Li Yan, Tan Yan, Hu Song, Xie Jun, Yan Zhantao, Zhang Xian, Zong Yun, Han-Zhang Han, Li Qing, Li Chong
Department of Respiratory Medicine, The Third Affiliated Hospital of Soochow University, 185 Juqian Road, Changzhou, China.
Department of Respiratory Medicine, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, China.
J Cancer. 2021 Apr 2;12(11):3222-3229. doi: 10.7150/jca.51405. eCollection 2021.
Lung adenocarcinoma (LADC) is classified into five main histological subtypes with distinct clinicopathologic characteristics: lepidic-predominant adenocarcinoma (LPA), acinar-predominant adenocarcinoma (APA), papillary-predominant adenocarcinoma (PPA), micropapillary-predominant adenocarcinoma (MPA) and solid-predominant adenocarcinoma (SPA). However, the mutational profiles of predominant histological subtypes have not been well defined. In this study, we aimed to reveal the genomic landscape of 5 main histological subtypes. We performed next-generation sequencing (NGS) in a cohort of 86 stage I invasive adenocarcinoma (IAC) patients, using a customized panel including 168 cancer-associated genes. Our analysis identified a total of 302 genomic alterations. Five subtypes showed different mutation profiles with LPA, APA, PPA, MPA and SPA had an average mutation rate of 1.95 (range: 0-5), 2.56 (range: 1-6), 3.5 (range: 1-7), 3.75 (range: 1-8) and 6.05 (range: 2-12), respectively (p=4.17e-06). Driver mutations occurred in 96.55% (83/86) of all patients. EGFR (73.3%), KRAS (9.3%), ALK (4.7%) and MET (4.7%) are the most commonly mutated lung cancer driver genes, TP53 is the top mutated tumor suppressor gene. SPA patients harbored more driver mutations and higher frequency of TP53 than LPA patients. Interestingly, mutations, which has been reported to be associated with high tumor mutation burden and better response to immunotherapy, were only detected from 5 SPA patients (p=0.001). No patients from other four cohorts harbored mutations. We revealed distinctive mutation landscape of the 5 major histological subtypes of LADC, evident by distinctive average mutation rate with SPA and LPA having the highest and lowest average mutation rate, respectively. SPA patients showed higher mutation rate of LRP1B and higher rates for PD-L1 positivity, indicating that SPA patients may have better response to immunotherapy.
肺腺癌（LADC）分为五种主要组织学亚型，具有不同的临床病理特征：以鳞屑样生长为主的腺癌（LPA）、以腺泡为主的腺癌（APA）、以乳头为主的腺癌（PPA）、以微乳头为主的腺癌（MPA）和以实体为主的腺癌（SPA）。然而，主要组织学亚型的突变谱尚未明确界定。在本研究中，我们旨在揭示5种主要组织学亚型的基因组图谱。我们对86例I期浸润性腺癌（IAC）患者进行了下一代测序（NGS），使用了一个包含168个癌症相关基因的定制panel。我们的分析共鉴定出302种基因组改变。五种亚型显示出不同的突变谱，LPA、APA、PPA、MPA和SPA的平均突变率分别为1.95（范围：0-5）、2.56（范围：1-6）、3.5（范围：1-7）、3.75（范围：1-8）和6.05（范围：2-12）（p=4.17e-06）。所有患者中有96.55%（83/86）发生驱动突变。EGFR（73.3%）、KRAS（9.3%）、ALK（4.7%）和MET（4.7%）是最常见的肺癌驱动基因突变，TP53是突变最多的肿瘤抑制基因。与LPA患者相比，SPA患者携带更多的驱动突变和更高频率的TP53突变。有趣的是，据报道与高肿瘤突变负荷和更好的免疫治疗反应相关的 突变仅在5例SPA患者中检测到（p=0.001）。其他四个队列中没有患者携带 突变。我们揭示了LADC的5种主要组织学亚型独特的突变图谱，其明显表现为平均突变率不同，其中SPA和LPA的平均突变率分别最高和最低。SPA患者显示出较高的LRP1B突变率和较高的PD-L1阳性率，表明SPA患者可能对免疫治疗有更好的反应。
