ABSTRACT
Background
Extrahepatic cholangiocarcinoma (ECC) is classified into two subtypes based on anatomic origin: distal extrahepatic (DECC) and perihilar (PHCC) cholangiocarcinoma. This study aimed to shed light on its genomic and transcriptomic profiles.
Research Design and Methods
The genomic alterations of 99 ECC (47 PHCC and 52 DECC) were investigated by next-generation sequencing of 96 genes. A subgroup of cases, representative of each subtype, was further investigated using transcriptomic analysis. Bioinformatics tools were applied for clustering and pathway analysis and defining the immune composition of the tumor microenvironment.
Results
PHCC had more frequent KRAS mutations (p = 0.0047), whereas TP53 mutations were more common in DECC (p = 0.006). Potentially actionable alterations included high-tumor mutational burden and/or microsatellite instability (7.1%), PI3KCA mutations (8.1%), and MYC (10.1%) and ERBB2 amplification (5.1%). The transcriptomic profiles showed the presence of three distinct clusters, which followed the anatomic origin and differed in immune microenvironment. DECC appeared to contain two distinct tumor subgroups, one enriched for druggable alterations and one lacking actionable opportunities.
Conclusions
This study provides new insights into the molecular landscape and the actionable alterations of ECC. Our findings represent a step toward improved ECC molecular taxonomy and therapeutic strategies for precision oncology.
Acknowledgments
The study was supported by the Associazione Italiana Ricerca Cancro [AIRC grant n. 12182]. The funding agencies had no role in the collection, analysis and interpretation of data and in the writing of the manuscript. This paper is dedicated to Dr. Fabio Bagante, a great man and a brilliant researcher, who will always be with us. We used the Editing Service of Taylor & Francis online for improving the presentation of our study.
Disclosure statement
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose
Author contributions
MS, AS, CL: study conception and design; BR, MM, AS, CL: histological revision and morphological analysis; FB, AM, SC, AG, AR, AS, CL: clinico-pathological analysis; MS, SB, BR, MB, SP, GP, PM, AM, CL: immunohistochemical and FISH analysis; MS, SB, CV, SVT, CC, FB, AM, AS, CL: molecular analysis; all authors: data elaboration; all authors: data interpretation and discussion; MS, CL: writing original draft; all authors: final editing and approval of the current version of the manuscript.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Supplemental data
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