Analysis of genetic alterations of DNA repair genes as prognostic marker of survival in cholangiocarcinoma

Background

The differences in the mutational characteristics of DNA repair genes and their prognostic role in cholangiocarcinoma (CCA) need further evaluation.

Methods

Mutation profiles of 1348 patients of CCA were downloaded from the cBioPortal database, and a dataset was created for the DNA repair genes. Genetic alterations (GA) in the DNA repair genes were filtered for oncogenicity using OncoKB, and all alteration of unknown significance and genes with mutations <10 were excluded from the analyses. Comparisons between the groups were made using the χ2 test or t-test as appropriate. Overall survival (OS) was estimated using Kaplan Meier curves and compared between groups using a log-rank test. The multivariate Cox proportional hazard regression model was used to evaluate prognostic significance among the selected GA.

Results

One hundred fifty-five cases of CCA with GA of oncologic significance in the DNA repair genes were characterized. The most common GA involved BAP1 (N=111, 10.5%), ATM (N=36, 3.4%), and BRCA2 (N=10, 0.9%). The frequency of GA in intrahepatic and extrahepatic CCA (excluding undifferentiated cases) was 11.5% and 3.4% in BAP1, 4.1% and 4.6% in ATM, and 0.7% and 3.4% in BRCA2, respectively. The median OS for BAP1 mutation versus wild type was 40.58 months versus 25.07 months (p=0.05), and ATM mutation versus wild type was 13.08 months versus 26.81 months (p=0.003). The median OS was not reached for BRCA2 mutation, whereas this was 26.68 months for wild type (p=0.008). The mean tumor mutational burden (TMB) was 2.80 ± 4.61 in the entire cohort, 0.31 ± 0.42 in the intrahepatic cohort, and 0.81 ± 3.1 in the extrahepatic cohort (p=0.001). On multivariate analysis, GA in BAP1 was associated with improved OS (HR 0.77, 95% CI 0.61-0.98, p=0.03), while GA in ATM correlated with poor OS (HR 1.57, 95% CI 1.07-2.29, p=0.02). No difference in the OS was observed based on GA in BRCA2 or TMB >10.

Conclusions

GA in DNA repair genes like BAP1 and ATM demonstrate prognostic significance and may represent new therapeutic targets for CCA.