Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study

• DOI: 10.1371/journal.pmed.1002162
• Publication Date: 2016-12-06T18:22:03Z
• Authors: Jianxin Shi; Xing Hua; Bin Zhu; Sarangan Ravichan...; Mingyi Wang; Cu Nguyen; Seth A. Brodie; Alessandro Palleschi; Marco Alloisio; Gianluca Pariscenti; Kristine Jones; Weiyin Zhou; Aaron J. Bouk; Joseph Boland; Belynda Hicks; Adam Risch; Hunter Bennett; Brian T. Luke; Lei Song; Jubao Duan; Pengyuan Liu; Takashi Kohno; Qingrong Chen; Daoud Meerzaman; Crystal Marconett; Ite Laird-Offringa; Ian Mills; Neil E. Caporaso; Mitchell H. Gail; Angela C. Pesatori; Dario Consonni; Pier Alberto Bert...; Stephen J. Chanock; Maria Teresa Landi
• Keywords: Nonsynonymous substitution; Exome

Background Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer and has a high risk distant metastasis at every disease stage. We aimed to characterize genomic landscape LUAD identify mutation signatures associated with tumor progression. Methods Findings performed an integrative analysis, incorporating whole exome sequencing (WES), determination DNA copy number methylation, transcriptome for 101 samples from Environment And Genetics in Etiology (EAGLE) study. detected driver genes by testing whether nonsynonymous rate was significantly higher than background replicated our findings public datasets 724 samples. subclonality analysis mutations based on mutant allele data alteration data. also tested association between clinical outcomes, including metastasis, survival, grade. identified two novel candidate genes, POU class 4 homeobox 2 (POU4F2) (mutated 9 [8.9%] samples) ZKSCAN1 6 [5.9%] samples), characterized their major deleterious mutations. part mutually exclusive gene set that included RTK/RAS/RAF pathway BRAF, EGFR, KRAS, MET, NF1, indicating important role this gene. Moreover, we observed strong associations methylation specific regions somatic patterns. In evolution four had lower fraction subclonal (FSM), TP53 (p = 0.007), KEAP1 0.012), STK11 0.0076), EGFR 0.0078), suggesting initiation these genes. Subclonal were enriched APOBEC-related < 2.5×10−50). The total 0.0039) transitions 5.5×10−4) increased metastasis. Our study’s limitations include small patients subgroup analyses single-sample design investigation subclonality. Conclusions These provide characterization pathogenesis distinct clonal suggest possible diverse carcinogenesis pathways endogenous exogenous exposures, may serve as foundation more effective treatments lethal disease. LUAD’s heterogeneity emphasizes need further study type associate outcomes.