Intrahepatic Cholangiocarcinoma: Genomic Heterogeneity Between Eastern and Western Patients

Abstract

PURPOSE Intrahepatic cholangiocarcinoma (IHCCA), a global health problem, is increasing in incidence and has differing etiologies worldwide. Next-generation sequencing (NGS) is rapidly being incorporated into the clinical management of biliary cancers. IHCCA is enriched with actionable mutations, and there are several promising targeted therapies under development. NGS data from Asia, where IHCCA is most prevalent, are limited. METHODS Comprehensive genomic profiling of formalin-fixed paraffin-embedded tumor tissue from 164 Asian and 283 Western patients with IHCCA was performed using NGS. We measured the distribution of DNA repair genetic aberrations (GAs) in IHCCA, along with actionable mutations. Also, we evaluated the association between DNA repair GAs and tumor mutation burden (TMB). Based on the TMB status, patients were distinguished into 3 levels: low (< 6 mut/Mb), intermediate (6-10 mut/Mb), and high (TMB-H; ≥ 10 mut/Mb). RESULTS Seventy-two percent of Asian patients had ≥ 1 actionable GA, with a significantly higher frequency in KMT2C , BRCA1/2, and DDR2 compared with Western patients ( P = .02, .003, and .003, respectively); 60.9% of Western patients had ≥ 1 actionable GA and higher frequency of CDKN2A/B and IDH1/2 GAs ( P = .0004 and < .001, respectively). GAs in nuclear factor kappa B pathway regulators and DNA repair genes occurred more frequently in Asian patients ( P = .006 and .001, respectively). There was a higher frequency of TMB-H in Asian compared with the Western cohort (12.2% v 5.9%; P = .07). CONCLUSION A higher burden of DNA repair mutations and frequency of patients with TMB-H in the Asian IHCCA cohort compared with the Western patients suggests a potential role for DNA repair and immune checkpoint inhibitors in the Asian population. Future clinical trials should account for this genetic heterogeneity.

Comprehensive Analysis of Genomic Mutation Signature and Tumor Mutation Burden for Prognosis of Intrahepatic Cholangiocarcinoma

“…Previous studies have reported comprehensive molecular alterations in biliary tract cancers [18,29]. In our study, the most relevant mutation was TP53 (26.7%), followed by TTN (20.7%), KRAS (19.1%), MUC2 (14.5%) and ARID1A (12.9%), which was consistent with Cao et al [31]. We also found some special mutation genes of iCCA in our study, such as IDH1 (7.5%), BAP1 (9.1%), PBRM1 (7.2%) and EPHA2 (7.9%).…”

“…We identi ed the median number of TMB in iCCAs was 1.25 (range 0.03-54.74). A large-scale examination of TMB on iCCA patients has been reported by Cao et al [31]. They analyzed the frequency and type of genetic aberrations in detail by comprehensive genomic profiling, and found the genomic heterogeneity between eastern and western patients of iCCA, but the relationship between TMB and prognosis was not mentioned.…”

Biliary Tract Cancers: Molecular Heterogeneity and New Treatment Options

“…In contrast, FGFR2-positive tumors seem to associate with BAP1 mutations [39]. In addition, molecular iCCA findings seem to vary depending on etiology, as demonstrated by a recent study that highlights a strong genetic heterogeneity between Western and Asian patients [41].…”

Targeted Therapies in Advanced Biliary Tract Cancer: An Evolving Paradigm

“…Genomic profile also varies considerably based on geographical location. A recently published study compared genomic profiling of 164 Chinese patients and 283 Western patients with iCCA [32]. The study reported a higher rate of mutations involving the DNA repair genes and higher tumor mutation burden (TMB) values (>10 mut/Mb) in the Chinese cohort, compared to the Western cohort.…”