DNA methylation profile in CpG-depleted regions uncovers a high-risk subtype of early-stage colorectal cancer.

Humans Colorectal Neoplasms / genetics DNA Methylation Prognosis Proportional Hazards Models Biomarkers, Tumor / genetics CpG Islands / genetics

Journal

Journal of the National Cancer Institute
ISSN: 1460-2105
Titre abrégé: J Natl Cancer Inst
Pays: United States
ID NLM: 7503089

Informations de publication

Date de publication:
10 01 2023
Historique:
received: 16 06 2022
revised: 27 07 2022
accepted: 23 08 2022
pubmed: 30 9 2022
medline: 12 1 2023
entrez: 29 9 2022
Statut: ppublish

Résumé

The current risk stratification system defined by clinicopathological features does not identify the risk of recurrence in early-stage (stage I-II) colorectal cancer (CRC) with sufficient accuracy. We aimed to investigate whether DNA methylation could serve as a novel biomarker for predicting prognosis in early-stage CRC patients. We analyzed the genome-wide methylation status of CpG loci using Infinium MethylationEPIC array run on primary tumor tissues and normal mucosa of early-stage CRC patients to identify potential methylation markers for prognosis. The machine-learning approach was applied to construct a DNA methylation-based prognostic classifier for early-stage CRC (MePEC) using the 4 gene methylation markers FAT3, KAZN, TLE4, and DUSP3. The prognostic value of the classifier was evaluated in 2 independent cohorts (n = 438 and 359, respectively). The comprehensive analysis identified an epigenetic subtype with high risk of recurrence based on a group of CpG loci in the CpG-depleted region. In multivariable analysis, the MePEC classifier was independently and statistically significantly associated with time to recurrence in validation cohort 1 (hazard ratio = 2.35, 95% confidence interval = 1.47 to 3.76, P < .001) and cohort 2 (hazard ratio = 3.20, 95% confidence interval = 1.92 to 5.33, P < .001). All results were further confirmed after each cohort was stratified by clinicopathological variables and molecular subtypes. We demonstrated the prognostic statistical significance of a DNA methylation profile in the CpG-depleted region, which may serve as a valuable source for tumor biomarkers. MePEC could identify an epigenetic subtype with high risk of recurrence and improve the prognostic accuracy of current clinical variables in early-stage CRC.

Sections du résumé

BACKGROUND
The current risk stratification system defined by clinicopathological features does not identify the risk of recurrence in early-stage (stage I-II) colorectal cancer (CRC) with sufficient accuracy. We aimed to investigate whether DNA methylation could serve as a novel biomarker for predicting prognosis in early-stage CRC patients.
METHODS
We analyzed the genome-wide methylation status of CpG loci using Infinium MethylationEPIC array run on primary tumor tissues and normal mucosa of early-stage CRC patients to identify potential methylation markers for prognosis. The machine-learning approach was applied to construct a DNA methylation-based prognostic classifier for early-stage CRC (MePEC) using the 4 gene methylation markers FAT3, KAZN, TLE4, and DUSP3. The prognostic value of the classifier was evaluated in 2 independent cohorts (n = 438 and 359, respectively).
RESULTS
The comprehensive analysis identified an epigenetic subtype with high risk of recurrence based on a group of CpG loci in the CpG-depleted region. In multivariable analysis, the MePEC classifier was independently and statistically significantly associated with time to recurrence in validation cohort 1 (hazard ratio = 2.35, 95% confidence interval = 1.47 to 3.76, P < .001) and cohort 2 (hazard ratio = 3.20, 95% confidence interval = 1.92 to 5.33, P < .001). All results were further confirmed after each cohort was stratified by clinicopathological variables and molecular subtypes.
CONCLUSIONS
We demonstrated the prognostic statistical significance of a DNA methylation profile in the CpG-depleted region, which may serve as a valuable source for tumor biomarkers. MePEC could identify an epigenetic subtype with high risk of recurrence and improve the prognostic accuracy of current clinical variables in early-stage CRC.

Identifiants

DOI: 10.1093/jnci/djac183 PMID: 36171645 PMC: PMC10089593
pubmed: 36171645
pii: 6726193
doi: 10.1093/jnci/djac183
pmc: PMC10089593
doi:

Substances chimiques

2-methylphenyl 4-ethoxycinnamate 0
Biomarkers, Tumor 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

52-61

Subventions

Organisme : NIH HHS
ID : U01 CA167551
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA220004
Pays : United States
Organisme : NIH HHS
ID : RO1CA194663
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA206110
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA167551
Pays : United States
Organisme : NCI NIH HHS
ID : U2C CA271902
Pays : United States

Informations de copyright

© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

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Auteurs

Huichuan Yu (H)

Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China.

Xiaolin Wang (X)

Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China.

Liangliang Bai (L)

Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China.

Guannan Tang (G)

Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China.

Kelly T Carter (KT)

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.

Ji Cui (J)

Departments of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

Pinzhu Huang (P)

Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

Li Liang (L)

Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China.

Yanqing Ding (Y)

Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China.

Muyan Cai (M)

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.

Meijin Huang (M)

Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China.

Huanliang Liu (H)

Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China.

Guangwen Cao (G)

Department of Epidemiology, Second Military Medical University, Shanghai, China.
ORCID: 0000-0002-8094-1278

Steven Gallinger (S)

Wallace McCain Centre for Pancreatic Cancer, Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON, Canada.

Rish K Pai (RK)

Department of laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, USA.
ORCID: 0000-0002-2692-221X

Daniel D Buchanan (DD)

Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia.
Genomic Medicine and Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, Victoria, Australia.

Aung Ko Win (AK)

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.

Polly A Newcomb (PA)

Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA.
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Jianping Wang (J)

Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China.

William M Grady (WM)

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.

Yanxin Luo (Y)

Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
ORCID: 0000-0002-5200-3997

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questionsmedicales.fr › Maladies de l'appareil digestif › Maladies gastro-intestinales › Maladies intestinales › Maladies du rectum › Tumeurs colorectales › DNA methylation profile in CpG-depleted...
questionsmedicales.fr › Phénomènes génétiques › Méthylation de l'ADN › DNA methylation profile in CpG-depleted...
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questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Analyse de survie › Modèles des risques proportionnels › DNA methylation profile in CpG-depleted...
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questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Ilots CpG › DNA methylation profile in CpG-depleted...