Genomic characterization of co-existing neoplasia and carcinoma lesions reveals distinct evolutionary paths of gallbladder cancer

Jianzhen Lin, Xinxin Peng, Kun Dong, Junyu Long, Xuejiao Guo, Hongyue Li, Yi Bai, Xu Yang, Dongxu Wang, Xin Lu, Yilei Mao, Xinting Sang, Xuwo Ji, Haitao Zhao () and Han Liang ()
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Jianzhen Lin: Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC)
Xinxin Peng: Precision Scientific (Beijing) Co. Ltd.
Kun Dong: Peking University Cancer Hospital & Institute
Junyu Long: Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC)
Xuejiao Guo: Precision Scientific (Beijing) Co. Ltd.
Hongyue Li: Precision Scientific (Beijing) Co. Ltd.
Yi Bai: Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC)
Xu Yang: Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC)
Dongxu Wang: Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC)
Xin Lu: Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC)
Yilei Mao: Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC)
Xinting Sang: Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC)
Xuwo Ji: Precision Scientific (Beijing) Co. Ltd.
Haitao Zhao: Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC)
Han Liang: The University of Texas MD Anderson Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25012-9

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