Mutational processes giving rise to lung adenocarcinomas (LADCs) in non-smokers remain elusive. We analyzed 138 LADC whole genomes, including 83 cases with minimal contribution of smoking-associated mutational signature. Genomic rearrangements were not correlated with smoking-associated mutations and frequently served as driver events of smoking-signature-low LADCs. Complex genomic rearrangements, including chromothripsis and chromoplexy, generated 74% of known fusion oncogenes, including EML4-ALK, CD74-ROS1, and KIF5B-RET. Unlike other collateral rearrangements, these fusion-oncogene-associated rearrangements were frequently copy-number-balanced, representing a genomic signature of early oncogenesis. Analysis of mutation timing revealed that fusions and point mutations of canonical oncogenes were often acquired in the early decades of life. During a long latency, cancer-related genes were disrupted or amplified by complex rearrangements. The genomic landscape was different between subgroups-EGFR-mutant LADCs had frequent whole-genome duplications with p53 mutations, whereas fusion-oncogene-driven LADCs had frequent SETD2 mutations. Our study highlights LADC oncogenesis driven by endogenous mutational processes READ ARTICLE
Cell DOI:10.1016/j.cell.2019.05.013
Authors: Jake June-Koo Lee, Seongyeol Park, Hansol Park, Sehui Kim, Jongkeun Lee, Junehawk Lee, Jeonghwan Youk, Kijong Yi, Yohan An, In Kyu Park, Chang Hyun Kang, Doo Hyun Chung, Tae Min Kim, Yoon Kyung Jeon, Dongwan Hong, Peter J Park, Young Seok Ju, Young Tae Kim
