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Analysis of DNA Damage Response Gene Alterations and Tumor Mutational Burden Across 17,486 Tubular Gastrointestinal Carcinomas: Implications for Therapy.
Oncologist 2019; 24(10):1340-1347O

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.

Authors+Show Affiliations

Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA aparna.parikh@mgh.harvard.edu.Foundation Medicine, Inc., Cambridge, Massachusetts, USA.Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.University of Chicago Medical Center, Chicago, Illinois, USA.Department of Medical Oncology, City of Hope National Medical Center, Duarte, California, USA.Department of Medical Oncology, City of Hope National Medical Center, Duarte, California, USA.The Angeles Clinic and Research Institute, Los Angeles, California, USA.Foundation Medicine, Inc., Cambridge, Massachusetts, USA. SUNY Upstate Medical University, Syracuse, New York, USA.Foundation Medicine, Inc., Cambridge, Massachusetts, USA.Foundation Medicine, Inc., Cambridge, Massachusetts, USA.Foundation Medicine, Inc., Cambridge, Massachusetts, USA.Foundation Medicine, Inc., Cambridge, Massachusetts, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31040255

Citation

Parikh, Aparna R., et al. "Analysis of DNA Damage Response Gene Alterations and Tumor Mutational Burden Across 17,486 Tubular Gastrointestinal Carcinomas: Implications for Therapy." The Oncologist, vol. 24, no. 10, 2019, pp. 1340-1347.
Parikh AR, He Y, Hong TS, et al. Analysis of DNA Damage Response Gene Alterations and Tumor Mutational Burden Across 17,486 Tubular Gastrointestinal Carcinomas: Implications for Therapy. Oncologist. 2019;24(10):1340-1347.
Parikh, A. R., He, Y., Hong, T. S., Corcoran, R. B., Clark, J. W., Ryan, D. P., ... Schrock, A. B. (2019). Analysis of DNA Damage Response Gene Alterations and Tumor Mutational Burden Across 17,486 Tubular Gastrointestinal Carcinomas: Implications for Therapy. The Oncologist, 24(10), pp. 1340-1347. doi:10.1634/theoncologist.2019-0034.
Parikh AR, et al. Analysis of DNA Damage Response Gene Alterations and Tumor Mutational Burden Across 17,486 Tubular Gastrointestinal Carcinomas: Implications for Therapy. Oncologist. 2019;24(10):1340-1347. PubMed PMID: 31040255.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Analysis of DNA Damage Response Gene Alterations and Tumor Mutational Burden Across 17,486 Tubular Gastrointestinal Carcinomas: Implications for Therapy. AU - Parikh,Aparna R, AU - He,Yuting, AU - Hong,Ted S, AU - Corcoran,Ryan B, AU - Clark,Jeff W, AU - Ryan,David P, AU - Zou,Lee, AU - Ting,David T, AU - Catenacci,Daniel V, AU - Chao,Joseph, AU - Fakih,Marwan, AU - Klempner,Samuel J, AU - Ross,Jeffrey S, AU - Frampton,Garrett M, AU - Miller,Vincent A, AU - Ali,Siraj M, AU - Schrock,Alexa B, Y1 - 2019/04/30/ PY - 2019/01/11/received PY - 2019/03/27/accepted PY - 2020/10/01/pmc-release PY - 2019/5/2/pubmed PY - 2019/5/2/medline PY - 2019/5/2/entrez KW - DNA damage response KW - Gastrointestinal cancers KW - Immunotherapy KW - Poly (ADP‐ribose) polymerase KW - Tumor mutational burden SP - 1340 EP - 1347 JF - The oncologist JO - Oncologist VL - 24 IS - 10 N2 - 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. SN - 1549-490X UR - https://www.unboundmedicine.com/medline/citation/31040255/Analysis_of_DNA_Damage_Response_Gene_Alterations_and_Tumor_Mutational_Burden_Across_17486_Tubular_Gastrointestinal_Carcinomas:_Implications_for_Therapy_ L2 - https://doi.org/10.1634/theoncologist.2019-0034 DB - PRIME DP - Unbound Medicine ER -