Human Molecular Genetics, Vol 6, 285-289, Copyright © 1997 by Oxford University Press
AM Dunning, M Chiano, NR Smith, J Dearden, M Gore, S Oakes, C Wilson, M Stratton, J Peto, D Easton, D Clayton and BA Ponder
Most multiple case families of young onset breast cancer and ovarian cancer
are thought to be due to highly penetrant mutations in the predisposing
genes BRCA1 and BRCA2. However, these mutations are uncommon in the
population and they probably account for only a few percent of all breast
cancer incidence. A much larger fraction of breast cancer might, in
principle, be due to common variants which confer more modest individual
risks. There are several common polymorphisms in the BRCA1 gene which
generate amino acid substitutions. We have examined the frequency of four
of these polymorphisms: Gln356Arg, Pro871Leu, Glu1038Gly and Ser1613Gly in
large series of breast and ovarian cancer cases and matched controls. Due
to strong linkage disequilibrium, these four sites generate only three
haplotypes with a frequency > 1.3%. The most common haplotypes, defined
by the alleles Gln356Pro871Glu1038Ser1613 and Gln356Leu871Gly1038Gly1613,
have frequencies of 0.57 and 0.32 respectively, and these frequencies do
not differ significantly between patient and control groups. Thus the most
common polymorphisms of the BRCA1 gene do not make a significant
contribution to breast or ovarian cancer risk. However, our data suggest
that the Arg356 allele may have a different genotype distribution in breast
cancer patients from that in controls (Arg356 homozygotes are more frequent
in the control groups, P = 0.01), indicating that it may be protective
against breast cancer. If this finding can be confirmed, it may provide an
insight into the structural features of the BRCA1 protein that are
important for its function.
ARTICLES
Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population
CRC Human Cancer Genetics Research Group, Addenbrooke's Hospital, Cambridge, UK.
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