Genomic Predictors of Ovarian Cancer Risk in the PLCO Trial
Abstract
Rationale: Ovarian cancer remains the deadliest gynecologic malignancy. Prior studies have indicated that around 20% of ovarian cancers are associated with identifiable inherited mutations (for example, mutations in the genes BRCA1 and BRCA2) that increase the risk of developing ovarian cancer, one of the highest proportions of any solid tumor. When these inherited risk mutations are identified in advance, patients have the opportunity to undergo highly effective and lifesaving interventions such as preventative removal of the fallopian tubes and ovaries. In addition to inherited mutations, the function of a gene can also be impacted by a process called promotor methylation, which effectively silences the gene in question and can lead to similar effects as a mutation. Constitutional promotor methylation of the BRCA1 gene has recently been identified as a possible risk factor for developing ovarian cancer and could be another indication to consider risk reduction strategies. Our group has also examined promotor methylation of the RAD51C gene (another ovarian cancer susceptibility gene) in ovarian tumors. This finding has not been assessed before in constitutional DNA and may represent another important cause of ovarian cancer risk. The Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial is a population-based, randomized study of cancer screening in nearly 150,000 people aged 55-74. The participants from the PLCO trial offer a unique population to assess for inherited risk of ovarian cancer. Female subjects enrolled in the PLCO trial provided DNA samples and completed detailed surveys with their reproductive history, hormone use, and family history of malignancies. Around 400 women enrolled in PLCO went on to develop ovarian cancer during the study. Prior detailed examinations of ovarian cancer risk factors have been assessed in this population, but no study has been done defining inherited mutations or constitutional methylation in this group. The central problem that this work addresses is the need to decrease ovarian cancer mortality through improving ovarian cancer prevention. Our goals are to (1) determine the frequency of inherited mutations in cases and controls in PLCO, (2) determine the frequency of constitutional promotor methylation of BRCA1 and RAD51C in cases and controls, (3) examine how these genomic changes (mutation and methylation) relate to clinical characteristics, and (4) see how inherited mutations and methylation interact with other known risk factors for ovarian cancer within the unique population of the PLCO trial. It is rare to have detailed information about hormone use, parity, age, race/ethnicity, and ovarian cancer screening results in a group of patients with OC who also have pre-diagnosis DNA samples. Our proposal is unique, in that other studies evaluating gene-environment interactions have focused on common variants and single nucleotide polymorphisms rather than our focus on pathogenic mutations and methylation. To further evaluate these findings, we will also assess how clinical ovarian cancer risk factors interact with inherited mutations within the large UK Biobank study. Understanding constitutional promotor methylation of BRCA1 and RAD51C and ovarian cancer risk is likely to expand the population eligible for OC risk-reduction efforts, and our methods should provide the most accurate and sensitive detection of this finding thus far. The assessment of interactions between genomic risk factors and other potentially modifiable risk factors for ovarian cancer will help guide the health behaviors of patients at risk. Finally, we plan to create an enduring resource by providing the sequencing and methylation results back to the PLCO study group for use in future investigation. Our multidisciplinary team is well positioned to carry out this project, combining expertise in inherited ovarian cancer and the clinical care of women who are at risk of ovar
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310173
Entities
People
- Barbara Norquist
Organizations
- United States Army
- University of Washington