Clinical and genomic features of Chinese lung cancer patients with germline mutations

Wenying Peng,Jing Bai,Ning Wang,Rongrong Chen,Meilin Jiang,Rui Zhong,Jia Li,Xuefeng Xia,Chen Chen,Pingping Dai,Lianpeng Chang,Jiaojiao Huan,Yanfang Guan,Luping Xu ,Bin Li,Jin Li,Bolin Chen,Ling Yang,Xin Yi,Xingxiang Pu,Fenglei Yu,Jiayin Wang,Yuting Yi,Fang Xu,Yanyan Zhang,Lin Wu

doi:10.1038/s41467-022-28840-5

Abstract

The germline mutation landscape in Chinese lung cancer patients has not been well defined. In this study, sequencing data of 1,021 cancer genes of 1,794 Chinese lung cancer patients was analyzed. A total of 111 pathogenic or likely pathogenic germline mutations were identified, significantly higher than non-cancer individuals (111/1794 vs. 84/10,588, p < 2.2e-16). BRCA1/2 germline mutations are associated with earlier onset age (median 52.5 vs 60 years-old, p = 0.008). Among 29 cancer disposition genes with germline mutations detected in Chinese cohort and/or TCGA lung cancer cohort, Only 11 from 29 genes are identified in both cohorts and BRCA2 mutations are significantly more common in Chinese cohort (p = 0.015). Chinese patients with germline mutations have different prevalence of somatic KRAS, MET exon 14 skipping and TP53 mutations compared to those without. Our findings suggest potential ethnic and etiologic differences between Western and Asian lung cancer patients.

Highlights

The germline mutation landscape in Chinese lung cancer patients has not been well defined
Germline DNA and paired tumor DNA were subjected to next generation sequencing (NGS) of 1021 cancer genes with an average sequencing depth of 285× (36×−441×) in germline DNA and 1248× (56×−4626×) in tumor DNA respectively (Fig. 1)
Comparison of the single-nucleotide polymorphism (SNP) data from the current cohort to that of individuals submitted to 1000 genomes project phase 3 (n = 2054)[14,15] revealed that the mean pairwise F-statistics (Fixation indices, Fst) difference was significant between the lung cancer patients in the current cohort and African (Fst = 0.07), European (Fst = 0.06), South Asian (Fst = 0.04) and Admixed American (Fst = 0.04) populations; the SNP

Summary

Introduction

The germline mutation landscape in Chinese lung cancer patients has not been well defined. Ovary cancer patients with BRCA1 or BRCA2 mutations benefit from Poly ADP-ribose polymerase inhibitor Olaparib while solid tumors with MMR mutations have demonstrated high response rate to immune checkpoint blockade[3,4] These well-known genes only account for a small fraction of the genetic burden in cancers and the genetic alterations that may be responsible for predisposition to many potentially inheritable cancers are largely unknown. Several well-known predisposition genetic variants including BRCA2 and CHEK2 have been found to have strong association with lung cancer risk[10] and rare pathogenic germline mutations in genes of Fanconi anemia pathway contribute to the risk of squamous lung cancers[11] All these pioneer studies are based on western populations and the germline mutation landscape in Asian lung cancer patients remains largely unknown. Prevalence of somatic mutations in KRAS, MET exon 14 skipping and TP53 is different in patients with P/LP germline mutations compared to those without

Methods

Results

Conclusion