Extrahepatic Cholangiocarcinoma: Genomic Variables Associated With Anatomic Location and Outcome

Area of Science:

• Genomic analysis of extrahepatic cholangiocarcinoma (ECA).
• Comparative genomics of perihilar cholangiocarcinoma (PCA) and distal cholangiocarcinoma (DCA).

Background:

• Extrahepatic cholangiocarcinoma (ECA) is a rare and aggressive biliary tract cancer.
• Understanding the genomic landscape of different ECA subtypes, PCA and DCA, is crucial for targeted therapies and improved patient outcomes.
• Previous studies have suggested potential genomic differences, but a comprehensive comparison is needed.

Purpose of the Study:

• To delineate the genomic distinctions between perihilar cholangiocarcinoma (PCA) and distal cholangiocarcinoma (DCA).
• To identify specific genomic alterations that serve as determinants of survival in ECA patients.
• To investigate the association between genomic profiles, clinicopathologic features, and patient outcomes.

Main Methods:

• Targeted next-generation sequencing was performed on tumor tissue from 224 consecutive ECA patients (2004-2022).
• Patients were stratified by anatomic subsite (PCA/DCA), disease extent (resectable/unresectable), and treatment received.
• Cox proportional hazards regression models were employed to analyze associations between genomic alterations, clinicopathologic variables, and survival outcomes.

Main Results:

• Distal cholangiocarcinoma (DCA) exhibited a higher frequency of TP53 alterations (69% vs. 33% in PCA) and epigenetic pathway alterations (45% vs. 29%).
• While KRAS alterations were similar, DCA showed enrichment in KRAS G12D mutations (19% vs. 9%).
• In unresectable disease, CDKN2A alterations (HR 2.59) and APC alterations (HR 5.11) were significantly associated with reduced survival. Irresectability, CDKN2Aalt, and APCalt were poor prognostic factors for the entire cohort.

Conclusions:

• CDKN2A and APC alterations are significant predictors of poor survival in extrahepatic cholangiocarcinoma (ECA), particularly in advanced stages.
• Perihilar cholangiocarcinoma (PCA) and distal cholangiocarcinoma (DCA) share considerable genetic similarities, supporting their co-analysis in future genomic studies.
• These findings highlight potential therapeutic targets and underscore the importance of considering specific genomic alterations in prognostic assessments for ECA.