L, MAZOYER, S, SOLOMON, E, WEBER, B, COUCH, F, STRUEWING, J, TONIN, P, DUROCHER, F, NAROD, S, SKOLNICK, M. H, LENOIR, G, SEROVA, O, FRIEDMAN, L, PONDER, B, STOPPA-LYONNET, D, EASTON, D, KING, M.-C, GOLDGAR, D. E, STRATTON, M, OFFIT, K, CALIGO, A, TOMLINSON, G, CANNON-ALBRIGHT, L, BISHOP, T, KELSELL, D
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Sprache:eng
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Zusammenfassung:Several BRCA1 mutations have now been found to occur in geographically diverse breast and ovarian cancer families. To investigate mutation origin and mutation-specific phenotypes due to BRCA1, we constructed a haplotype of nine polymorphic markers within or immediately flanking the BRCA1 locus in a set of 61 breast/ovarian cancer families selected for having one of six recurrent BRCA1 mutations. Tests of both mutations and family-specific differences in age at diagnosis were not significant. A comparison of the six mutations in the relative proportions of cases of breast and ovarian cancer was suggestive of an effect (P = .069), with 57% of women presumed affected because of the 1294 del 40 BRCA1 mutation having ovarian cancer, compared with 14% of affected women with the splice-site mutation in intron 5 of BRCA1. For the BRCA1 mutations studied here, the individual mutations are estimated to have arisen 9-170 generations ago. In general, a high degree of haplotype conservation across the region was observed, with haplotype differences most often due to mutations in the short-tandem-repeat markers, although some likely instances of recombination also were observed. For several of the instances, there was evidence for multiple, independent, BRCA1 mutational events.
ISSN:0002-9297
1537-6605