Abstract 230: Characterizing pathogenic germline variants in a large Chinese lung cancer cohort
Authors: Wu Xiaoying , Fan Xiaojun , Pang Jiaohui , Bao Hua , Yin Jiani , Tang Haimeng , Wu Xue , Shao Yang 
Published: June 2023

Abstract
Objective: To characterize germline pathogenic/likely pathogenic variants (GPVs) in Chinese lung cancer patients and analyze the prevalence of the GPVs and their association with lung cancer risk as well as various clinical and genomic features.
Methods: A total of 17,904 Chinese lung cancer patients were included in the study. Samples of all 17,904 patients were subjected to next-generation targeted sequencing by using a panel covering more than 400 cancer genes, of which 146 are known cancer predisposition genes. Baseline somatic mutations of 5,460 patients were also obtained by targeted sequencing. Germline variants were called from white blood cells, and the GPVs were determined according to the 2015 ACMG Guideline. The prevalence of the GPVs as well as corresponding pathways in the whole cohort and in various subgroups was compared. The odds ratios of the GPVs for lung cancer risk were estimated by case-control analysis based on the local cohort and the gnomAD East Asia database. Interaction between GPVs and somatic mutations was investigated.
Results: Among 17,904 patients, 1,738 patients (9.7%) carried 1,840 GPVs from 87 cancer susceptibility genes. SBDS (1.37%), TSHR (1.20%), BLM (0.62%), BRCA2 (0.62%) and ATM (0.45%) were the top 5 genes with the highest prevalence in the whole cohort. GPVs in thirteen genes including FANCF, KIT, LHCGR, MAP2K2, NRAS, etc. have not been reported in lung cancer patients previously. GPVs in certain genes showed histological variation. GPVs in PTEN, BRCA2, WRN, RAD51C, JAK2 and ERBB2 were more enriched in lung squamous cell carcinoma compared with lung adenocarcinoma (LUAD). At pathway level, homologous recombination repair (HRR, 2.09%), TP53 pathway (0.83%), nucleotide excision repair (NER, 0.7%), Fanconi anemia (FA, 0.6%) and DNA damage sensor (0.53%) ranked the first 5 pathways with the highest overall prevalence. Case-control analysis showed SBDS c.184A&gt;T(p.K62*) had the highest odds ratio for lung cancer risk (OR=14.42, P&lt;0.001), followed by JAK2 c.1849G&gt;T(p.V617F)(OR=10.8, P=0.002) and MUTYH c.55C&gt;T(p.R19*)(OR=9.77, P=0.004). The rate of second hit was 4.74% in 464 patients with germline alterations in tumor suppressor genes. Patients with second hit had a higher percentage with family cancer history (68.2% vs. 35.2%, P=0.011), and tumors with second hit showed higher tumor mutation burden (P=3.2e-05) and chromosome instability score (CIS, P=0.12). PGVs in certain genes were associated with early onset of lung cancer, and co-occurrence analysis showed there existed germline-somatic mutation interaction in lung cancer.
Conclusion: Chinese lung cancer patients have a relatively high carry rate of PGVs. PGVs are distributed in multiple pathways and dominated by DNA damage repair associated pathways. The association between identified PGVs and lung cancer risk requires further studies to verify.
Citation Format: Xiaoying Wu, Xiaojun Fan, Jiaohui Pang, Hua Bao, Jiani Yin, Haimeng Tang, Xue Wu, Yang Shao. Characterizing pathogenic germline variants in a large Chinese lung cancer cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 230.