Targeted Sequencing Analysis of Predominant Histological Subtypes in Resected Stage I Invasive Lung Adenocarcinoma

Yan Li; Yan Tan; Song Hu; Jun Xie; Zhantao Yan; Xian Zhang; Yun Zong; Han Han-Zhang; Qing Li; Chong Li

doi:10.7150/jca.51405

Targeted Sequencing Analysis of Predominant Histological Subtypes in Resected Stage I Invasive Lung Adenocarcinoma

J Cancer. 2021 Apr 2;12(11):3222-3229. doi: 10.7150/jca.51405. eCollection 2021.

Authors

Yan Li^{1

2}, Yan Tan³, Song Hu¹, Jun Xie¹, Zhantao Yan³, Xian Zhang¹, Yun Zong¹, Han Han-Zhang⁴, Qing Li³, Chong Li¹

Affiliations

¹ Department of Respiratory Medicine, The Third Affiliated Hospital of Soochow University, 185 Juqian Road, Changzhou, China.
² Department of Respiratory Medicine, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, China.
³ Department of Pathology, The Third Affiliated Hospital of Soochow University, 185 Juqian Road, Changzhou, China.
⁴ Burning Rock Biotech, Guangzhou, Guangdong, 510300, China.

Abstract

Objective: 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. Patients and Methods: 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. Results: 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, LRP1B 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 LRP1B mutations. Conclusions: 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.

Keywords: adenocarcinoma; immunotherapy; mutational profile; next-generation sequencing; pathological subtypes.