Comparative analysis of genomic profiles and clinical outcomes in cholangiocarcinoma and gallbladder cancer

Q: What genomic alterations are most frequent across biliary tract carcinoma (BTC) patients?

The most frequently altered genes include TP53 (56.6%), KRAS (27.9%), CDKN2A (21.3%), TERT (17.8%), and MCL1 (14.3%).

Q: How do genomic profiles differ between cholangiocarcinoma (CCA) and gallbladder cancer (GBC)?

CCA shows higher ARID1A and PBRM1 mutations and more MCL1 amplifications, while GBC shows higher frequencies of TP53 alterations, ARID2, TERT, CCNE1 amplifications, and SOX2 amplifications, with enrichment of DDR and p53 signaling pathways.

Q: Which factors are linked to overall survival in the MSKCC cohort?

In the MSKCC cohort, high tumor mutational burden correlated with poorer overall survival, while PBRM1 mutations were associated with improved survival.

Sep 22, 2026

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Cholangiocarcinoma (CCA) and gallbladder cancer (GBC) show distinct biology and treatment responses, likely shaped by differences in genomic landscapes. A retrospective analysis of next-generation sequencing from 258 patients with biliary tract carcinoma (188 CCA, 70 GBC) was performed, with an external MSKCC cohort for comparison. Key alterations included TP53, KRAS, CDKN2A, TERT, and MCL1. CCA featured ARID1A and PBRM1 mutations and MCL1 amplification, whereas GBC had higher TP53, ARID2, TERT, CCNE1, and SOX2 alterations, enriched DDR and p53 signaling pathways, and actionable alterations in 39.9%. CCA also showed longer OS than GBC.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages12

Reading Time30 min

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Comparative genomic alterations in BTC subtypes

Frequency patterns of key mutated and amplified genes

Actionable genomic alterations and germline findings

Clinical outcome associations and cross-cohort validation

Overall survival differences between CCA and GBC

Tumor mutational burden and PBRM1 effects in MSKCC

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN Comparative analysis of genomic profiles and clinical outcomesin cholangiocarcinoma and gallbladder cancer Weiqun Lu1,6, Rujiao Liu2,3,6, Cuicui Liu4, Jiaohui Pang4, Jiani Yin4 & Zhe Zhang2,5􀀍 Cholangiocarcinoma (CCA) and gallbladder cancer (GBC) exhibit distinct biological behaviors and treatment responses, potentially driven by differences in their genomic landscapes. However, genomic investigations of biliary tract carcinoma (BTC) remain limited. A retrospective analysis was performed on next-generation sequencing data from 258 patients with BTC (188 with CCA, 70 with GBC), with an external cohort from Memorial Sloan-Kettering Cancer Center (MSKCC cohort) included for comparison. The most frequently altered genes in BTC included TP53 (56.6%), KRAS (27.9%), CDKN2A (21.3%), TERT (17.8%), and MCL1 (14.3%). CCA was predominantly characterized by mutations in ARID1A (15.4% vs. 5.7%, P = 0.04) and PBRM1 (10.1% vs. 0%, P = 0.003), as well as MCL1 amplifications (17.0% vs. 5.7%, P = 0.03), while GBC showed higher frequencies of TP53 alterations (78.6% vs. 47.9%, P < 0.001), ARID2 (15.7% vs. 3.7%, P = 0.002), TERT (24.3% vs. 11.2%, P = 0.02), CCNE1 amplifications (21.4% vs. 2.7%, P < 0.001), and SOX2 amplifications (4.3% vs. 0%, P = 0.02) . GBC also exhibited an enrichment of alterations in the DNA damage response (DDR) (84.3% vs. 71.3%, P = 0.04) and p53 signaling (88.6% vs. 59.6%, P < 0.001) pathways. Additionally, 39.9% of patients with BTC harbored at least one actionable genomic alteration. Germline variants were detected in 7.0%(18/258) of patients, with the majority occurring in DDR (61.1%) and p53 (22.2%) pathways. Comparisons with the MSKCC cohort revealed similar genomic features and alterations. Patients with CCA exhibited significantly longer overall survival (OS) than patients with GBC (median OS, 41.2 vs. 24.3 months, P = 0.003) . In the MSKCC cohort, high tumor mutational burden (TMB-Hmed) correlated with poorer OS (HR = 1.43, P = 0.01), while PBRM1 mutations were associated with improved survival (HR = 0.50, P = 0.02). This study underscores the distinct genomic profiles of GBC and CCA, offering valuable insights into the molecular underpinnings of these aggressive cancers and supporting the development of precision medicine strategies. Keywords Biliary tract carcinoma, Cholangiocarcinoma, Gallbladder cancer, Genetic profiling, Prognostic biomarkers Biliary tract carcinoma (BTC) is an aggressive malignancy originating from the epithelial cells lining the bile ducts, encompassing cholangiocarcinoma (CCA) and gallbladder cancer (GBC) . In recent years, both the incidence and mortality rates of BTC have risen significantly1,2. Due to the lack of early symptoms, most patients are diagnosed at advanced stages3, resulting in a generally poor prognosis, with a 5-year survival rate of less than 10% for those with unresectable BTC4,5. Although non-radical surgeries and traditional systemic therapies can offer life-prolonging benefits, the overall prognosis for patients with advanced BTC treated with conventional regimens remains dismal, with no substantial survival improvements observed in recent years6. Consequently, there is an urgent need for novel therapeutic strategies. Previous molecular profiling studies utilizing whole- 1Department of Gastrointestinal Surgery Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, People’s Republic of China. 2Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong-An Road, Shanghai 200032, People’s Republic of China. 3Phase I Clinical Trial Center, Fudan University Shanghai Cancer Center, Shanghai 200032, People’s Republic of China. 4Geneseeq Research Institute, Nanjing Geneseeq Technology Inc, Nanjing 210032, Jiangsu, People’s Republic of China. 5Department of Medical Oncology, Fudan University Shanghai Cancer

FAQs

What genomic alterations are most frequent across biliary tract carcinoma (BTC) patients?

The most frequently altered genes include TP53 (56.6%), KRAS (27.9%), CDKN2A (21.3%), TERT (17.8%), and MCL1 (14.3%).

How do genomic profiles differ between cholangiocarcinoma (CCA) and gallbladder cancer (GBC)?

CCA shows higher ARID1A and PBRM1 mutations and more MCL1 amplifications, while GBC shows higher frequencies of TP53 alterations, ARID2, TERT, CCNE1 amplifications, and SOX2 amplifications, with enrichment of DDR and p53 signaling pathways.

Which factors are linked to overall survival in the MSKCC cohort?

In the MSKCC cohort, high tumor mutational burden correlated with poorer overall survival, while PBRM1 mutations were associated with improved survival.

Sep 22, 2026

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