Tracing Oncogene Rearrangements in the Mutational History of Lung Adenocarcinoma

• Published in: Cell 2019-06, Vol.177 (7), p.1842-1857.e21
• Main Authors: Lee, Jake June-Koo, Park, Seongyeol, Park, Hansol, Kim, Sehui, Lee, Jongkeun, Lee, Junehawk, Youk, Jeonghwan, Yi, Kijong, An, Yohan, Park, In Kyu, Kang, Chang Hyun, Chung, Doo Hyun, Kim, Tae Min, Jeon, Yoon Kyung, Hong, Dongwan, Park, Peter J., Ju, Young Seok, Kim, Young Tae
• Format: Article
• Language: English
• Subjects: Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - metabolism; Adenocarcinoma of Lung - pathology; balanced rearrangement; chromoplexy; chromothripsis; complex genomic rearrangement; Female; fusion oncogene; Gene Rearrangement; Humans; lung adenocarcinoma; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Mutation; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; p53; SETD2; tumor initiation; whole-genome duplication
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2019.05.013

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. [Display omitted] •Driver fusion oncogenes in LADCs are generated from complex genomic rearrangements•These rearrangements are frequently copy-number balanced, resembling germline events•Fusions often arise in early decades of life, leaving long latency to diagnosis•SETD2 inactivation is cooperative with fusion oncogenes in TP53-wild-type LADCs Driver fusion oncogenes in human lung adenocarcinoma of non-smokers are generated from complex genomic rearrangements and often arise in early decades of life, long before diagnosable disease.