The goal of our work is to examine the complex nature of genetic susceptibility to
cancer, focusing on breast and ovarian cancer. This work has progressed from early
studies, focused on rare but dramatic families with multiple cases of cancer, due in large
part to mutations in the BRCA1 and BRCA2 genes, to more population-based studies of
these genes in isolated populations. These studies have revealed that, even in the setting
of BRCA1/2 mutations, the situation is more complex than expected, with both
environmental and genetic modifiers likely to exist.
Building on studies of founder BRCA1/2 mutations among Ashkenazi Jews that
suggested the risk of breast cancer among female mutation carriers was approximately
50% by age 70, one of our main goals is to identify genetic modifiers of this risk. We
participate in the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)
in this effort. Our hope is that the genetic loci identified as possible modifiers of
BRCA1/2, and the experience we will gain in performing large-scale genotyping and
analysis, will be applicable to the overwhelming fraction of breast and ovarian cancer that
occurs in women who do not carry germline mutations in these two genes.
The majority of the genetic variants underlying susceptibility to breast and
ovarian cancer, however, are yet to be discovered and this predisposition is likely to be
polygenic in nature – the interaction of mutations in multiple genes, each with a weak
effect, in combination with environmental influences. Segregation analyses of breast
cancer in families without BRCA1 or BRCA2 mutations suggest that a significant
component of the residual clustering is due to recessive alleles. But the best way to
identify such susceptibility genes is not clear. Much attention has been given to the
possibility of identifying susceptibility alleles for complex diseases in large case-control
association studies using very dense sets of genetic markers emanating from the Human
Genome Project. We are participating in the Breast Cancer Association Consortium
(BCAC) which represents over 50,000 breast cancer case and control subjects to more
definitively study common variants. We are also pursuing the mapping of susceptibility
genes in populations with reduced genetic complexity and high levels of consanguinity.
This may provide an efficient means of identifying additional breast cancer susceptibility
alleles, particularly those acting in an autosomal recessive fashion.
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