Linkage of DNA methylation quantitative trait loci to human cancer risk.
Epigenetic regulation and, in particular, DNA methylation have been linked to the underlying genetic sequence. DNA methylation quantitative trait loci (meQTL) have been identified through significant associations between the genetic and epigenetic codes in physiological and pathological contexts. We propose that interrogating the interplay between polymorphic alleles and DNA methylation is a powerful method for improving our interpretation of risk alleles identified in genome-wide association studies that otherwise lack mechanistic explanation. We integrated patient cancer risk genotype data and genome-scale DNA methylation profiles of 3,649 primary human tumors, representing 13 solid cancer types. We provide a comprehensive meQTL catalog containing DNA methylation associations for 21% of interrogated cancer risk polymorphisms. Differentially methylated loci harbor previously reported and as-yet-unidentified cancer genes. We suggest that such regulation at the DNA level can provide a considerable amount of new information about the biology of cancer-risk alleles.
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain. Electronic address: hheyn@idibell.cat.
Holger
H
Heyn
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
Sergi
S
Sayols
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
Catia
C
Moutinho
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
Enrique
E
Vidal
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
Jose V
JV
Sanchez-Mut
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
Olafur A
OA
Stefansson
Thoracic Surgery, Department of Surgery, University of Michigan Medical School, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA.
Ernest
E
Nadal
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
Sebastian
S
Moran
The Icelandic Cancer Society, Molecular and Cell Biology Research Laboratory, 101 Reykjavik, Iceland; Department of Medicine, University of Iceland, 101 Reykjavik, Iceland.
Jorunn E
JE
Eyfjord
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
Eva
E
Gonzalez-Suarez
Breast Cancer and Systems Biology Unit, Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908 Barcelona, Catalonia, Spain.
Miguel Angel
MA
Pujana
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain; Department of Physiological Sciences II, School of Medicine, University of Barcelona, 08036 Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Catalonia, Spain. Electronic address: mesteller@idibell.cat.
Manel
M
Esteller
D000483:Alleles; D019175:DNA Methylation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D011110:Polymorphism, Genetic; D040641:Quantitative Trait Loci