| Title | Genomic characterization of co-existing neoplasia and carcinoma lesions reveals distinct evolutionary paths of gallbladder cancer |
| Authors | Lin, Jianzhen Peng, Xinxin Dong, Kun Long, Junyu Guo, Xuejiao Li, Hongyue Bai, Yi Yang, Xu Wang, Dongxu Lu, Xin Mao, Yilei Sang, Xinting Ji, Xuwo Zhao, Haitao Liang, Han |
| Affiliation | Chinese Acad Med Sci & Peking Union Med Coll CAMS, Peking Union Med Coll Hosp, Dept Liver Surg, State Key Lab Complex Severe & Rare Dis, Beijing, Peoples R China Nanjing Med Univ, Affiliated Hosp 1, Pancreas Ctr, Pancreas Inst, Nanjing, Peoples R China Precis Sci Beijing Co Ltd, Beijing, Peoples R China Peking Univ Canc Hosp & Inst, Dept Pathol, Key Lab Carcinogenesis & Translat Res, Minist Educ, Beijing, Peoples R China Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA |
| Keywords | PRENEOPLASTIC LESIONS MICROSATELLITE INSTABILITY GENETIC MODEL BETA-CATENIN COPY NUMBER MUTATIONS DYSPLASIA ADENOMAS HETEROZYGOSITY EXPRESSION |
| Issue Date | 6-Aug-2021 |
| Publisher | NATURE COMMUNICATIONS |
| 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. The progression from biliary tract intraepithelial neoplasia (BilIN) to gallbladder carcinoma (GBC) remains unclear. Here the authors use genomics to analyze coexisting GBC lesions, low-grade and high-grade BilINs, revealing two distinct evolutionary paths for GBC development. |
| URI | http://hdl.handle.net/20.500.11897/623450 |
| ISSN | 2041-1723 |
| DOI | 10.1038/s41467-021-25012-9 |
| Indexed | SCI(E) |
| Appears in Collections: | 北京肿瘤医院 |
