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

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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article number22087
JournalScientific reports
Volume10
Issue number1
DOIs
StatePublished - Dec 2020

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Genomic profiling reveals high frequency of DNA repair genetic aberrations in gallbladder cancer'. Together they form a unique fingerprint.

Cite this