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

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

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.

Conflict of interest statement

L.W. reports personal fees from AstraZeneca, Roche, Bristol-Myers Squibb, MSD, Pfizer, Lilly, Boehringer Ingelheim, Merck, Innovent and Hengrui outside the submitted work. J.B., Y.Y., R.C., Y.Z.,C.C., Jin L., J.H., P.D., Y.G., L.C., L.Y., and X.Y are current employees of Geneplus-Beijing. The remaining authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1. Study scheme of patient cohort.
Fig. 1. Study scheme of patient cohort.
Patients diagnosed with lung caner went through targeted sequencing as part of clinical care from November 2017 to August 2018 were included for further analysis. NGS next generation sequencing. WBC white blood cells. ACMG American college of medical genetics and genomics, NSCLC non-small cell lung cancer, SCLC small cell lung cancer, P/LP pathogenic or likely pathogenic.
Fig. 2. Genetic architecture of 1794 lung…
Fig. 2. Genetic architecture of 1794 lung cancer patients.
a Pairwise Fst difference between the Chinese lung cancer cohort and other populations. b Principal component analysis (PCA) of Chinese Lung cancer patients and other populations in 1000 genome project. AFR African. AMR Admixed American. ASN East Asian. EUR European. SAS South Asian.
Fig. 3. Distribution of P/LP germline mutations…
Fig. 3. Distribution of P/LP germline mutations and the age at diagnosis.
a Bar plot indicated the prevalence of P/LP germline mutation (dark brown). The genes, number of patients, and mutation frequency of each gene are shown in the pie plot. Genes (SLX4, RUNX1, RAD51B, RAD51, PTCH2, NF1, MRE11A, GALNT12, FLCN, FANCC, FAM175A, CDH1, BARD1 and BAP1) with germline mutations detected in one patient were grouped as others. b Frequency of pathogenic and likely pathogenic germline variants in patients of different ages (n = 1715 patients with information on age of onset). Bar plot and lines shows the frequency of germline variants in patients under certain age (bar) and frequency in female and male patients (lines). c The panels show the age of onset for patients without germline mutations (n = 1611 patients) (light brown dots) and patients with different germline genes (n = 104 patients) (dark brown dots). Horizontal lines indicate median age. P value is calculated by the Mann–Whitney test (*p = 0.021, **p = 0.008).
Fig. 4. Commonly somatic cancer gene mutations…
Fig. 4. Commonly somatic cancer gene mutations in lung cancer patients with and without germline variants.
a Genomic landscape of somatic mutation in patients with P/LP germline mutation. Stacked plots (top) show the number of somatic mutations (SNV/indels, CNV and SV) in each tumor sample (column). The gender, histology subtype and clinical stage are shown on the bottom. Bar plot on the right shows the mutation frequency of each gene. b Normalized bar plot illustrates the frequency of nine commonly mutated genes. Stripped bars represent patients with P/LP germline variants. Open bars represent patients without pathogenic germline variants. *Statistic difference between two cohorts: TP53, p = 0.016. KRAS, p = 0.015 and MET, p = 0.027. P value is calculated with Chi-square test (EGFR, TP53, KRAS) or Fisher’s exact test (c-MET, ALK, ROS-1, ERBB2, RET, BRAF).

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