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

Research Paper

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

Yan Li1,4*, Yan Tan2*, Song Hu1*, Jun Xie1, Zhantao Yan2, Xian Zhang1, Yun Zong1, Han Han-Zhang3, Qing Li2✉, Chong Li1✉

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

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Li Y, Tan Y, Hu S, Xie J, Yan Z, Zhang X, Zong Y, Han-Zhang H, Li Q, Li C. Targeted Sequencing Analysis of Predominant Histological Subtypes in Resected Stage I Invasive Lung Adenocarcinoma. J Cancer 2021; 12(11):3222-3229. doi:10.7150/jca.51405. Available from https://www.jcancer.org/v12p3222.htm

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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, pathological subtypes, next-generation sequencing, mutational profile, immunotherapy