Genomic Profiling and Prognostic Value Analysis of Genetic Alterations in Chinese Resected Lung Cancer With Invasive Mucinous Adenocarcinoma.

Lei Cai,Lei Cai,Lei Cai,Minyan Xing,Minyan Xing,Guojie Xia,Junrong Yan,Chao Pan,Chao Pan,Chao Pan,Fufeng Wang,Jian Zeng,Jian Zeng,Jian Zeng,Yang Xu,Xiancong Huang,Jiangfeng Wang,Jiangfeng Wang,Jiangfeng Wang,Xiancong Huang,Jinxiao Liang,Jinxiao Liang,Jinxiao Liang,Xiancong Huang,Yang Shao,Ju Jin,Qinqin Xu,Xiaoling Xu,Xiaoling Xu,Xiaoling Xu,Youhua Jiang,Liang Zhu,Liang Zhu,Liang Zhu

doi:10.3389/fonc.2020.603671

Abstract

BackgroundInvasive mucinous adenocarcinoma (IMA) of the lung is a distinct histological subtype with unique clinical and pathological features. Despite previous genomic studies on lung IMA, the genetic characteristics and the prognosis-related biomarkers in Chinese surgically resected lung IMA remain unclear.MethodsWe collected 76 surgically resected primary tumors of invasive lung adenocarcinoma, including 51 IMA and 25 non-mucinous adenocarcinomas (non-IMA). IMA was further divided into pure-IMA (mucinous features≥90%) and mixed-IMA subgroups. Comprehensive genomic profiling based on targeted next-generation sequencing (NGS) of 425 genes was explored and genomic characteristics were evaluated for the correlation with postoperative disease-free survival (DFS).ResultsIMA had a unique genetic profile, with more diverse driver mutations and more tumor drivers/suppressors co-occurrence than that of non-IMA. The frequency of EGFR (72.0% vs. 40.0% vs. 23.1%, p=0.002) and ALK (undetected vs. 20.0% vs. 26.9%, p=0.015) alterations showed a trend of gradual decrease and increase from non-IMA to mixed-IMA to pure-IMA, respectively. The frequency of KRAS mutations in pure-IMA was higher than that in mixed-IMA, albeit statistically insignificant (23.1% vs. 4.0%, p=0.10). TP53 mutation was significantly less in pure-IMA compared to mixed-IMA and non-IMA (23.1% vs. 52.0% vs. 56.0%, p=0.03). Besides, IMA exhibited less arm-level amplifications (p=0.04) and more arm-level deletions (p=0.004) than non-IMA, and the frequency of amplification and deletion also showed a trend of gradual decrease and increase from non-IMA to mixed-IMA to pure-IMA, respectively. Furthermore, prognosis analysis in stage III IMA patients showed that patients harboring alterations in EGFR (mDFS=30.3 vs. 16.0 months, HR=0.19, P=0.027) and PI3K pathway (mDFS=36.0 vs. 16.0 months, HR=0.12, P=0.023) achieved prolonged DFS, while patients with poorly differentiated tumors (mDFS=14.1 vs. 28.0 months, HR=3.75, p=0.037) or with KRAS mutations (mDFS=13.0 vs. 20.0 months, HR=6.95, p=0.027) had shorter DFS. Multivariate analysis showed that KRAS mutations, PI3K pathway alterations, and tumor differentiation status were independent factors that have statistically significant influences on clinical outcomes of IMA patients.ConclusionOur study provided genomic insights into Chinese surgically resected lung IMA. We also identified several genomic features that may serve as potential biomarkers on postoperative recurrence in IMA patients with stage III disease.

Highlights

Lung cancer is the leading cause of cancer-related mortality among various malignancies worldwide [1]
The frequency of EGFR mutations was significantly lower while the frequency of ALK fusion was significantly higher in invasive mucinous adenocarcinoma (IMA) compared to non-mucinous adenocarcinomas (non-IMA), which was consistent with the previous studies [14,15,16,17,18,19, 32]
The comparison of mixed-IMA and pure-IMA showed that there was no statistical difference in the frequency of EGFR or ALK variations, suggesting that these gene-level changes might happen in the entire tumor when lung adenocarcinoma harbors mucinous components

Summary

Introduction

Lung cancer is the leading cause of cancer-related mortality among various malignancies worldwide [1]. According to the lung adenocarcinoma classification system proposed by the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) in 2011 [6], invasive mucinous adenocarcinoma (IMA) is considered to be a distinct subtype of lung adenocarcinoma. IMA has a low incidence, accounting for only 2%–5% of lung invasive adenocarcinoma, and IMA is associated with poor survival outcomes [6, 8]. Some distinct clinic-pathological features were observed within the IMA subtype. Several pathological parameters of the MIA tumors, such as the mucin spread size, tumor cell spread size, and invasive size, were negatively correlated with poor prognosis [11]. Invasive mucinous adenocarcinoma (IMA) of the lung is a distinct histological subtype with unique clinical and pathological features. Despite previous genomic studies on lung IMA, the genetic characteristics and the prognosis-related biomarkers in Chinese surgically resected lung IMA remain unclear

Methods

Results

Conclusion