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.