Analysis of DNA Damage Response Gene Alterations and Tumor Mutational Burden Across 17,486 Tubular Gastrointestinal Carcinomas: Implications for Therapy

Abstract

Alterations in the DNA damage response (DDR) pathway contribute to chemotherapy and radiotherapy resistance. The relevance of DDR defects in gastrointestinal cancers (GI) is understudied. This article characterizes DDR‐defective GI malignancies, exploring genomic context and tumor mutational burden to provide a foundation for future studies.

Abstract

Background.

Alterations in the DNA damage response (DDR) pathway confer sensitivity to certain chemotherapies, radiation, and other DNA damage repair targeted therapies. BRCA1/2 are the most well‐studied DDR genes, but recurrent alterations are described in other DDR pathway members across cancers. Deleterious DDR alterations may sensitize tumor cells to poly (ADP‐ribose) polymerase inhibition, but there are also increasing data suggesting that there may also be synergy with immune checkpoint inhibitors. The relevance of DDR defects in gastrointestinal (GI) cancers is understudied. We sought to characterize DDR‐defective GI malignancies and to explore genomic context and tumor mutational burden (TMB) to provide a platform for future rational investigations.

Materials and Methods.

Tumor samples from 17,486 unique patients with advanced colorectal, gastroesophageal, or small bowel carcinomas were assayed using hybrid‐capture‐based comprehensive genomic profiling including sequencing of 10 predefined DDR genes: ARID1A, ATM, ATR, BRCA1, BRCA2, CDK12, CHEK1, CHEK2, PALB2, and RAD51. TMB (mutations per megabase [mut/Mb]) was calculated from up to 1.14 Mb of sequenced DNA. Clinicopathologic features were extracted and descriptive statistics were used to explore genomic relationships among identified subgroups.

Results.

DDR alterations were found in 17% of cases: gastric adenocarcinoma 475/1,750 (27%), small bowel adenocarcinoma 148/666 (22%), esophageal adenocarcinoma 467/2,501 (19%), and colorectal cancer 1,824/12,569 (15%). ARID1A (9.2%) and ATM (4.7%) were the most commonly altered DDR genes in this series, followed by BRCA2 (2.3%), BRCA1 (1.1%), CHEK2 (1.0%), ATR (0.8%), CDK12 (0.7%), PALB2 (0.6%), CHEK1 (0.1%) and RAD51 (0.1%). More than one DDR gene alteration was found in 24% of cases. High microsatellite instability (MSI‐H) and high TMB (TMB‐H, ≥20 mut/Mb) were found in 19% and 21% of DDR‐altered cases, respectively. Of DDR‐altered/TMB‐H cases, 87% were also MSI‐H. However, even in the microsatellite stable (MSS)/DDR‐wild‐type (WT) versus MSS/DDR‐altered, TMB‐high was seen more frequently (0.4% vs. 3.3%, P < .00001.) Median TMB was 5.4 mut/Mb in the MSS/DDR‐altered subset versus 3.8 mut/Mb in the MSS/DDR‐WT subset ( P ≤ .00001), and ATR alterations were enriched in the MSS/TMB‐high cases.

Conclusion.

This is the largest study to examine selected DDR defects in tubular GI cancers and confirms that DDR defects are relatively common and that there is an association between the selected DDR defects and a high TMB in more than 20% of cases. Microsatellite stable DDR‐defective tumors with elevated TMB warrant further exploration.

Implications for Practice.

Deleterious DNA damage response (DDR) alterations may sensitize tumor cells to poly (ADP‐ribose) polymerase inhibition, but also potentially to immune checkpoint inhibitors, owing to accumulation of mutations in DDR‐defective tumors. The relevance of DDR defects in gastrointestinal (GI) cancers is understudied. This article characterizes DDR‐defective GI malignancies and explores genomic context and tumor mutational burden to provide a platform for future rational investigations.

Translated abstract

摘要

背景 DNA 损伤修复 (DDR) 通路的改变与某些化疗、放疗和其他 DNA 损伤修复靶向治疗的敏感性密切相关。 BRCA1/2 是研究最深入的 DDR 基因，但也有研究描述癌症的其他 DDR 通路成员反复出现突变。DDR 基因的毒化改变可能使肿瘤细胞对多聚 ADP 核糖聚合酶抑制敏感，但也有越来越多的数据表明，也可能与免疫检查点抑制剂具有协同作用。DDR 缺陷在胃肠道 (GI) 肿瘤中的相关性研究尚不充分。本文旨在描述 DDR 缺陷的 GI 恶性肿瘤，探讨其基因组结构和肿瘤突变负荷 (TMB)，为未来的合理研究提供基础。

材料和方法 采用基于杂交捕获综合基因组分析 17 486 例晚期结直肠癌、胃食管癌或小肠癌患者的肿瘤样本,包括 10 个预先确定的 DDR 基因序列: ARID1A、ATM、ATR、BRCA1、BRCA2、CDK12、CHEK1、CHEK2、PALB2 以及 RAD51。通过1.14 Mb 的测序 DNA计算出TMB[每百万碱基的突变数(mut/Mb)]。提取临床病理特征，采用描述性统计方法探讨筛选出的亚群之间的基因组关系。

结果 17% 的患者发现 DDR 改变:胃腺癌 475/1 750 (27%)、小肠腺癌 148/666 (22%)、食管腺癌 467/2 501 (19%)、结直肠癌 1 824/12 569 (15%)。 ARID1A (9.2%) 与 ATM (4.7%) 是本系列中最常见的 DDR 基因改变，其次为 BRCA2 (2.3%)、 BRCA1 (1.1%)、 CHEK2 (1.0%)、 ATR (0.8%)、 CDK12 (0.7%)、 PALB2 (0.6%)、 CHEK1 (0.1%) 和 RAD51 (0.1%)。24% 的患者出现了一种以上的 DDR 基因改变。DDR 改变的患者中，高微卫星不稳定性 (MSI‐H) 和高 TMB (TMB‐H, ≥20 mut/Mb) 分别占 19% 和 21%。DDR 改变/TMB‐H 患者 87% 为 MSI‐H。在微卫星稳定 (MSS)/DDR‐野生型 (WT) 与 MSS/DDR‐改变的患者中，TMB‐H 同样更为常见(0.4% vs. 3.3%， P < 0.000 01.)。MSS/DDR‐改变组的 TMB 平均值为 5.4 mut/Mb，MSS/DDR‐WT 组 TMB 平均值为 3.8 mut/Mb ( P ≤ 0.000 01)，而 MSS/TMB‐H 患者的 ATR 改变相对富集。

结论 本文是对 GI 管状腺癌经选 DDR 缺陷规模最大的研究，结果证实 DDR 缺陷相对比较常见，并且超过 20% 的患者经选 DDR 缺陷与高 TMB 相关。微卫星稳定的 DDR 缺陷肿瘤 TMB 升高，值得进一步研究。

实践意义:DDR 基因的毒化改变可能使肿瘤细胞对多聚 ADP 核糖聚合酶抑制敏感，但也可能由于 DDR 缺陷肿瘤中突变的积累，而对免疫检查点抑制剂敏感。DDR 缺陷在胃肠道 (GI) 肿瘤中的相关性研究尚不充分。本文描述了 DDR 缺陷的 GI 恶性肿瘤，探讨了其基因组结构和肿瘤突变负荷，为未来的合理研究提供了基础。