Abstract
Background
Intrahepatic cholangiocarcinoma (IHCCA), a global health problem, is rising in incidence and has differing etiologies worldwide. Next-generation sequencing (NGS) showed that IHCCA is enriched with a relatively high number of actionable mutations with a promising novel targeted therapies anti-tumor activity. However, NGS data from Asia where IHCCA is most prevalent are very limited.
Methods
Comprehensive genomic profiling using NGS on 164 Asian and 283 Western IHCCA paraffin-embedded tumor was performed. We measured the distribution of DNA repair genetic aberrations (GAs) along with coexisting actionable mutations. We classified our patients according to the tumor mutation burden (TMB) score into: TMB-low (<6 mutations/Mb), TMB-intermediate (6–10 mutations/Mb), and TMB-high (>10 mutations/Mb). Then, we assessed the association between DNA repair GAs and TMB.
Results
Among Asian cohort, 118 patients (72%) had ≥1 actionable GA with significantly higher frequency in KMT2C, BRCA1/2, and DDR2 as compared with Western patients (P=0.02, 0.003, and 0.003, respectively). In Western cohort, 154 patients (60.9%) had >1 actionable GA with higher frequency of CDKN2A/B and IDH1/2 GAs (P=0.0004 and <0.001, respectively). Out of 9 most common dysregulated pathways in cancer, GAs in nuclear factor-κB and DNA repair pathways occurred more frequently in Asian patients (P=0.006, and 0.001, respectively). Also, 10.4% of Asian IHCCA patients had TMB-high as compared with 5.7% in Western cohort (P=0.2). Moreover, Asian and Western patients who have combined direct and caretaker DNA repair GAs have a higher rate of TMB-intermediate and TMB-high as compared with patients without DNA repair GAs (P<0.001, and 0.05, respectively).
Conclusions
Comprehensive genomic profiling of IHCCA suggests a higher TMB-high and DNA repair mutation frequency in Asian as compared with the Western patients. Future clinical trials should account for this genetic heterogeneity.
Keywords: Intrahepatic cholangiocarcinoma (IHCCA), Asian, Western, genomic profiling