Analysis of DNA Damage Response Gene Alterations and Tumor Mutational Burden Across 17,486 Tubular Gastrointestinal Carcinomas: Implications for Therapy
Analysis of DNA Damage Response Gene Alterations and Tumor Mutational Burden Across 17,486 Tubular Gastrointestinal Carcinomas: Implications for Therapy
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DOI：
10.1634/theoncologist.2019-0034
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发表时间：
2019-10-01
期刊：
影响因子：
5.8
通讯作者：
Schrock, Alexa B.
中科院分区：
文献类型：
--
作者：
Parikh, Aparna R.;He, Yuting;Schrock, Alexa B.
DNA损伤反应（DDR）途径的改变赋予对某些化疗、放疗和其他DNA损伤修复靶向治疗的敏感性。BRCA 1/2是研究最充分的DDR基因，但在癌症的其他DDR通路成员中描述了复发性改变。有害的DDR改变可能使肿瘤细胞对聚（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协同作用。DDR缺陷在胃肠道（GI）癌症中的相关性研究不足。我们试图描述DDR缺陷的GI恶性肿瘤，并探索基因组背景和肿瘤突变负荷（TMB），为未来的合理研究提供平台。材料和方法使用基于杂交捕获的综合基因组谱分析，包括10个预定义的DDR基因的测序，对来自17，486名患有晚期结直肠癌、胃食管癌或小肠癌的独特患者的肿瘤样品进行分析：ARID 1A、ATM、ATR、BRCA 1、BRCA 2、CDK 12、CHEK 1、CHEK 2、PALB 2和RAD 51。TMB（每兆碱基突变数[mut/Mb]）由最多1.14 Mb的测序DNA计算。提取临床病理学特征，并使用描述性统计来探索确定的亚组之间的基因组关系。结果17%的病例中发现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%）。ARID 1A（9.2%）和ATM（4.7%）是该系列中最常见的DDR基因改变，其次是BRCA 2（2.3%）、BRCA 1（1.1%）、CHEK 2（1.0%）、ATR（0.8%）、CDK 12（0.7%）、PALB 2（0.6%）、CHEK 1（0.1%）和RAD 51（0.1%）。在24%的病例中发现了一个以上的DDR基因改变。高微卫星不稳定性（MSI-H）和高TMB（TMB-H，>= 20 mut/Mb）分别见于19%和21%的DDR改变病例。在DDR改变/TMB-H病例中，87%也是MSI-H。然而，即使在微卫星稳定（MSS）/DDR野生型（WT）与MSS/DDR改变中，TMB高也更常见（0.4%对3.3%，P < .00001）。MSS/DDR-WT亚组的中位TMB为5.4 mut/Mb，而MSS/DDR-WT亚组为3.8 mut/Mb（P
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