Abstract 02: Pan-cancer analysis of hotspot mutations in genes encoding the members of mitogen activated protein kinase (MAPK) and phosphoinosidtide-3 kinase (PI3K) pathways among smokers and non-smokers
Authors: Aung Kyaw L. , Pugh Trevor J. , Stockley Tracy , Wang Lisa , Korpanty Greg , Serra Stefano , Shaw Patricia , Tsao Ming S. , Dhani Neesha , Mackay Helen , Shepherd Frances A. , Kamel-Reid Suzanne , Siu Lillian L. , Bedard Philippe L. 
Published: May 2016

Abstract
Background: In lung cancer, the MAPK pathway is activated mainly by KRAS and EGFR mutations in smokers and non-smokers, respectively. It is relatively unknown how smoking affects MAPK and PI3K pathways across multiple cancers.
Methods: Mutation data and smoking status were available from 854 solid tumor patients whose tumors were profiled by NGS with Illumina MiSeq TruSeq Amplicon Cancer Panel (48 genes, 212 amplicons) in the Princess Margaret Cancer Centre Integrated Molecular Profiling in Advanced Cancer Trial (IMPACT). The panel included hotspot exons of EGFR, ERBB2, KRAS, NRAS, BRAF, PIK3CA, PTEN and AKT1. Mutation frequencies between smokers and non-smokers (never smoker + former light smoker [&lt;5pack year]) were compared using Chi-Square test or Fisher's exact test.
Results: Lung cancers (N=101) from smokers contained more KRAS mutations (38% vs.12%, P=0.004) while those from non-smokers had more EGFR mutations (34% vs. 10%, P=0.003). In contrast, non-lung cancers (N=753) had no difference in KRAS mutation frequencies between smokers and non-smokers (19% vs.17%, P=0.47). Too few EGFR and NRAS mutations were found in this cohort for meaningful analysis. Across the cohorts, there was no difference in BRAF, PIK3CA, or PTEN mutation frequency between smokers and non-smokers (BRAF, 5% vs. 4.5%, P=0.6; PIK3CA, 14% vs.15%, P=0.8; PTEN, 4.5% vs. 3.6%, P=0.6). Five non-lung cancers (4 non-smokers, 1 smoker) had AKT1 mutations. All nine cases with ERBB2 mutations (2 lung and 7 non-lung cancers) were non-smokers. No difference in KRAS, BRAF, PIK3CA and PTEN mutation frequencies between smokers and non-smokers was observed within specific cancers; breast, cervix, colorectal, endometrium, ovarian, pancreatobiliary and upper aerodigestive (P values&gt;0.05, N= 107, 36, 126, 55, 167, 70, 81 respectively).
Conclusions: Our data suggest that, with the exception of lung cancer, there is no difference in frequencies of hotspot mutations in critical genes encoding MAPK and PI3K pathways members between smokers and non-smokers across multiple cancers analysed. ERBB2 hotspot mutations (N=9) were exclusively found in non-smokers.
Citation Format: Kyaw L. Aung, Trevor J. Pugh, Tracy Stockley, Lisa Wang, Greg Korpanty, Stefano Serra, Patricia Shaw, Ming S. Tsao, Neesha Dhani, Helen Mackay, Frances A. Shepherd, Suzanne Kamel-Reid, Lillian L. Siu, Philippe L. Bedard. Pan-cancer analysis of hotspot mutations in genes encoding the members of mitogen activated protein kinase (MAPK) and phosphoinosidtide-3 kinase (PI3K) pathways among smokers and non-smokers. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 02.