Project Details
Description
PROJECT SUMMARY
Breast and ovarian cancer are two of the most common cancers among women in the US. Approximately 15%
to 20% of cases exhibit a family history of breast or ovarian cancer suggesting strong heritable components.
Clinical germline genetic testing of cancer predisposition gene panels is now widely used in an effort to identify
women at risk for these cancers. The identification of pathogenic mutations in established predisposition genes
can result in improved risk management for ovarian or breast cancer, depending on the gene, for tested
patients and their family members. For instance, MRI screening for early detection of breast cancer is
recommended for all individuals with pathogenic mutations in high and moderate risk breast cancer genes, and
carriers of BRCA1 and BRCA2 mutation carriers can benefit from prophylactic mastectomy and/or
oophorectomy for reduction of cancer risk. Furthermore, ovarian cancer patients with germline or somatic
BRCA1 and BRCA2 mutations may benefit from targeted therapy with platinum agents or PARP inhibitors. The
efficacy of these clinical interventions show the promise of identifying pathogenic mutations in genes that
predispose to these cancers. However, the utility of results from panel testing has been limited because the
levels of risk for breast and ovarian cancer associated with mutations in several of the panel genes has not
been clear. Importantly, recent studies have established that germline pathogenic mutations in RAD51C and
RAD51D are associated with substantially increased risks of ovarian cancer, and moderate and high risks of
triple negative breast cancer (TNBC), respectively, and RAD51D mutations are associated with moderate risks
of breast cancer overall. While these genes have important roles in susceptibility to breast and ovarian cancer,
much remains to be learned about how to use testing results for the benefit of those with germline pathogenic
mutations or variants of uncertain significance or with somatic inactivation of the genes in tumors. In this
precision medicine oriented project we propose to define the contribution of RAD51C and RAD51D mutations
to ovarian and breast cancer. In Aim 1 we propose to define the risks of ovarian and breast cancer associated
with inherited RAD51C and RAD51D mutations in high-risk families and the general population. In Aim 2, we
propose to comprehensively characterize the functional properties and functional domains of RAD51C and
RAD51D that influence cancer risks and response to therapeutic agents, leading to classification of the clinical
relevance of many variants of uncertain significance (VUS). In Aim 3, we propose to evaluate the influence of
targeted therapy on RAD51C and RAD51D deficient tumors in preclinical models. At the conclusion of the
study we expect to have improved understanding of RAD51C and RAD51D-associated cancer susceptibility
and the responsiveness of ovarian tumors deficient in RAD51C or RAD51D to specific therapeutic agents.
Status | Finished |
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Effective start/end date | 5/1/18 → 4/30/23 |
Funding
- National Cancer Institute: $451,372.00
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