Abstract 4692: Relationships between somatic genomic alterations, tumor stage and progression-free survival in cervical cancer

Abstract

Abstract Background: Cervical cancer is a major public health problem worldwide. We have recently identified novel significantly recurrent somatic mutations in HLA-B, ERBB2 and MAPK1 in cervical squamous cell carcinomas. However, the significance of somatic mutations and copy number alterations for clinical phenotype in cervical cancer is not well understood. This study seeks to identify relationships between somatic genomic alterations, epidemiological exposures, tumor stage (FIGO) and progression-free survival in cervical carcinomas. Methods: Cervical tumors were surgically resected or biopsied from 100 Norwegian women with tumor stages I - IV. Patients were subsequently followed for 0-109 months (mean=25 months). Whole exome sequencing (WES) was performed on DNA extracted from tumors and corresponding normal blood. Somatic single nucleotide variants and small insertion/deletions were identified by the MuTect and Indelocator algorithms respectively. The ABSOLUTE algorithm was used to classify mutations as clonal or subclonal. Somatic copy number (CN) data were derived from WES data using the CapSeg algorithm, and significantly recurrent CN alterations were identified by GISTIC2.0 analysis (q<0.25). HPV typing was done by the multiplex fluorescent f-HPV DNA and MassARRAY assays. The log-rank test was used to compare survival curves. Results: Non-localized tumors (FIGO stages ≥ II) were associated with focal amplification of the FGFR2 gene on chromosomal cytoband 10q26 (GISTIC q = 0.18531). Indeed, 6 of 8 (75%) tumors with FGFR2 amplification were non-localized, in contrast to 16 of 92 (17%) tumors without FGFR2 amplification (p = 0.001). In addition, patients with somatic ERBB2 mutations and/or amplifications (p = 0.04), somatic TP53 mutations and/or deletions (p = 0.04), or infection with multiple HPV types (p = 0.02) had poorer prognosis (progression-free survival). We also observed a trend for higher frequency of subclonal driver events in patients with poorer survival (p = 0.07). Conclusion: We have identified novel relationships between somatic genomic alterations, tumor stage and patient prognosis in cervical cancer. Our data suggest a potential for exploring FGFR2 inhibition in non-localized cervical carcinomas with FGFR2 alterations in a clinical trial context. Citation Format: Akinyemi I. Ojesina, Bradley Murray, Line Bjorge, Kathrine Woie, Camilla Krakstad, Lee Lichtenstein, Chandra Sekhar Pedamallu, Amaro Taylor-Weiner, Samuel S. Freeman, Andrew D. Cherniack, Michael S. Lawrence, Kristian Cibulskis, Scott L. Carter, Heather Walline, Thomas E. Carey, Olav K. Vintermyr, Bjorn Bertelsen, Christopher P. Crum, Gad Getz, Matthew Meyerson, Helga B. Salvesen. Relationships between somatic genomic alterations, tumor stage and progression-free survival in cervical cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4692. doi:10.1158/1538-7445.AM2014-4692