Abstract 486: Pathogenic drivers and their comutations in genes frequently altered in cancer
Authors: Kotoula Vassiliki , Fountzilas Elena , Koliou Georgia-Angeliki , Papadopoulou Kyriaki , Giannoulatou Eleni , Tikas Ioannis , Zagouri Flora , Christodoulou Christos , Pentheroudakis Georgios , Koutras Angelos , Pectasides Dimitrios , Fountzilas George 
Published: August 2019

Abstract
Background - aim: The as yet publicized results from Precision Oncology trials highlight the need to define parameters that may interfere with the actionability of common pathogenic drivers. One such parameter may be the presence of multiple drivers within the same tumor. Here, we investigated the properties of single and coexisting pathogenic mutations in genes frequently altered and targeted across cancers.
Methods: We examined informative deep sequencing data for TP53, PIK3CA, KRAS and BRCA1 from 2672 paraffin tumors that were obtained at first diagnosis (88% stage I-III; 12% stage IV) from patients with breast (n=1745), colorectal (n=524), nasopharyngeal (n=143), gastric (n=102), biliary tree (n=81), nasopharyngeal (n=143) and ovarian (n=77) cancer. Single mutation corresponds to the presence of a pathogenic mutation in only one of these genes; co-mutation, to the presence of pathogenic mutations in ≥2 genes. We examined the status of single and co-mutations compared to disease stage and patient overall survival (OS) stratified by tumor type.
Results: Pathogenic mutations in any of the 4 genes were observed in 1337 (50% of all tumors) and co-mutation in 347 tumors (28% of tumors with mutations in these genes). Single mutations and co-mutations were observed in 481 (36.0%) and 322 (24.1%) tumors for TP53, respectively; in 350 (26.0%) and 198 (14.8%) for PIK3CA; in 80 (6%) and 198 (14.8%) for KRAS; and, in 51 (3.9%) and 120 (9.0%) for BRCA1. Co-mutations of BRCA1 and KRAS were more frequent than single mutations in the two genes across tumor types (p’s&lt;0.010). The same was observed for PIK3CA and TP53 except for breast cancer, where single mutations were more frequent than co-mutations (p’s&lt;0.001). Compared to stage I-III, stage IV tumors were more frequently mutated in TP53, KRAS and BRCA1 (p’s&lt;0.010) but were significantly less often mutated in PIK3CA (p&lt;0.001). Co-mutation rates for BRCA1, KRAS and TP53 did not differ between stage I-III and IV tumors but these were significantly different for PIK3CA (33.5% in I-III vs. 64.3% in IV; p&lt;0.001). Upon stratification by tumor type, in stage I-III disease, compared to tumors with co-mutations, single BRCA1, TP53 and KRAS mutations conferred similar OS, but single PIK3CA mutations conferred significantly lower risk for death (HR 0.52; 95%CI 0.35-0.77; p&lt;0.001). In stage IV disease, compared to no mutations, single KRAS or TP53 were associated with poor OS (p=0.017 and p=0.025, respectively) but this effect disappeared in patients with KRAS/TP53 co-mutated tumors.
Conclusions: Co-mutation patterns of known cancer drivers vary with respect to the affected gene, tumor type and disease stage. Known drivers have distinct prognostic impact when occurring singly or co-altered in the non-metastatic and metastatic setting, which may need to be considered in Precision Oncology trials.
Citation Format: Vassiliki Kotoula, Elena Fountzilas, Georgia-Angeliki Koliou, Kyriaki Papadopoulou, Eleni Giannoulatou, Ioannis Tikas, Flora Zagouri, Christos Christodoulou, Georgios Pentheroudakis, Angelos Koutras, Dimitrios Pectasides, George Fountzilas. Pathogenic drivers and their comutations in genes frequently altered in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 486.