Study
PLCO
(Learn more about this study)
Project ID
2019-0022
Initial CDAS Request Approval
Aug 12, 2019
Title
Contribution of Inherited Risk to the Development of Ovarian Carcinoma in the PLCO Trial
Summary
Ovarian, primary peritoneal, and fallopian tube carcinoma (collectively referred to as OC) remains the deadliest gynecologic malignancy. Previous studies from single institutions and clinical trials have demonstrated that nearly 20% of OC is associated with inherited mutations, one of the highest proportions of any solid tumor. However, the rate and distribution of inherited mutations in healthy women whose OC was detected during an ovarian carcinoma screening protocol is unknown. We plan to determine the rate of inherited pathogenic mutations in known and candidate OC susceptibility genes in women diagnosed with OC as participants in the PLCO screening trial. We will use BROCA, our in-house multiplex sequencing assay, which can detect all classes of mutations in all known and candidate OC susceptibility genes, utilizing germline DNA samples derived from blood. Genes included in this panel include known OC risk genes BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2, and EPCAM; possible OC risk genes ATM, BARD1, NBN, PALB2, and TP53; and candidate OC risk genes ATR, BAP1, CHEK1, CHEK2, FAM175A, FANCM, GEN1, MRE11A, PTEN, RAD51B, RECQL, RINT1, STK11, SLX4, and XRCC2. All sequencing steps, including bioinformatics and mutation interpretation are done within our laboratory. The well characterized women (with data such as family history of breast and ovarian carcinoma) from the PLCO trial offer a unique population of women with OC to assess for inherited risk. While up to 20% of inherited mutations are in genes other than BRCA1 and BRCA2, the precise contribution of those genes to inherited risk of OC is uncertain. Given the overall rarity of non-BRCA mutations, we plan to pool these women with OC from the PLCO trial with other sequenced populations of women with OC that were sequenced with the same methodology to aid in determining the clinical characteristics of women with mutations in non-BRCA genes and to clarify risks of OC.
Aims
Aim 1: Determine the rate of inherited mutations in known and candidate genes associated with ovarian carcinoma risk within ovarian carcinoma patients diagnosed while participating in an ovarian carcinoma screening trial. We will use BROCA, our multiplex sequencing assay, to detect all classes of inherited mutations in all known and suspected ovarian carcinoma risk genes, utilizing DNA extracted from blood samples.
Aim 2: Determine the clinical characteristics of ovarian carcinoma patients with and without inherited mutations in known and candidate ovarian carcinoma risk genes who were diagnosed while participating in an ovarian carcinoma screening trial. We will assess age, family history, stage of malignancy, histologic subtype of malignancy, and oncologic outcome in women with and without inherited mutations.
Collaborators
Barbara Norquist (University of Washington)
Britton Trabert (National Cancer Institute)
