Abstract POSTER-CTRL-1206: The mutational landscape of fallopian tube carcinoma

Abstract

Abstract Fallopian tube (FT) carcinoma is a rare gynecological malignancy, whose incidence is most likely underestimated due to misdiagnoses as ovarian cancer. Recent advances in pathology with more thorough serial sectioning techniques have led to better identification. We undertook to define germline and somatic mutations in 98 FT carcinoma cases enrolled at diagnosis in IRB-approved studies at the University of Washington, excluding cases with carcinoma identified at the time of risk-reducing surgery. We sequenced DNA from blood and neoplastic tissue using BROCA, a targeted capture and massively parallel genomic sequencing approach that detects all classes of mutation in 64 genes. The fraction of all primary ovarian, peritoneal and FT carcinoma defined as a FT primary increased over time in our tissue bank: FT diagnoses accounted for 23% of cases in the past five years compared to 5% in the previous 10 years (p=0.002). Of 98 subjects with FT carcinoma, 32 (33%) had loss of function germline mutations in 9 genes. Mutations in BRCA1 were identified in 18 (19%), making up the largest number of germline mutations, and in BRCA2 in 4 (4%). Germline mutations were also identified in 6 other known breast and/or ovarian cancer susceptibility genes including 2 in BRIP1 (2%), 2 in CHECK2 (2%), and 1 each in BARD1, BLM, MRE11A, and ATM (1%). One mutation was found in the FA gene FANCL. Additionally, we found 1 mosaic mutations in TP53 (1%) and 2 in PPM1D (2%). Together germline and mosaic mutations were identified in 34 (35%) of cases. We sequenced neoplastic DNA with BROCA in 30 FT carcinomas and found 27 somatic mutations in TP53 (90%), 1 in PTEN (3%) and 1 in CHEK2 (3%). The germline mutation rate was higher in FT carcinoma compared to our previous studies in ovarian carcinoma (35% versus 22%), though the identified genes were similar. Recently identified ovarian cancer susceptibility genes such as BRIP1, BARD1, and PPM1D are also associated with hereditary fallopian tube cancer. Known breast cancer genes (i.e. CHEK2, MRE11A, ATM) and other cancer associated genes (BLM, FANCL) require further study to prove their association with FT or ovarian cancer risk. An increased pathological recognition of the FT as a primary site of disease is changing the relative distribution of FT, ovarian, and peritoneal carcinoma in some centers. Citation Format: M.I. Harrell, T. Walshb, K.J. Agnew, B. Norquist, M.K. Lee, S. Bernards, K.P. Pennington, E.M. Swisher. The mutational landscape of fallopian tube carcinoma [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1206.