SNP rs16906252C>T Is an Expression and Methylation Quantitative Trait Locus Associated with an Increased Risk of Developing MGMT-Methylated Colorectal Cancer.
OBJECTIVE
Methylation of the MGMT promoter is the major cause of O6-methylguanine methyltransferase deficiency in cancer and has been associated with the T variant of the promoter enhancer SNP rs16906252C>T. We sought evidence for an association between the rs16906252C>T genotype and increased risk of developing a subtype of colorectal cancer featuring MGMT methylation, mediated by genotype-dependent epigenetic silencing within normal tissues.


METHODS
By applying a molecular pathologic epidemiology case-control study design, associations between rs16906252C>T and risk for colorectal cancer overall, and colorectal cancer stratified by MGMT methylation status, were estimated using multinomial logistic regression in two independent retrospective series of colorectal cancer cases and controls. The test sample comprised 1,054 colorectal cancer cases and 451 controls from Sydney, Australia. The validation sample comprised 612 colorectal cancer cases and 245 controls from the Australasian Colon Cancer Family Registry (ACCFR). To determine whether rs16906252C>T was linked to a constitutively altered epigenetic state, quantitative allelic expression and methylation analyses were performed in normal tissues.


RESULTS
An association between rs16906252C>T and increased risk of developing MGMT-methylated colorectal cancer in the Sydney sample was observed [OR, 3.3; 95% confidence interval (CI), 2.0-5.3; P < 0.0001], which was replicated in the ACCFR sample (OR, 4.0; 95% CI, 2.4-6.8; P < 0.0001). The T allele demonstrated about 2.5-fold reduced transcription in normal colorectal mucosa from cases and controls and was selectively methylated in a minority of normal cells, indicating that rs16906252C>T represents an expression and methylation quantitative trait locus.


CONCLUSIONS
We provide evidence that rs16906252C>T is associated with elevated risk for MGMT-methylated colorectal cancer, likely mediated by constitutive epigenetic repression of the T allele. Clin Cancer Res; 22(24); 6266-77. ©2016 AACR.
Medical Epigenetics Laboratory, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
Joice
J
Kuroiwa-Trzmielina
Department of Medicine (Oncology), Stanford University, Stanford, California.|School of Public Health (Epidemiology), Harbin Medical University, Harbin, PR China.
Fan
F
Wang
Medical Epigenetics Laboratory, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.|Cure Brain Cancer Foundation Biomarkers and Translational Research Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
Robert W
RW
Rapkins
Integrated Cancer Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
Robyn L
RL
Ward
Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Australia.
Daniel D
DD
Buchanan
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Australia.
Aung Ko
AK
Win
Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Australia.
Mark
M
Clendenning
Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Australia.|Envoi Specialist Pathologists, Herston, Australia.|School of Medicine, University of Queensland, Herston, Australia.
Christophe
C
Rosty
Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Australia.
Melissa C
MC
Southey
Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Australia.|Department of Medicine, The University of Melbourne, Parkville, Australia.
Ingrid M
IM
Winship
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Australia.|Department of Epidemiology and Institute of Health and Environment, School of Public Health, Seoul National University, Seoul, Korea.
John L
JL
Hopper
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Australia.
Mark A
MA
Jenkins
School of Mathematics and Statistics, University of New South Wales, Sydney, Australia.
Jake
J
Olivier
Department of Pathology, School of Medical Sciences, University of New South Wales, Sydney, Australia.
Nicholas J
NJ
Hawkins
Department of Medicine (Oncology), Stanford University, Stanford, California. mhitchin@stanford.edu.
Megan P
MP
Hitchins
D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D012189:Retrospective Studies; D012306:Risk; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D019853:O(6)-Methylguanine-DNA Methyltransferase; D045643:DNA Repair Enzymes