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 ra...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/78636 |
| _version_ | 1811288578465988608 |
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| author | Minsu Kang Hee Young Na Soomin Ahn Ji-Won Kim Sejoon Lee Soyeon Ahn Ju Hyun Lee Jeonghwan Youk Haesook T Kim Kui-Jin Kim Koung Jin Suh Jun Suh Lee Se Hyun Kim Jin Won Kim Yu Jung Kim Keun-Wook Lee Yoo-Seok Yoon Jee Hyun Kim Jin-Haeng Chung Ho-Seong Han Jong Seok Lee |
| author_facet | Minsu Kang Hee Young Na Soomin Ahn Ji-Won Kim Sejoon Lee Soyeon Ahn Ju Hyun Lee Jeonghwan Youk Haesook T Kim Kui-Jin Kim Koung Jin Suh Jun Suh Lee Se Hyun Kim Jin Won Kim Yu Jung Kim Keun-Wook Lee Yoo-Seok Yoon Jee Hyun Kim Jin-Haeng Chung Ho-Seong Han Jong Seok Lee |
| author_sort | Minsu Kang |
| collection | DOAJ |
| description | 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 nine patients (81.8%). Of these, eight patients (88.9%) had a total of 11 subclones expanded at least sevenfold during metastasis. These subclones harbored putative metastasis-driving mutations in cancer-related genes such as SMAD4, ROBO1, and DICER1. In mutational signature analysis, six 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. |
| first_indexed | 2024-04-13T03:38:39Z |
| format | Article |
| id | doaj.art-eb1e776b7b494318b86d6c03670cbe69 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-13T03:38:39Z |
| publishDate | 2022-12-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj.art-eb1e776b7b494318b86d6c03670cbe692022-12-22T03:04:14ZengeLife Sciences Publications LtdeLife2050-084X2022-12-011110.7554/eLife.78636Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumorsMinsu Kang0https://orcid.org/0000-0001-6491-2277Hee Young Na1Soomin Ahn2https://orcid.org/0000-0002-1979-4010Ji-Won Kim3https://orcid.org/0000-0001-6426-9074Sejoon Lee4Soyeon Ahn5Ju Hyun Lee6Jeonghwan Youk7Haesook T Kim8Kui-Jin Kim9Koung Jin Suh10Jun Suh Lee11Se Hyun Kim12https://orcid.org/0000-0002-2292-906XJin Won Kim13Yu Jung Kim14Keun-Wook Lee15Yoo-Seok Yoon16Jee Hyun Kim17Jin-Haeng Chung18Ho-Seong Han19Jong Seok Lee20Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaDepartment of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaDepartment of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of KoreaDepartment of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea; Genealogy Inc, Seoul, Republic of KoreaCenter for Precision Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaMedical Research Collaboration Center, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaDepartment of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaDepartment of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaDepartment of Data Science, Dana Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, United StatesBiomedical Research Institute, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaDepartment of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaDepartment of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaDepartment of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaDepartment of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaDepartment of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaDepartment of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaDepartment of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaDepartment of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaDepartment of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaDepartment of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaDepartment of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaWe 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 nine patients (81.8%). Of these, eight patients (88.9%) had a total of 11 subclones expanded at least sevenfold during metastasis. These subclones harbored putative metastasis-driving mutations in cancer-related genes such as SMAD4, ROBO1, and DICER1. In mutational signature analysis, six 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.https://elifesciences.org/articles/78636gallbladder adenocarcinomaclonal evolutioncarcinogenesismetastasis |
| spellingShingle | Minsu Kang Hee Young Na Soomin Ahn Ji-Won Kim Sejoon Lee Soyeon Ahn Ju Hyun Lee Jeonghwan Youk Haesook T Kim Kui-Jin Kim Koung Jin Suh Jun Suh Lee Se Hyun Kim Jin Won Kim Yu Jung Kim Keun-Wook Lee Yoo-Seok Yoon Jee Hyun Kim Jin-Haeng Chung Ho-Seong Han Jong Seok Lee Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors eLife gallbladder adenocarcinoma clonal evolution carcinogenesis metastasis |
| title | Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors |
| title_full | Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors |
| title_fullStr | Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors |
| title_full_unstemmed | Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors |
| title_short | Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors |
| title_sort | gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors |
| topic | gallbladder adenocarcinoma clonal evolution carcinogenesis metastasis |
| url | https://elifesciences.org/articles/78636 |
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