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open access
....BRCA1-associated cancer is age-dependent, and whether or not this is stochastic or influenced by other factors (modifiers of penetrance) is a question that has not been fully explored: Both stochastic elements and modifying factors may be instrumental in diseases causation. Modifying factors may be genetic, environmental, or both. This study was designed to validate previous reports of normal genetic variants that contribute to modifying BRCA1 penetrance.....
Background Common genetic variants have been shown to modify BRCA1 penetrance. The
aim of this study was to validate these reports in a special cohort of Norwegian BRCA1
mutation carriers that were selected for their extreme age of onset of disease.
Methods
The ten variants rs13387042, rs3803662, rs8170, rs9397435, rs700518, rs10046, rs3834129,
rs1045485, rs2363956 and rs16942 were selected to be tested on samples from our biobank.
We selected female BRCA1 mutation carriers having had a diagnosis of breast or ovarian
cancer below 40 years of age (young cancer group, N = 40), and mutation carriers having
had neither breast nor ovarian cancer above 60 years of age (i.e., old no cancer group,
N = 38). Relative risks and odd ratios of belonging to the young cancer versus old
no cancer groups were calculated as a function of having or not having the SNPs in
question.
Results Five of the ten variants were found to be significantly associated
with early onset cancer. Some of the variation between our results and those previously
reported may be ascribed to stochastic effects in our limited number of patient studies,
and/or genetic drift in linkage disequilibrium in the genetically isolated Norwegian
population. This is in accordance with the understanding that the SNPs are markers
in linkage disequilibrium with their respective disease-causing genetic variants,
and that this may vary between different populations.
Conclusions The results confirmed
associations previously reported, with the notion that the degree of association may
differ between other populations, which must be considered when discussing the clinical
use of the associations described.
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