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

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.

Clinical significance of DNA damage response mutations in stage I and stage IIIa NSCLC

“…Deleterious DDR mutations have been reported to be associated with high TMB in solid tumors including lung cancer 10,16,26,29‐34 . In this study, we found that deleterious alterations in the DDR pathway were associated with a higher number of gene mutations, and we also observed significantly higher TMB in the DDR‐mut subgroup in the pan lung cancer dataset for both the selected 74 DDR genes and six genes.…”

“…Deleterious DDR mutations have been reported to be associated with high TMB in solid tumors including lung cancer. 10,16,26,[29][30][31][32][33][34] In this study, we found that deleterious alterations in the DDR pathway were associated with a higher number of gene mutations, and we also observed significantly higher TMB in the DDR-mut subgroup in the pan lung cancer dataset for both the selected 74 DDR genes and six genes. It has been reported that deleterious DDR gene mutations are an independent predictor of better response to immune checkpoint inhibitors in colorectal cancer 15 and NSCLC.…”

“…Similarly, no association was found in advanced NSCLC 26 and small‐cell lung cancer (SCLC). 29 In addition, deleterious mutations in DDR genes did not affect CD8‐positive lymphocytes and TAM infiltration in the tumor. However, it was noted that alterations in the BER, FA and HR pathways could affect immune cell infiltration in the tumor area.…”

“…Although a few studies have shown that DDR gene mutations can upregulate PD‐L1 expression in gastroesophageal cancer 27 and breast cancer, 28 this study did not find an association between DDR gene status and PD‐L1 expression in early‐stage NSCLC. Similarly, no association was found in advanced NSCLC 26 and small‐cell lung cancer (SCLC) 29 . In addition, deleterious mutations in DDR genes did not affect CD8‐positive lymphocytes and TAM infiltration in the tumor.…”

ATM—the gene at the moment in non-small cell lung cancer

“…Of the DNA damage response and repair genes frequently mutated in NSCLC, ATM mutations are the most prevalent occurring in ~9% of LUAD and ~4% of lung squamous cell carcinoma based on The Cancer Genome Atlas (TCGA) cohorts ( 7 , 8 ). They are also found in ~8% of small cell lung cancers ( 9 ). Unlike commonly mutated oncogenes, ATM mutations are not localized to specific amino acids or functional domains, and are instead scattered throughout the ATM gene which spans ~150 kilobases.…”