PMID- 35130881 OWN - NLM STAT- MEDLINE DCOM- 20220323 LR - 20220323 IS - 1741-7015 (Electronic) IS - 1741-7015 (Linking) VI - 20 IP - 1 DP - 2022 Feb 7 TI - Common DNA methylation changes in biliary tract cancers identify subtypes with different immune characteristics and clinical outcomes. PG - 64 LID - 10.1186/s12916-021-02197-w [doi] LID - 64 AB - BACKGROUND: DNA methylation-associated studies on biliary tract cancer (BTC), including cholangiocarcinoma (CCA) and gallbladder cancer (GBC), may improve the BTC classification scheme. We proposed to identify the shared methylation changes of BTCs and investigate their associations with genomic aberrations, immune characteristics, and survival outcomes. METHODS: Multi-dimensional data concerning mutation, DNA methylation, immune-related features, and clinical data of 57 CCAs and 48 GBCs from Eastern Hepatobiliary Surgery Hospital (EHSH) and 36 CCAs in the TCGA-CHOL cohort were analyzed. RESULTS: In our cohort including 24 intrahepatic CCAs (iCCAs), 20 perihilar CCAs (pCCAs), 13 distal CCAs (dCCAs), and 48 GBCs, 3369 common differentially methylated regions (DMRs) were identified by comparing tumor and non-tumor samples. A lower level of methylation changes of these common DMRs was associated with fewer copy number variations, fewer mutational burden, and remarkably longer overall survival (OS, hazard ratio [HR] = 0.07, 95% confidence interval [CI] 0.01-0.65, P = 0.017). Additionally, a 12-marker model was developed and validated for prognostication after curative surgery (HR = 0.21, 95% CI 0.10-0.43, P < 0.001), which exhibited undifferentiated prognostic effects in subgroups defined by anatomic location (iCCAs, d/pCCAs, GBCs), TNM stage, and tumor purity. Its prognostic utility remained significant in multivariable analysis (HR = 0.26, 95% CI 0.11-0.59, P = 0.001). Moreover, the BTCs with minimal methylation changes exhibited higher immune-related signatures, infiltration of CD8(+) lymphocytes, and programmed death-ligand 1 (PD-L1) expression, indicating an inflamed tumor immune microenvironment (TIME) with PD-L1 expression elicited by immune attack, potentially suggesting better immunotherapy efficacy. CONCLUSIONS: In BTCs, DNA methylation is a powerful tool for molecular classification, serving as a robust indicator of genomic aberrations, survival outcomes, and tumor immune microenvironment. Our integrative analysis provides insights into the prognostication after curative surgery and patient selection for immunotherapy. CI - (c) 2022. The Author(s). FAU - Qiu, Zhiquan AU - Qiu Z AD - Department of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery Hospital, Secondary Military Medicine University, No. 225 Changhai Road, Shanghai, 200438, China. FAU - Ji, Jun AU - Ji J AD - Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Secondary Military Medicine University, Shanghai, China. FAU - Xu, Yu AU - Xu Y AD - Department of Medicine, Burning Rock Biotech, Guangzhou, China. FAU - Zhu, Yan AU - Zhu Y AD - Department of Pathology, Changhai Hospital, Shanghai, China. FAU - Gao, Chunfang AU - Gao C AD - Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Secondary Military Medicine University, Shanghai, China. FAU - Wang, Guoqiang AU - Wang G AD - Department of Medicine, Burning Rock Biotech, Guangzhou, China. FAU - Li, Chengcheng AU - Li C AD - Department of Medicine, Burning Rock Biotech, Guangzhou, China. FAU - Zhang, Yuzi AU - Zhang Y AD - Department of Medicine, Burning Rock Biotech, Guangzhou, China. FAU - Zhao, Jing AU - Zhao J AD - Department of Medicine, Burning Rock Biotech, Guangzhou, China. FAU - Wang, Chenyang AU - Wang C AD - Department of Research and Development, Burning Rock Biotech, Guangzhou, China. FAU - Wen, Xiaofang AU - Wen X AD - Department of Medicine, Burning Rock Biotech, Guangzhou, China. FAU - Zhang, Zhou AU - Zhang Z AD - Department of Bioinformatics, Burning Rock Biotech, Guangzhou, China. FAU - Li, Bingsi AU - Li B AD - Department of Research and Development, Burning Rock Biotech, Guangzhou, China. FAU - Zhang, Zhihong AU - Zhang Z AD - Department of Research and Development, Burning Rock Biotech, Guangzhou, China. FAU - Cai, Shangli AU - Cai S AD - Department of Medicine, Burning Rock Biotech, Guangzhou, China. FAU - Li, Bin AU - Li B AD - Department of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery Hospital, Secondary Military Medicine University, No. 225 Changhai Road, Shanghai, 200438, China. libinjeff@126.com. FAU - Jiang, Xiaoqing AU - Jiang X AD - Department of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery Hospital, Secondary Military Medicine University, No. 225 Changhai Road, Shanghai, 200438, China. jxq1225@sina.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220207 PL - England TA - BMC Med JT - BMC medicine JID - 101190723 SB - IM MH - *Bile Duct Neoplasms/drug therapy/genetics/pathology MH - Bile Ducts, Intrahepatic/pathology MH - *Biliary Tract Neoplasms/drug therapy/genetics/pathology MH - DNA Copy Number Variations MH - DNA Methylation/genetics MH - Humans MH - Tumor Microenvironment PMC - PMC8822710 OTO - NOTNLM OT - Biliary tract cancer OT - DNA methylation OT - Immune characteristic OT - Prognostication COIS- Y. Xu, G. Wang, C. Li, Y. Zhang, J. Zhao, C. Wang, X. Wen, Z. Zhang, B. Li, H. Zhang, Z. Zhang, and S. Cai are employees of Burning Rock Biotech. The other authors declare that they have no competing interests.. EDAT- 2022/02/09 06:00 MHDA- 2022/03/24 06:00 PMCR- 2022/02/07 CRDT- 2022/02/08 05:37 PHST- 2021/09/23 00:00 [received] PHST- 2021/11/23 00:00 [accepted] PHST- 2022/02/08 05:37 [entrez] PHST- 2022/02/09 06:00 [pubmed] PHST- 2022/03/24 06:00 [medline] PHST- 2022/02/07 00:00 [pmc-release] AID - 10.1186/s12916-021-02197-w [pii] AID - 2197 [pii] AID - 10.1186/s12916-021-02197-w [doi] PST - epublish SO - BMC Med. 2022 Feb 7;20(1):64. doi: 10.1186/s12916-021-02197-w.