Department of Pulmonary and Critical Care Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shanxi, China.
Department of Pulmonary Medicine, Xi'an International Medical Center Hospital, Xi'an, Shanxi, China.
Cancer Med. 2023 Feb;12(4):4486-4495. doi: 10.1002/cam4.5148. Epub 2022 Aug 26.
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.
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.
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.
We exhaustively describe the genomic alteration profile of Chinese SCLC patients and provide further evidence that HRR gene mutations are prevalent in SCLC patients.
同源重组缺陷（HRD）是一种众所周知的生物标志物，可预测聚 ADP 核糖聚合酶 1（PARP）抑制剂和铂类药物的反应。作为一种侵袭性癌症，小细胞肺癌（SCLC）对铂类药物敏感，但复发迅速。在此，我们旨在阐明中国 SCLC 队列中同源重组修复（HRR）相关基因的基因组改变模式，并进一步分析 HRR 基因突变与免疫检查点抑制剂（ICI）反应的已知生物标志物之间的关系，包括肿瘤突变负担（TMB）和程序性细胞死亡配体 1（PD-L1）表达。
对 133 例中国 SCLC 患者进行了 543 个癌症相关基因的下一代测序（NGS）靶向捕获测序，分析了基因组图谱，并计算了 TMB。使用 SP142 PD-L1 免疫组化检测评估了 133 例患者中的 90 例 PD-L1 表达。
在 133 例 SCLC 患者中，有 47 例（35.3%）存在 HRR 基因突变。ATM（8.3%）是该队列中最常突变的 HRR 基因，其次是 NBN（4.5%）。在 11 例（23.4%）和 4 例（8.5%）患者中分别发现了 HRR 基因的致病性体细胞和种系突变。HRR 基因突变与 KMT2D 基因突变共同发生。HRR 基因突变患者（HRR-Mut）与无 HRR 基因突变患者（HRR-WT）之间存在几种基因组改变差异。结果表明，TP53 和 RB1 是两组中常见的突变基因。KMT2D 基因突变和 RTK-RAS 通路中的基因在 HRR-Mut 组中更频繁发生。此外，我们发现 HRR 基因突变与高 TMB 相关（Wilcoxon，p=0.048），但 HRR 基因突变状态与 PD-L1 表达无关。
我们详尽描述了中国 SCLC 患者的基因组改变图谱，并提供了进一步的证据表明 HRR 基因突变在 SCLC 患者中普遍存在。
