Genomic profiling reveals high frequency of DNA repair genetic aberrations in gallbladder cancer

Abstract DNA repair gene aberrations (GAs) occur in several cancers, may be prognostic and are actionable. We investigated the frequency of DNA repair GAs in gallbladder cancer (GBC), association with tumor mutational burden (TMB), microsatellite instability (MSI), programmed cell death protein 1 (P...

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Autores principales:	Reham Abdel-Wahab, Timothy A. Yap, Russell Madison, Shubham Pant, Matthew Cooke, Kai Wang, Haitao Zhao, Tanios Bekaii-Saab, Elif Karatas, Lawrence N. Kwong, Funda Meric-Bernstam, Mitesh Borad, Milind Javle
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cdca34fc38034e9aa293b19e7e061208
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spelling	oai:doaj.org-article:cdca34fc38034e9aa293b19e7e0612082021-12-02T11:57:56ZGenomic profiling reveals high frequency of DNA repair genetic aberrations in gallbladder cancer10.1038/s41598-020-77939-62045-2322https://doaj.org/article/cdca34fc38034e9aa293b19e7e0612082020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-77939-6https://doaj.org/toc/2045-2322Abstract DNA repair gene aberrations (GAs) occur in several cancers, may be prognostic and are actionable. We investigated the frequency of DNA repair GAs in gallbladder cancer (GBC), association with tumor mutational burden (TMB), microsatellite instability (MSI), programmed cell death protein 1 (PD-1), and its ligand (PD-L1) expression. Comprehensive genomic profiling (CGP) of 760 GBC was performed. We investigated GAs in 19 DNA repair genes including direct DNA repair genes (ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, and RAD50) and caretaker genes (BAP1, CDK12, MLL3, TP53, and BLM) and classified patients into 3 groups based on TMB level: low (< 5.5 mutations/Mb), intermediate (5.5–19.5 mutations/Mb), and high (≥ 19.5 mutations/Mb). We assessed MSI status and PD-1 & PD-L1 expression. 658 (86.6%) had at least 1 actionable GA. Direct DNA repair gene GAs were identified in 109 patients (14.2%), while 476 (62.6%) had GAs in caretaker genes. Both direct and caretaker DNA repair GAs were significantly associated with high TMB (P = 0.0005 and 0.0001, respectively). Tumor PD-L1 expression was positive in 119 (15.6%), with 17 (2.2%) being moderate or high. DNA repair GAs are relatively frequent in GBC and associated with coexisting actionable mutations and a high TMB.Reham Abdel-WahabTimothy A. YapRussell MadisonShubham PantMatthew CookeKai WangHaitao ZhaoTanios Bekaii-SaabElif KaratasLawrence N. KwongFunda Meric-BernstamMitesh BoradMilind JavleNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-8 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Reham Abdel-Wahab Timothy A. Yap Russell Madison Shubham Pant Matthew Cooke Kai Wang Haitao Zhao Tanios Bekaii-Saab Elif Karatas Lawrence N. Kwong Funda Meric-Bernstam Mitesh Borad Milind Javle Genomic profiling reveals high frequency of DNA repair genetic aberrations in gallbladder cancer
description	Abstract DNA repair gene aberrations (GAs) occur in several cancers, may be prognostic and are actionable. We investigated the frequency of DNA repair GAs in gallbladder cancer (GBC), association with tumor mutational burden (TMB), microsatellite instability (MSI), programmed cell death protein 1 (PD-1), and its ligand (PD-L1) expression. Comprehensive genomic profiling (CGP) of 760 GBC was performed. We investigated GAs in 19 DNA repair genes including direct DNA repair genes (ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, and RAD50) and caretaker genes (BAP1, CDK12, MLL3, TP53, and BLM) and classified patients into 3 groups based on TMB level: low (< 5.5 mutations/Mb), intermediate (5.5–19.5 mutations/Mb), and high (≥ 19.5 mutations/Mb). We assessed MSI status and PD-1 & PD-L1 expression. 658 (86.6%) had at least 1 actionable GA. Direct DNA repair gene GAs were identified in 109 patients (14.2%), while 476 (62.6%) had GAs in caretaker genes. Both direct and caretaker DNA repair GAs were significantly associated with high TMB (P = 0.0005 and 0.0001, respectively). Tumor PD-L1 expression was positive in 119 (15.6%), with 17 (2.2%) being moderate or high. DNA repair GAs are relatively frequent in GBC and associated with coexisting actionable mutations and a high TMB.
format	article
author	Reham Abdel-Wahab Timothy A. Yap Russell Madison Shubham Pant Matthew Cooke Kai Wang Haitao Zhao Tanios Bekaii-Saab Elif Karatas Lawrence N. Kwong Funda Meric-Bernstam Mitesh Borad Milind Javle
author_facet	Reham Abdel-Wahab Timothy A. Yap Russell Madison Shubham Pant Matthew Cooke Kai Wang Haitao Zhao Tanios Bekaii-Saab Elif Karatas Lawrence N. Kwong Funda Meric-Bernstam Mitesh Borad Milind Javle
author_sort	Reham Abdel-Wahab
title	Genomic profiling reveals high frequency of DNA repair genetic aberrations in gallbladder cancer
title_short	Genomic profiling reveals high frequency of DNA repair genetic aberrations in gallbladder cancer
title_full	Genomic profiling reveals high frequency of DNA repair genetic aberrations in gallbladder cancer
title_fullStr	Genomic profiling reveals high frequency of DNA repair genetic aberrations in gallbladder cancer
title_full_unstemmed	Genomic profiling reveals high frequency of DNA repair genetic aberrations in gallbladder cancer
title_sort	genomic profiling reveals high frequency of dna repair genetic aberrations in gallbladder cancer
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/cdca34fc38034e9aa293b19e7e061208
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Genomic profiling reveals high frequency of DNA repair genetic aberrations in gallbladder cancer

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