Abstract 99P
Background
Lung cancer is one of the malignant tumors with high morbidity and mortality in the world. PARP inhibitors have become a new line of cancer therapy The mechanism and efficacy of PARP inhibitors have been well studied in some cancers, especially homologous recombination (HR)-deficient ovarian cancer, and several cell line experiments have shown that HR-deficient lung cancers are sensitive to PARP inhibitor. Meanwhile, HHR gene is a potential biomarker for immunotherapy. Herein, we evaluated the characteristics of HRR related gene mutations in Chinese patients with lung adenocarcinoma (LUAD) or lung squamous cell carcinoma (LUSC).
Methods
Tumor specimens from 748 NSCLC patients were analyzed by DNA based NGS with a 1021 gene panel in this study. We analyzed 36 HRR genes, including CHEK1/2, BRCA1/2, BRIP1, CDK12, ATM/ATR, FANCA/C/D2/E/F/G/L/M, MRE11A, NBN, RAD50/51/52, RAD51B/C/D et al.
Results
666 of 746 patients were LUAD and 82 patients were LUSC. The proportions of HRR gene mutations in LUAD was 32.28% (215/666) and in LUSC was 41.5% (34/82). The top 5 mutated HRR genes in LUAD were TAM (35/666, 5.26%), FANCM (33/666, 4.95%), CDK12 (21/666, 3.15%), BRCA2 (21/666, 3.15%), ATR (18/666, 2.70%). In LUSC, the top 5 mutated HRR genes were BRCA2 (10/82, 12.2%), ATR (6/82, 7.32%), FANCM (6/82, 7.32%), FANCA (5/82, 6.10%), CDK12 (5/82, 6.10%). Interestingly, BRCA1 gene mutation was not found in LUSC. There was a significant difference in the frequency of five HRR genes between LUAD and LUSC, including BRCA2 (P=0.00034), CHEK2 (P=0.03521), FANCG (P=0.0009), BLM (P=0.02572), FAM175A. (P=0.03012). The proportion of tumor mutational burden-high (TMB-H) (≥10 mut/Mb) was significantly higher in HRR mutant than HRR wild-type LUAD or LUSC (LUAD: 36.84% vs 8.82%，P<0.0001, LUSC: 75.86% vs 32.08%，P<0.0001).
Conclusions
In terms of HRR gene mutations, we report that LUAD and LUSC have different mutation landscape. Mutations in HRR genes may serve as a biomarker for PARP inhibitors or ICIs in LUAD and LUSC, which also needs more trials to verify.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.