TY - JOUR
T1 - Genomic characterization of co-existing neoplasia and carcinoma lesions reveals distinct evolutionary paths of gallbladder cancer
AU - Lin, Jianzhen
AU - Peng, Xinxin
AU - Dong, Kun
AU - Long, Junyu
AU - Guo, Xuejiao
AU - Li, Hongyue
AU - Bai, Yi
AU - Yang, Xu
AU - Wang, Dongxu
AU - Lu, Xin
AU - Mao, Yilei
AU - Sang, Xinting
AU - Ji, Xuwo
AU - Zhao, Haitao
AU - Liang, Han
N1 - Funding Information:
This study is supported by a faculty scholar award from the University of Texas MD Anderson Cancer Center (to H. Liang), an International Science and Technology Cooperation Project (2016YFE0107100 to H. Zhao), CAMS Innovation Fund for Medical Science (CIFMS, 2017-I2M-4-003 to H. Zhao), National Ten-thousand Talent Program (to H. Zhao), Beijing Science and Technology Cooperation Special Award Subsidy Project (to H. Zhao), and CAMS Initiative for Innovative Medicine (CAMS-2018-I2M-3-001, to H. Zhao). We gratefully acknowledge the support from the Suzhou New District, Jiangsu Province, China (to X.J.). We thank Kamalika Mojumdar for editorial assistance.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Gallbladder carcinoma is the most common cancer of the biliary tract with dismal survival largely due to delayed diagnosis. Biliary tract intraepithelial neoplasia (BilIN) is the common benign tumor that is suspected to be precancerous lesions. However, the genetic and evolutionary relationships between BilIN and carcinoma remain unclear. Here we perform whole-exome sequencing of coexisting low-grade BilIN (adenoma), high-grade BilIN, and carcinoma lesions, and normal tissues from the same patients. We identify aging as a major factor contributing to accumulated mutations and a critical role of CTNNB1 mutations in these tumors. We reveal two distinct carcinoma evolutionary paths: carcinoma can either diverge earlier and evolve more independently or form through the classic adenoma/dysplasia-carcinoma sequence model. Our analysis suggests that extensive loss-of-heterozygosity and mutation events in the initial stage tend to result in a cancerous niche, leading to the subsequent BilIN-independent path. These results reframes our understanding of tumor transformation and the evolutionary trajectory of carcinogenesis in the gallbladder, laying a foundation for the early diagnosis and effective treatment of gallbladder cancer.
AB - Gallbladder carcinoma is the most common cancer of the biliary tract with dismal survival largely due to delayed diagnosis. Biliary tract intraepithelial neoplasia (BilIN) is the common benign tumor that is suspected to be precancerous lesions. However, the genetic and evolutionary relationships between BilIN and carcinoma remain unclear. Here we perform whole-exome sequencing of coexisting low-grade BilIN (adenoma), high-grade BilIN, and carcinoma lesions, and normal tissues from the same patients. We identify aging as a major factor contributing to accumulated mutations and a critical role of CTNNB1 mutations in these tumors. We reveal two distinct carcinoma evolutionary paths: carcinoma can either diverge earlier and evolve more independently or form through the classic adenoma/dysplasia-carcinoma sequence model. Our analysis suggests that extensive loss-of-heterozygosity and mutation events in the initial stage tend to result in a cancerous niche, leading to the subsequent BilIN-independent path. These results reframes our understanding of tumor transformation and the evolutionary trajectory of carcinogenesis in the gallbladder, laying a foundation for the early diagnosis and effective treatment of gallbladder cancer.
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U2 - 10.1038/s41467-021-25012-9
DO - 10.1038/s41467-021-25012-9
M3 - Article
C2 - 34362903
AN - SCOPUS:85112623137
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4753
ER -