Germline mutations in the BRCA1/2 genes are associated with significant risk of developing ovarian cancer. However, there is substantial interindividual variability in both the incidence rates and age at diagnosis in BRCA1/2 mutation carriers, implying that while germline mutations in BRCA1/2 may be necessary to explain the Mendelian pattern of cancer in some families, they may not be sufficient to completely describe interindividual variability in cancer risk. Although there is a wealth of epidemiologic information about exposure-related risk modifiers of ovarian cancer in the general population, their role in hereditary ovarian cancer is not well defined. Our current model of hereditary ovarian cancer risk prediction is based on prevalence estimates derived from small, selective populations, which compromises our ability to personalize ovarian cancer prevention strategies. Currently risk reducing salpingo-oophorectomy (RRSO) offers the highest degree of risk reduction (70-95%). Because of the younger age of onset of ovarian cancer in women with BRCA1/2 mutations, RRSO is recommended at age 35 or when childbearing is complete, often inducing surgical menopause and its associated short- and long-term morbidities. Without more specific estimates of the individual risk of developing ovarian cancer or the age of onset, women considering RRSO must weigh the pros and cons of undergoing surgery and consider the optimal timing of RRSO in the face of uncertainty, leading to significant numbers of women who choose not to undergo RRSO, or who delay the decision until they reach menopause. Evidence suggests that additional modifying factors influence cancer penetrance among BRCA1/2 mutation carriers. A better understanding of the pathways that modify both ovarian cancer incidence and its timing could lessen the uncertainty associated with ovarian cancer risk estimates and translate into more specific cancer prevention strategies for individual women, based on their personal modifier profile. We propose an enhancement of the current prevalence model through: 1) identification and quantification of reproductive and exposure-related risk factors involved in DNA damage recognition and repair pathways that influence 8RCA ?//2-associated ovarian cancer risk;2) exploration of their interaction with genotypes at other loci; and 3) development and evaluation of a web-based patient decision aid (PtDA) to complement the genetic counseling session and facilitate decision-making regarding hereditary ovarian cancer risk management.
Prophylactic oophorectomy offers the greatest degree of protection from ovarian cancer in women with mutations in BRCA1/2. However, the decision to undergo surgery is challenged by the uncertainties of individual risk and the adverse short- and long-term consequences of the surgery. The goal of this project is to investigate genetic and non-genetic factors which might provide more precise estimates of risk, and incorporate this personalized risk information into a decision aid to complement the testing process.
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