SCI

21 April 2023

The evolution of lung cancer and impact of subclonal selection in TRACERx

（Nature；IF: 69.504）

Frankell AM, Dietzen M, Al Bakir M, Lim EL, Karasaki T, Ward S, Veeriah S, Colliver E, Huebner A, Bunkum A, Hill MS, Grigoriadis K, Moore DA, Black JRM, Liu WK, Thol K, Pich O, Watkins TBK, Naceur-Lombardelli C, Cook DE, Salgado R, Wilson GA, Bailey C, Angelova M, Bentham R, Martínez-Ruiz C, Abbosh C, Nicholson AG, Le Quesne J, Biswas D, Rosenthal R, Puttick C, Hessey S, Lee C, Prymas P, Toncheva A, Smith J, Xing W, Nicod J, Price G, Kerr KM, Naidu B, Middleton G, Blyth KG, Fennell DA, Forster MD, Lee SM, Falzon M, Hewish M, Shackcloth MJ, Lim E, Benafif S, Russell P, Boleti E, Krebs MG, Lester JF, Papadatos-Pastos D, Ahmad T, Thakrar RM, Lawrence D, Navani N, Janes SM, Dive C, Blackhall FH, Summers Y, Cave J, Marafioti T, Herrero J, Quezada SA, Peggs KS, Schwarz RF, Van Loo P, Miedema DM, Birkbak NJ, Hiley CT, Hackshaw A, Zaccaria S; 

CORRESPONDENCE TO: m.jamal-hanjani@ucl.ac.uk

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource. 

肺癌是全世界与癌症有关的死亡的主要原因。在此，我们分析了1,644个在手术时或随访期间取样的肿瘤，这些肿瘤来自于TRACERx研究的首批421名非小细胞肺癌患者。该项目目的在于揭示肺癌的演变，并解决主要研究终点：确定肿瘤内异质性和临床结果之间的关系。在肺腺癌中，40个常见的癌症基因中，有22个基因的突变处于显著的亚克隆选择之下，包括经典的肿瘤启动器，如TP53和KRAS。我们定义了驱动因素、突变过程和全基因组加倍（WGD）事件之间的演变依赖性。尽管患者有吸烟史，但8%的肺腺癌缺乏烟草诱导突变的证据。

与从不吸烟的人相比，这些肿瘤的EGFR突变和RET、ROS1、ALK和MET致癌异构体的检测率也相似，这表明它们有类似的病因和发病机制。大的亚克隆扩增与阳性亚克隆选择有关。携带最近的亚克隆扩增的肿瘤患者，在系统发育分支的末端，其无病生存期明显缩短。

19%的肿瘤检测到亚克隆性WGD，10%的肿瘤同时存在多个亚克隆WGD。亚克隆WGD与较短的无病生存期有关。拷贝数的异质性与手术后1年内的胸外复发有关。这些数据证明了克隆扩增、WGD和拷贝数不稳定在决定非小细胞肺癌复发的时间和模式方面的重要性，并提供了一个全面的临床癌症演变数据库。

来源 | 健康界

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