Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors
We aimed to elucidate the evolutionary trajectories of gallbladder adenocarcinoma (GBAC) using multi-regional and longitudinal tumor samples. Using whole-exome sequencing data, we constructed phylogenetic trees in each patient and analyzed mutational signatures. A total of 11 patients including 2 rapid autopsy cases were enrolled. The most frequently altered gene in primary tumors was ERBB2 and TP53 (54.5%), followed by FBXW7 (27.3%). Most mutations in frequently altered genes in primary tumors were detectable in concurrent precancerous lesions (biliary intraepithelial neoplasia, BilIN), but a substantial proportion was subclonal. Subclonal diversity was common in BilIN (n=4). However, among subclones in BilIN, a certain subclone commonly shrank in concurrent primary tumors. In addition, selected subclones underwent linear and branching evolution, maintaining subclonal diversity. Combined analysis with metastatic tumors (n=11) identified branching evolution in 9 patients (81.8%). Of these, 8 patients (88.9%) had a total of 11 subclones expanded at least 7-fold during metastasis. These subclones harbored putative metastasis-driving mutations in cancer-related genes such as SMAD4, ROBO1, and DICER1. In mutational signature analysis, 6 mutational signatures were identified: 1, 3, 7, 13, 22, and 24 (cosine similarity >0.9). Signatures 1 (age) and 13 (APOBEC) decreased during metastasis while signatures 22 (aristolochic acid) and 24 (aflatoxin) were relatively highlighted. Subclonal diversity arose early in precancerous lesions and clonal selection was a common event during malignant transformation in GBAC. However, selected cancer clones continued to evolve and thus maintained subclonal diversity in metastatic tumors.
The raw sequence data underlying this manuscript are available as fastq files at the NCBI SRA database under the BioProject number PRJNA821382.
Whole-exome sequencing of gallbladder carcinomaNCBI SRA, PRJNA821382.
Gallbladder Cancer (MSK, Cancer 2018)cBioPortal, Gallbladder Cancer (MSK, Cancer 2018).
Gallbladder Carcinoma (Shanghai, Nat Genet 2014)cBioPortal, Gallbladder Carcinoma (Shanghai, Nat Genet 2014).
Article and author information
Seoul National University Bundang Hospital Research Fund (No. 16-2021-001)
- Ji-Won Kim
Small Grant for Exploratory Reserach (NRF-2018R1D1A1A02086240)
- Ji-Won Kim
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Human subjects: This study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Seoul National University Bundang Hospital (Number: B-1902/522-303). Informed consent was waived because of the retrospective and anonymous nature of the study.
- Samra Turajlic, The Francis Crick Institute, United Kingdom
- Received: March 14, 2022
- Preprint posted: April 1, 2022 (view preprint)
- Accepted: December 6, 2022
- Accepted Manuscript published: December 8, 2022 (version 1)
- Accepted Manuscript updated: December 16, 2022 (version 2)
- Version of Record published: December 21, 2022 (version 3)
© 2022, Kang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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