Aberrant DNA methylation of cancer-associated genes in gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST).
Karen Balassiano
,
Sheila Lima
,
Mazda Jenab
(1)
,
Kim Overvad
(2)
,
Anne Tjonneland
(3)
,
Marie Christine Boutron-Ruault
(4)
,
Françoise Clavel-Chapelon
(5)
,
Federico Canzian
(6)
,
Rudolf Kaaks
(7)
,
Heiner Boeing
(8)
,
Karina Meidtner
(9)
,
Antonia Trichopoulou
(10)
,
Pagona Laglou
,
Paolo Vineis
(11, 12)
,
Salvatore Panico
(13)
,
Domenico Palli
(14)
,
Sara Grioni
(15)
,
Rosario Tumino
(16)
,
Eiliv Lund
(17)
,
H Bas Bueno-De-Mesquita
(18)
,
Mattjis E Numans
,
Petra H M Peeters
(19, 20)
,
J. Ramon Quirós
,
María-José Sánchez
(21, 22)
,
Carmen Navarro
(23, 24)
,
Eva Ardanaz
(21, 25)
,
Miren Dorronsoro
(26)
,
Göran Hallmans
(27)
,
Roger Stenling
,
Roy Ehrnström
,
Sara Regner
,
Naomi E Allen
(28)
,
Ruth C Travis
,
Kay-Tee Khaw
(29)
,
G Johan A Offerhaus
,
Nuria Sala
(30)
,
Elio Riboli
(31)
,
Pierre Hainaut
(32)
,
Jean-Yves Scoazec
(33)
,
Bakary S Sylla
,
Carlos A Gonzalez
,
Zdenko Herceg
1
Unit of Nutrition, Environment, and Cancer
2 Department of Cardiology
3 Danish Cancer Society
4 CESP - Centre de recherche en épidémiologie et santé des populations
5 E3N - Nutrition, hormones et cancer: épidémiologie et prévention
6 Department of Cancer Epidemiology
7 Division of Cancer Epidemiology
8 German Institute of Human Nutrition Potsdam-Rehbrücke
9 Department of Epidemiology
10 Department of Hygiene, Epidemiology and Medical Statistics
11 Centre for Environment and Health
12 HuGeF - Human Genetics Foundation
13 Department of Clinical and Experimental Medicine
14 Molecular and Nutritional Epidemiology Unit
15 Epidemiology
16 Cancer Registry
17 Institute of Community Medicine
18 RIVM - National Institute for Public Health and the Environment [Bilthoven]
19 Julius Centre for Health Sciences and Primary Care
20 Julius Center for Health Sciences and Primary Care
21 CIBERESP - Consorcio de Investigación Biomédica en Red especializado en Epidemiología y Salud Pública
22 Granada Cancer Registry
23 CIBERESP
24 Epidemiology Department
25 Navarra Public Health Institute
26 Epidemiology and Health Information
27 Department of Public Health and Clinical Medicine/Nutritional Research
28 Cancer Epidemiology Unit
29 School of Clinical Medicine
30 ICO - Catalan Institute of Oncology = Instituto Catalán de Oncología
31 Department of Epidemiology and Public Health
32 IACR - International Agency for Cancer Research
33 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
2 Department of Cardiology
3 Danish Cancer Society
4 CESP - Centre de recherche en épidémiologie et santé des populations
5 E3N - Nutrition, hormones et cancer: épidémiologie et prévention
6 Department of Cancer Epidemiology
7 Division of Cancer Epidemiology
8 German Institute of Human Nutrition Potsdam-Rehbrücke
9 Department of Epidemiology
10 Department of Hygiene, Epidemiology and Medical Statistics
11 Centre for Environment and Health
12 HuGeF - Human Genetics Foundation
13 Department of Clinical and Experimental Medicine
14 Molecular and Nutritional Epidemiology Unit
15 Epidemiology
16 Cancer Registry
17 Institute of Community Medicine
18 RIVM - National Institute for Public Health and the Environment [Bilthoven]
19 Julius Centre for Health Sciences and Primary Care
20 Julius Center for Health Sciences and Primary Care
21 CIBERESP - Consorcio de Investigación Biomédica en Red especializado en Epidemiología y Salud Pública
22 Granada Cancer Registry
23 CIBERESP
24 Epidemiology Department
25 Navarra Public Health Institute
26 Epidemiology and Health Information
27 Department of Public Health and Clinical Medicine/Nutritional Research
28 Cancer Epidemiology Unit
29 School of Clinical Medicine
30 ICO - Catalan Institute of Oncology = Instituto Catalán de Oncología
31 Department of Epidemiology and Public Health
32 IACR - International Agency for Cancer Research
33 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
Karen Balassiano
- Fonction : Auteur
Sheila Lima
- Fonction : Auteur
Federico Canzian
- Fonction : Auteur
- PersonId : 763126
- ORCID : 0000-0002-4261-4583
- IdRef : 18925243X
Pagona Laglou
- Fonction : Auteur
Salvatore Panico
- Fonction : Auteur
- PersonId : 757530
- ORCID : 0000-0002-5498-8312
Mattjis E Numans
- Fonction : Auteur
J. Ramon Quirós
- Fonction : Auteur
Roger Stenling
- Fonction : Auteur
Roy Ehrnström
- Fonction : Auteur
Sara Regner
- Fonction : Auteur
Ruth C Travis
- Fonction : Auteur
G Johan A Offerhaus
- Fonction : Auteur
Elio Riboli
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- PersonId : 757264
- ORCID : 0000-0001-6795-6080
- IdRef : 030854032
Jean-Yves Scoazec
- Fonction : Auteur
- PersonId : 757689
- ORCID : 0000-0003-1604-6823
Bakary S Sylla
- Fonction : Auteur
Carlos A Gonzalez
- Fonction : Auteur
Zdenko Herceg
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- Fonction : Auteur correspondant
- PersonId : 935265
- ORCID : 0000-0003-4109-3154
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Résumé
Epigenetic events have emerged as key mechanisms in the regulation of critical biological processes and in the development of a wide variety of human malignancies, including gastric cancer (GC), however precise gene targets of aberrant DNA methylation in GC remain largely unknown. Here, we have combined pyrosequencing-based quantitative analysis of DNA methylation in 98 GC cases and 64 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and in cancer tissue and non-tumorigenic adjacent tissue of an independent series of GC samples. A panel of 10 cancer-associated genes (CHRNA3, DOK1, MGMT, RASSF1A, p14ARF, CDH1, MLH1, ALDH2, GNMT and MTHFR) and LINE-1 repetitive elements were included in the analysis and their association with clinicopathological characteristics (sex, age at diagnosis, anatomical sub-site, histological sub-type) was examined. Three out of the 10 genes analyzed exhibited a marked hypermethylation, whereas two genes (ALDH2 and MTHFR) showed significant hypomethylation, in gastric tumors. Among differentially methylated genes, we identified new genes (CHRNA3 and DOK1) as targets of aberrant hypermethylation in GC, suggesting that epigenetic deregulation of these genes and their corresponding cellular pathways may promote the development and progression of GC. We also found that global demethylation of tumor cell genomes occurs in GC, consistent with the notion that abnormal hypermethylation of specific genes occurs concomitantly with genome-wide hypomethylation. Age and gender had no significant influence on methylation states, but an association was observed between LINE-1 and MLH1 methylation levels with histological sub-type and anatomical sub-site. This study identifies aberrant methylation patters in specific genes in GC thus providing information that could be exploited as novel biomarkers in clinics and molecular epidemiology of GC.