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 (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.

PD-L1, TMB, MSI, and Other Predictors of Response to Immune Checkpoint Inhibitors in Biliary Tract Cancer

“…Based on these premises, mutations in DDR genes have been recently studied in BTC, reporting interesting data on their possible role and their impact on modifying the responses to ICIs [ 62 ]. First, the proportion of DDR gene mutations in BTC has been reported to occur in approximately 30% of patients, while Breast Related Cancer Antigens (BRCA) mutations seem to fluctuate between 1% and 7%, according to previous reports [ 63 , 64 , 65 ]. A recently published study by Spizzo and colleagues analyzed tumor samples from 1292 BTC patients (iCCA, n = 746; eCCA, n = 189; GBC, n = 353) using next-generation sequencing [ 66 ].…”

Analytic validation and clinical utilization of the comprehensive genomic profiling test, GEM ExTra®

“…Eighteen of 30 tumor types harbored at least 1 sample with high TMB. However, we found tumors of the appendix and gallbladder associated with low TMB only, with some studies suggesting low mutagenic burden for these tumor types [ 20 , 21 ].…”

Gallbladder Cancer: Current Insights in Genetic Alterations and Their Possible Therapeutic Implications

“…Out of 92 articles, 30 were excluded due to: no data for adenocarcinoma of the gallbladder available (N = 12), overlapping cohorts (N = 8), the wrong type of article (N = 5), no genetic alteration frequency data available (N = 3), wrong study population (N = 1), and not written in English (N = 1). A total of 62 articles were included for final data extraction, describing a total of 3893 GBC samples from individual patients [ 18 , 19 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ,…”

“…Only frequently occurring genetic alterations (>5% [ 18 , 19 ] across all studies and in >5 of all included GBC samples) were included. Per genetic alteration, weighted average of reported frequencies was calculated by using the number of samples analyzed in a study as the weight.…”

“…Out of 92 articles, 30 were excluded due to: no data for adenocarcinoma of the gallbladder available (N = 12), overlapping cohorts (N = 8), the wrong type of article (N = 5), no genetic alteration frequency data available (N = 3), wrong study population (N = 1), and not written in English (N = 1). A total of 62 articles were included for final data extraction, describing a total of 3893 GBC samples from individual patients [18,19,. A2 shows the results for all frequent gene mutations.…”