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 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.
Neuhausen
S L
SL
Department of Medical Informatics, University of Utah School of Medicine, Salt Lake City 84108, USA.
Mazoyer
S
S
Friedman
L
L
Stratton
M
M
Offit
K
K
Caligo
A
A
Tomlinson
G
G
Cannon-Albright
L
L
Bishop
T
T
Kelsell
D
D
Solomon
E
E
Weber
B
B
Couch
F
F
Struewing
J
J
Tonin
P
P
Durocher
F
F
Narod
S
S
Skolnick
M H
MH
Lenoir
G
G
Serova
O
O
Ponder
B
B
Stoppa-Lyonnet
D
D
Easton
D
D
King
M C
MC
Goldgar
D E
DE
D000483:Alleles; D019313:BRCA1 Protein; D001943:Breast Neoplasms / Q000235:genetics; D002874:Chromosome Mapping; D005192:Family Health; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D014157:Transcription Factors / Q000235:genetics*
D019313:BRCA1 Protein; D005819:Genetic Markers; D009363:Neoplasm Proteins; D014157:Transcription Factors