Epigenome-wide development and validation of a prognostic methylation score in intrahepatic cholangiocarcinoma based on machine learning strategies.

Intrahepatic cholangiocarcinoma (ICC) adjuvant therapy (AT) machine learning overall survival (OS) prognostic methylation score (PMS)

Journal

Hepatobiliary surgery and nutrition
ISSN: 2304-3881
Titre abrégé: Hepatobiliary Surg Nutr
Pays: China (Republic : 1949- )
ID NLM: 101600750

Informations de publication

Date de publication:
01 Aug 2023
Historique:
received: 13 10 2021
accepted: 23 03 2022
medline: 21 8 2023
pubmed: 21 8 2023
entrez: 21 8 2023
Statut: ppublish

Résumé

Clinical parameter-based nomograms and staging systems provide limited information for the prediction of survival in intrahepatic cholangiocarcinoma (ICC) patients. In this study, we developed a methylation signature that precisely predicts overall survival (OS) after surgery. An epigenome-wide study of DNA methylation based on whole-genome bisulfite sequencing (WGBS) was conducted for two independent cohorts (discovery cohort, n=164; validation cohort, n=170) from three hepatobiliary centers in China. By referring to differentially methylated regions (DMRs), we proposed the concept of prognostically methylated regions (PMRs), which were composed of consecutive prognostically methylated CpGs (PMCs). Using machine learning strategies (Random Forest and the least absolute shrinkage and selector regression), a prognostic methylation score (PMS) was constructed based on 14 PMRs in the discovery cohort and confirmed in the validation cohort. The C-indices of the PMS for predicting OS in the discovery and validation cohorts were 0.79 and 0.74, respectively. In the whole cohort, the PMS was an independent predictor of OS [hazard ratio (HR) =8.12; 95% confidence interval (CI): 5.48-12.04; P<0.001], and the C-index (0.78) of the PMS was significantly higher than that of the Johns Hopkins University School of Medicine (JHUSM) nomogram (0.69, P<0.001), the Eastern Hepatobiliary Surgery Hospital (EHBSH) nomogram (0.67, P<0.001), American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system (0.61, P<0.001), and MEGNA prognostic score (0.60, P<0.001). The patients in quartile 4 of PMS could benefit from adjuvant therapy (AT) (HR =0.54; 95% CI: 0.32-0.91; log-rank P=0.043), whereas those in the quartiles 1-3 could not. However, other nomograms and staging system failed to do so. Further analyses of potential mechanisms showed that the PMS was associated with tumor biological behaviors, pathway activation, and immune microenvironment. The PMS could improve the prognostic accuracy and identify patients who would benefit from AT for ICC patients, and might facilitate decisions in treatment of ICC patients.

Sections du résumé

Background UNASSIGNED
Clinical parameter-based nomograms and staging systems provide limited information for the prediction of survival in intrahepatic cholangiocarcinoma (ICC) patients. In this study, we developed a methylation signature that precisely predicts overall survival (OS) after surgery.
Methods UNASSIGNED
An epigenome-wide study of DNA methylation based on whole-genome bisulfite sequencing (WGBS) was conducted for two independent cohorts (discovery cohort, n=164; validation cohort, n=170) from three hepatobiliary centers in China. By referring to differentially methylated regions (DMRs), we proposed the concept of prognostically methylated regions (PMRs), which were composed of consecutive prognostically methylated CpGs (PMCs). Using machine learning strategies (Random Forest and the least absolute shrinkage and selector regression), a prognostic methylation score (PMS) was constructed based on 14 PMRs in the discovery cohort and confirmed in the validation cohort.
Results UNASSIGNED
The C-indices of the PMS for predicting OS in the discovery and validation cohorts were 0.79 and 0.74, respectively. In the whole cohort, the PMS was an independent predictor of OS [hazard ratio (HR) =8.12; 95% confidence interval (CI): 5.48-12.04; P<0.001], and the C-index (0.78) of the PMS was significantly higher than that of the Johns Hopkins University School of Medicine (JHUSM) nomogram (0.69, P<0.001), the Eastern Hepatobiliary Surgery Hospital (EHBSH) nomogram (0.67, P<0.001), American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system (0.61, P<0.001), and MEGNA prognostic score (0.60, P<0.001). The patients in quartile 4 of PMS could benefit from adjuvant therapy (AT) (HR =0.54; 95% CI: 0.32-0.91; log-rank P=0.043), whereas those in the quartiles 1-3 could not. However, other nomograms and staging system failed to do so. Further analyses of potential mechanisms showed that the PMS was associated with tumor biological behaviors, pathway activation, and immune microenvironment.
Conclusions UNASSIGNED
The PMS could improve the prognostic accuracy and identify patients who would benefit from AT for ICC patients, and might facilitate decisions in treatment of ICC patients.

Identifiants

DOI: 10.21037/hbsn-21-424 PMID: 37601000 PMC: PMC10432305
pubmed: 37601000
doi: 10.21037/hbsn-21-424
pii: hbsn-12-04-478
pmc: PMC10432305
doi:

Types de publication

Journal Article

Langues

eng

Pagination

478-494

Informations de copyright

2023 Hepatobiliary Surgery and Nutrition. All rights reserved.

Déclaration de conflit d'intérêts

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-21-424/coif). The authors have no conflicts of interest to declare.

