||5R03CA092776-02 Interpret this number
||University Of Pittsburgh
||Hormones, DNA Repair, BRCA1/2 and Ovarian Cancer Preven*
DESCRIPTION (provided by applicant):
Ovarian cancer is an insidious disease and a potent killer. Prevention is
currently the best way to reduce morbidity and mortality. Determining
etiologic factors and identifying women at an increased risk is the first step
in devising an effective prevention program. For women carrying a BRCA1/2
mutation, prevention is even more critical because they are 10 times more
likely to develop the disease than women are in general. However, the
considerable variability in penetrance and age at onset of BRCA1/2-associated
disease suggests the existence of common, modifying factors. Identifying such
factors is important because it will enable us to develop strategies for risk
assessment and targeted prevention efforts. Sex steroid hormones have been
implicated in ovarian cancer; thus, factors that alter the availability of
these hormones could impact ovarian cancer risk in general and among BRCA1/2
carriers. Polymorphisms in genes along the sex steroid pathways may be such
factors. Evidence is mounting for a role of these polymorphisms in several
hormonally-related diseases, such as breast cancer. There is also evidence of
a role for these gene variants in ovarian cancer. The emerging role of BRCA1
in DNA repair suggests a link between DNA repair genes polymorphisms and
BRCA1/2-associated disease. No study has examined these possibilities. We will
undertake a case-control study to determine the effects of these polymorphisms
on ovarian cancer risk in general and among BRCA1/2 carriers. We will also
determine the degree to which exogenous and endogenous hormonal factors modify the risk associated with these polymorphisms. We will obtain genotype data
using banked DNA from 300 Ashkenazi Jewish women with histologically-confirmed
invasive epithelial ovarian cancer and 300 healthy Ashkenazi Jewish women
frequency matched by 5-year age groups to cases. The women previously
participated in an NCI-funded study of the epidemiology of ovarian cancer in
Jewish women. Detailed data on gynecologic and reproductive history have
already been obtained by the parent study using a standardized in-person
interview. DNA was also obtained and used to determine the BRCA1/2 status of
study participants. This study will identify the most promising allelic
variants among the proposed genes, which we will further investigate in a
large, multi-national population-based case-control study. This study will
also develop the infrastructure needed to undertake a multi-national study
examining genetic and environmental determinants of ovarian cancer. The
expertise and data we will collect will promote future innovative research
into understanding ovarian cancer.
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