For lung adenocarcinoma, arm aneuploidy landscape among primary and metastatic sites, and among different driver and frequently mutated gene groups have not been previously studied. We collected the largest cohort of LUAD patients (n=3533) to date and analyzed the profiles of chromosome arm aneuploidy (CAA), and its association with different metastatic sites and mutated gene groups. Our results showed distant metastasis (bone, brain, liver) were characterized by high CAA burden and biased towards arm losses compared to regional metastasis (pleura, chest) and primary tumors. Moreover, EGFR, MET, PIK3CA, PKHD1 and RB1 mutant groups were found to have high CAA burden, while those with BRAF, ERBB2 and KRAS mutations belonged to the low CAA burden group. Comparing EGFR L858R and EGFR 19del mutants, distinct CAA co-occurrences were observed. Network-based stratification with population based genomic evolution analysis revealed two distinct subtypes of LUAD with different CAA signatures and unique CAA order of acquisition. In summary, our study presented a comprehensive characterization of arm aneuploidy landscape and evolutionary trajectories in lung adenocarcinoma, which could provide basis for both biological and clinical investigations in the future.

对于肺腺癌，以前没有研究过原发和转移部位之间以及不同驱动基因组和频繁突变基因组之间的手臂非整倍体景观。我们收集了迄今为止最大的 LUAD 患者队列 (n=3533)，并分析了染色体臂非整倍性 (CAA) 的概况及其与不同转移位点和突变基因组的关联。我们的结果表明，与区域转移（胸膜、胸部）和原发性肿瘤相比，远处转移（骨、脑、肝）的特征是 CAA 负担高，并且偏向于手臂损失。此外，发现EGFR、MET、PIK3CA、PKHD1和RB1突变组CAA负担高，而BRAF、ERBB2和KRAS突变组属于低CAA负担组。比较 EGFR L858R 和 EGFR 19del 突变体，观察到不同的 CAA 共现。基于网络的分层和基于人群的基因组进化分析揭示了两种不同的 LUAD 亚型，具有不同的 CAA 特征和独特的 CAA 获取顺序。总之，我们的研究全面描述了肺腺癌的臂非整倍体景观和进化轨迹，可为未来的生物学和临床研究提供基础。