PO.MCB08.04 · 分子与细胞生物学
1209例肺癌基因组中染色体不稳定性的全景
Panorama of chromosomal instability in 1209 lung cancer genomes
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
肺癌是全球男性和女性癌症死亡的首要原因。它是一种高度异质性的疾病，主要由吸烟驱动。约20%的肺癌发生于从不吸烟者。从不吸烟肺癌（LCINS）与吸烟患者的肺癌在患者血统、性别、肿瘤组织学和临床特征方面存在重大差异。LCINS更常见于亚洲人和女性，且以腺癌为主。EGFR突变在LCINS中富集，而KRAS和TP53突变在吸烟患者的肿瘤中更为常见。我们对LCINS病因学的理解仍然有限。在此，我们通过Sherlock-Lung项目以及已发表的研究，对来自四大洲30个不同地点收集的1,209例全基因组测序肺癌开展了一项全面研究。在这些肿瘤中，1024例为腺癌，864例为LCINS。该队列代表了迄今为止最大的肺癌基因组学队列。我们的研究聚焦于体细胞结构变异（SV），即大规模的染色体重排。我们在1209个肿瘤样本中共检测到182,429个体细胞SV，平均每个样本151个SV。复杂SV（如染色体碎裂，chromothripsis）与简单SV分开研究，因为它们通过一次性灾难性的染色体破碎和重接产生。我们队列中约三分之二的SV属于复杂事件。我们使用非负矩阵分解，基于事件拓扑结构解卷积出共8个复杂SV特征和8个简单SV特征。它们很可能代表了各异的分子机制。其中，由双着丝粒染色体驱动的染色质桥特征是最丰富的复杂SV；中位大小的缺失是最常见的简单SV。SV在吸烟患者的肿瘤中更为丰富；然而，在LCINS中，它们更为复杂，且在肿瘤发生中发挥更重要的作用。由于诱变和正向选择的联合效应，不同特征的SV断点在基因组中呈现出各异的分布。许多已确立的癌症驱动基因被多种SV特征反复重排，提示这些基因组不稳定性机制存在功能趋同。EGFR突变和KRAS突变深刻且独立地塑造了SV格局。EGFR突变型肿瘤具有更高的SV负荷和更多的癌症驱动性SV。相比之下，KRAS突变与较低的SV负荷和较少的驱动性SV相关。我们的研究加深了对肺癌基因组格局和病因学的理解。
查看英文原文 English abstract
Lung cancer is the leading cause of cancer death worldwide in both men and women. It is a highly heterogeneous disease primarily driven by tobacco smoking. About 20% of lung cancers occur among never smokers. There are major differences between lung cancers in patients who have never smoked (LCINS) and who have smoked in patient ancestry, sex, tumor histology and clinical features. LCINS occur more frequently in Asians and females and are predominantly adenocarcinomas. EGFR mutations are enriched in LCINS, whereas KRAS and TP53 mutations are more common in tumors from patients who have smoked. Our understanding of the etiology of LCINS is still limited. Here, we perform a comprehensive study in 1,209 whole-genome sequenced lung cancers collected from 30 different locations across four continents through Sherlock-Lung Project as well as published studies. Among these tumors, 1024 of them are adenocarcinomas and 864 are LCINS. This cohort represents the largest genomics cohort in lung cancer to date. Our study focuses on somatic structural variations (SVs) which are large-scale chromosomal rearrangements. In total, we detect 182,429 somatic SVs in 1209 tumor samples with an average of 151 SVs per sample. Complex SVs, such as chromothripsis, are studied separately from simple SVs because they arise through one-time catastrophic chromosome shattering and rejoining. About two-thirds of the SVs in our cohort are part of complex events. We deconvolute a total of 8 complex SV signatures based on event topology and 8 simple SV signatures using non-negative matrix factorization. They likely represent divergent molecular mechanisms. Among these, chromatin bridge signature, driven by dicentric chromosomes, is the most abundant complex SVs; and median size deletion is the most common simple SVs. SVs are more abundant in tumors from patients who have smoked; however, they are more complex and play more important roles in tumorigenesis in LCINS. The SV breakpoints have distinct distributions across the genome depending on the signatures due to combined effects of mutagenesis and positive selection. Many established cancer-driving genes are recurrently rearranged by multiple SV signatures suggesting functional convergence of these genome instability mechanisms. EGFR mutations and KRAS mutations profoundly and independently shape the SV landscape. EGFR mutant tumors have higher SV burden and more cancer-driving SVs. In contrast, KRAS mutations are associated with lower SV burden and fewer driver SVs. Our study has deepened our understanding of genomic landscape and etiology of lung cancer.
利益披露 Disclosure
Y. Yang, None..
T. Zhang, None..
L. Yang, None..
M. Landi, None.