Abstract 95: Somatic mutations and copy number variations in cancer-associated genes in 695 ovarian cancer patients
Authors: Stover Elizabeth H. , Howitt Brooke , Lindeman Neal I. , Garraway Levi A. , Matulonis Ursula A. 
Published: July 2016

Background: Recent genomic studies have improved molecular understanding of ovarian cancer but have had limited impact on therapeutic improvements. We sought to review somatic mutations and copy-number variations (CNVs) in cancer-associated genes in the tumors of 695 patients with ovarian, peritoneal, or fallopian tube cancer (ovarian cancer) at Dana-Farber Cancer Institute, with associated pathologic and clinical data.

Methods: Testing was performed on formalin-fixed tumor tissue without germline analysis, with IRB approval and patient consent. 310 patients underwent genotyping for 471 mutations in 41 cancer-related genes (OncoMap test). 388 patients underwent next-generation sequencing (NGS) of 300 cancer-associated genes (OncoPanel test). Most samples were primary tumors, with a small subset recurrent. The majority of tumors were adenocarcinoma/carcinoma histology.

Results: Of 310 patients tested by OncoMap, 102 had at least one variant. Among tumors with adenocarcinoma/carcinoma histology, mutations were most frequent in TP53, KRAS, PIK3CA, JAK3, MET, and CTNNB1. Gene alterations varied by subtype and supported previously reported associations including BRAF in borderline, KRAS in mucinous, PIK3CA in clear cell, and PIK3CA/CTNNB1/AKT1 in endometrioid tumors. From 388 patients tested by OncoPanel, 3903 single nucleotide variants were detected. Variants were classified by clinical pathologists according to evidence-based potential clinical relevance. 27 variants were “Tier 1” (evidence confirming clinical utility in ovarian cancer) and 127 variants were “Tier 2” (possible clinical utility in specific contexts). Tier 1 variants were most frequent in BRCA1 and BRCA2. Common Tier 2 variants included alterations in TP53, PIK3CA, KRAS, PTEN, BRCA1, BRCA2, ARID1A, and BRAF. Several alterations may be considered “actionable” in terms of eligibility for clinical trials. Finally, 227 patients tested by OncoPanel had CNV data for the panel of cancer-associated genes. CNVs were numerous with 12368 CNVs reported. CNVs were classified as 1-copy deletion (n = 6033), 2-copy deletion (n = 108), high amplification (n = 114), and low amplification (n = 6103). Among adenocarcinoma/carcinoma tumors, 2-copy deletions were frequent in RB1, PTEN, CDKN2A, and MAP2K4, and common highly amplified genes were CCNE1, KRAS, AKT2, ERBB2, and MECOM.

Conclusions: Genotyping and/or NGS of cancer-associated genes in formalin-fixed tissue from ovarian tumors is feasible and can identify potentially clinically actionable alterations. Preliminary correlations with survival and treatment response are being explored.

Citation Format: Elizabeth H. Stover, Brooke Howitt, Neal I. Lindeman, Levi A. Garraway, Ursula A. Matulonis. Somatic mutations and copy number variations in cancer-associated genes in 695 ovarian cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 95.