Références

Nucleic Acids Res. 2017 May 5;45(8):4452-4462
pubmed: 28119415
Hepatology. 2019 May;69(5):2091-2106
pubmed: 30615206
Nature. 2014 Apr 10;508(7495):263-8
pubmed: 24590075
Cancer Control. 2017 Jul-Sep;24(3):1073274817729241
pubmed: 28975832
Nat Rev Gastroenterol Hepatol. 2020 Dec;17(12):755-772
pubmed: 32681074
Clin Cancer Res. 2007 Apr 1;13(7):2254-60
pubmed: 17404110
Cancer Res. 2012 Jun 1;72(11):2901-11
pubmed: 22593196
Oncologist. 2015 Jun;20(6):640-7
pubmed: 25956404
JAMA Surg. 2017 May 17;152(5):e170117
pubmed: 28297009
Cancer Sci. 2020 Feb;111(2):323-333
pubmed: 31799781
J Biol Chem. 2007 Nov 30;282(48):35308-17
pubmed: 17878165
EBioMedicine. 2019 May;43:127-137
pubmed: 31056473
Cell Rep. 2017 Jun 27;19(13):2878-2880
pubmed: 28658632
J Immunother Cancer. 2021 Mar;9(3):
pubmed: 33692217
Cancer Cell Int. 2021 Jul 12;21(1):371
pubmed: 34253205
Nat Commun. 2021 Feb 16;12(1):1045
pubmed: 33594072
Surg Today. 2020 Aug;50(8):931-940
pubmed: 32040618
Br J Cancer. 2016 Jan 19;114(2):230-6
pubmed: 26625006
Mod Pathol. 2005 Mar;18(3):412-20
pubmed: 15467712
Epigenetics Chromatin. 2018 Jun 29;11(1):37
pubmed: 29958539
Arch Pathol Lab Med. 2007 Jun;131(6):923-30
pubmed: 17550320
Ann Surg Oncol. 2012 Aug;19(8):2506-14
pubmed: 22411204
Lung Cancer. 2014 Jan;83(1):23-9
pubmed: 24246507
Nat Genet. 2020 Aug;52(8):778-789
pubmed: 32661416
Genet Mol Biol. 2021 Mar 12;44(1):e20200216
pubmed: 33721012
Cancer Prev Res (Phila). 2013 Dec;6(12):1348-55
pubmed: 24089088
Cancer Sci. 2010 Aug;101(8):1913-9
pubmed: 20545696
Nat Genet. 2017 May;49(5):730-741
pubmed: 28319090
Cancer Cell. 2022 Jan 10;40(1):70-87.e15
pubmed: 34971568
Nat Cell Biol. 2013 Dec;15(12):1486-1494
pubmed: 24270891
Nature. 2020 Apr;580(7801):93-99
pubmed: 32238934
Int J Clin Exp Med. 2015 Apr 15;8(4):4762-8
pubmed: 26131050
Genome Biol. 2014 Feb 24;15(2):R38
pubmed: 24565500
Gut. 2019 Jan;68(1):101-110
pubmed: 29101262
Cancer Discov. 2017 Oct;7(10):1116-1135
pubmed: 28667006
Front Oncol. 2019 Jan 29;9:27
pubmed: 30761271
Ann Surg Oncol. 2019 Aug;26(8):2549-2557
pubmed: 31020501
Hepatology. 2014 Feb;59(2):544-54
pubmed: 24002901
Commun Biol. 2020 Aug 3;3(1):422
pubmed: 32747663
Hepatol Res. 2022 Jan;52(1):5-66
pubmed: 34050584
Am J Pathol. 2002 Sep;161(3):1015-22
pubmed: 12213730
Epigenetics. 2012 Nov;7(11):1249-57
pubmed: 22983262
J Hepatol. 2021 Aug;75(2):363-376
pubmed: 33887357
J Cell Mol Med. 2019 Mar;23(3):2184-2193
pubmed: 30648816
Cancer Manag Res. 2018 Oct 02;10:4113-4123
pubmed: 30323667
Nat Commun. 2016 Nov 28;7:13525
pubmed: 27892457
PeerJ. 2020 Jan 22;8:e8458
pubmed: 32002338
Leuk Lymphoma. 2017 Feb;58(2):257-265
pubmed: 27401303
JAMA Surg. 2014 May;149(5):432-8
pubmed: 24599477
Br J Surg. 2018 Jun;105(7):848-856
pubmed: 29193010
J Clin Oncol. 2013 Mar 20;31(9):1188-95
pubmed: 23358969
Nat Mater. 2017 Nov;16(11):1155-1161
pubmed: 29035356

Auteurs

Xing Chen (X)

Department of Liver Surgery & Liver Transplantation, Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China.

Liangqing Dong (L)

Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China.
Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.

Lu Chen (L)

Department of Hepatobiliary Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.

Yuan Wang (Y)

The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China.
Department of Research and Development, Jiangsu Gaomei Genomics, Nanjing, China.

Jinpeng Du (J)

Department of Liver Surgery & Liver Transplantation, Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China.

Lijie Ma (L)

Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China.
Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.

Xiaokai Yan (X)

Department of Oncology, the Second Affiliated Hospital of Zunyi Medical University, Zunyi, China.

Jiwei Huang (J)

Department of Liver Surgery & Liver Transplantation, Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China.

Mingheng Liao (M)

Department of Liver Surgery & Liver Transplantation, Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China.

Xiangzheng Chen (X)

Department of Liver Surgery & Liver Transplantation, Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China.

Dongming Liu (D)

Department of Hepatobiliary Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.

Jin Li (J)

Department of Research and Development, Jiangsu Gaomei Genomics, Nanjing, China.

Bo Zhang (B)

The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China.

Wen Teng (W)

The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China.

Kefei Yuan (K)

Department of Liver Surgery & Liver Transplantation, Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China.

Deqiang Sun (D)

The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China.
Department of Research and Development, Jiangsu Gaomei Genomics, Nanjing, China.
Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Qiang Gao (Q)

Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China.
Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.

Yong Zeng (Y)

Department of Liver Surgery & Liver Transplantation, Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China.

Classifications MeSH