韩国科学技术院的Young Seok Ju研究组与韩国首尔大学医院的Young Tae Kim研究组合作，阐述了癌基因重排在肺腺癌突变史中的作用。2019年6月13日出版的《细胞》杂志发表了这一成果。
研究人员分析了138例肺腺癌病人组织的全基因组序列，其中有83例与吸烟引起的相关突变没有太大关联。他们发现，基因组重排与吸烟相关的突变不存在关联，但却是吸烟相关突变低的病人患肺腺癌的驱使因素。复杂的基因组重排产生了74%的已知癌基因融合，包括EML4-ALK、CD74-ROS1和KIF5B-RET等。与其他附带性重排不同，这些与融合癌基因相关的重排常常是拷贝数均衡的，这体现了早期肿瘤发生的一个基因组特征。通过分析突变产生的时间，研究人员发现经典癌基因的融合和点突变通常发生在青幼年时期。在长期的潜伏中，这些癌症相关基因被复杂的重排所破坏或扩增。不同的肺腺癌亚群间的基因组全貌并不同——EGFR突变的肺腺癌带有较高频率全基因组倍增以及p53突变；而癌基因融合导致的肺腺癌里则拥有较高频率的SETD2突变。这项工作提示，内源性突变的积累过程能够驱使肺腺癌的产生。
研究人员表示，吸烟是导致肺腺癌的主要原因，但对于非吸烟者而言，基因突变如何导致了肺腺癌的产生却不清楚。
附：英文原文
Title: Tracing Oncogene Rearrangements in the Mutational History of Lung Adenocarcinoma
Author: 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
Issue&Volume: Jun 13, 2019 Volume 177Issue 7
Abstract: 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.
DOI: https://doi.org/10.1016/j.cell.2019.05.013
Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30511-2