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

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.

Keywords: DNA damage response; Gastrointestinal cancers; Immunotherapy; Poly (ADP‐ribose) polymerase; Tumor mutational burden.

Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

© AlphaMed Press 2019.

Figures

Figure 1.

Venn diagram showing overlap of gastrointestinal (GI) cases defined by the indicated molecular features. (A): MSI‐H cases, TMB‐H cases, and DDR‐altered cases within the GI cohort (n = 13,129 with available microsatellite instability [MSI] data). (B): MSI‐H cases, TMB‐H cases, and cases with GA in MMR genes (MLH1, MSH2, MSH6, PMS2) within the DDR‐altered GI cohort (n = 2,248 with available MSI data). Abbreviations: DDR, DNA damage response; GA, genomic alteration; MMR, mismatch repair; MSI‐H, high microsatellite instability; mut, mutations; pts, patients; TMB‐H, high tumor mutational burden.

Figure 2.

Percentage of patients with tumors harboring at least one DDR GA. Abbreviations: DDR, DNA damage response; CRC, colorectal cancer; GA, genomic alteration; GI, gastrointestinal.

Figure 3.

TMB‐H prevalence and TMB score box plot for subgroup with GA in each gene or feature. Abbreviations: DDR, DNA damage response; GA, genomic alteration; MSI‐H, high microsatellite instability; MSS, microsatellite stable; TMB, tumor mutational burden; TMB‐H, high tumor mutational burden; WT, wild‐type.

Figure 4.

TMB and MSI distribution in cases with GA in each indicated gene or genomic feature. Abbreviations: DDR, DNA damage response; GA, genomic alteration; MSI‐H, high microsatellite instability; MSS, microsatellite stable; WT, wild‐type.

Figure 5.

MSS samples only: TMB‐H prevalence and TMB score box plot for subgroup with GA in each gene or feature. Abbreviations: DDR, DNA damage response; GA, genomic alteration; MSS, microsatellite stable; TMB, tumor mutational burden; TMB‐H, high tumor mutational burden; WT, wild‐type.