Mutational landscape of homologous recombination‐related genes in small‐cell lung cancer

Abstract

Abstract Background Homologous recombination deficiency (HRD) is a well‐known biomarker which could predict poly‐ADP ribose polymerase 1 (PARP) inhibitor and platinum drug response. As an aggressive cancer, small‐cell lung cancer (SCLC) is sensitive to platinum drugs, but relapse occurs rapidly. Herein, we aim to illustrate the genomic alteration patterns of homologous recombination repair (HRR)‐related genes in a Chinese SCLC cohort and further analyze the relationship among HRR gene mutations and known biomarkers of immune checkpoint inhibitor (ICI) response, including tumor mutation burden (TMB) and programmed cell death‐ligand 1 (PD‐L1) expression. Methods Next‐generation sequencing (NGS)‐based target capture sequencing of 543 cancer‐related genes was performed to analyze the genomic profiles of 133 Chinese SCLC patients, and TMB was calculated. PD‐L1 expression was evaluated in 90 out of 133 patients using the SP142 PD‐L1 immunohistochemistry assay. Results Among the 133 patients with SCLC, 47 (35.3%) had HRR gene mutations. ATM (8.3%) was the most frequently mutated HRR gene in the cohort, followed by NBN (4.5%). Pathogenic somatic and germline mutations of HRR genes were identified in 11 (23.4%) and 4 (8.5%) patients, respectively. HRR gene mutations cooccurred with KMT2D gene mutations. There were several differences in genomic alterations between patients with HRR gene mutations (HRR‐Mut) and without HRR mutations (HRR‐WT). The results revealed that TP53 and RB1 were commonly mutated genes in both groups. Mutations in the KMT2D gene and genes in the RTK‐RAS pathway occurred more frequently in the HRR‐Mut group. Furthermore, we found that mutations in HRR genes were associated with high TMB (Wilcoxon, p = 0.048), but there was no correlation of HRR gene mutation status with PD‐L1 expression. Conclusions We exhaustively describe the genomic alteration profile of Chinese SCLC patients and provide further evidence that HRR gene mutations are prevalent in SCLC patients.

Keywords

• biomarker
• homologous recombination deficiency
• immunotherapy
• small‐cell lung cancer