Polymorphisms in methyl-group metabolism genes and risk of sporadic colorectal cancer with relation to the CpG island methylator phenotype.
BACKGROUND
The CpG island methylator phenotype (CIMP), together with extensive promoter methylation, is regarded as one of the mechanisms involved in colorectal carcinogenesis. The mechanisms underlying CIMP in sporadic colorectal cancer are poorly understood. Genes involved in methyl-group metabolism are likely to affect DNA methylation and thereby influence an individual's risk of CIMP. The aim of the present study was to evaluate whether polymorphisms in the genes encoding methyl-group metabolism pathway predispose to CIMP+ and/or CIMP- CRC.


METHODS
We examined the potential association between the polymorphisms of MTHFR 677C>T, TS 5'UTR 2R/3R, TS 3'UTR 1494del6, DeltaDNMT3B -149C>T and DNMT3B -283T>C in a group of 46 CIMP+ CRC cases, 140 CIMP- CRC cases and 140 healthy controls. The CIMP status of the CRC cases was determined by MS-PCR in tumor tissue by a panel of five markers (CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1), which was also followed by analyzing hMLH1 methylation and BRAF V600E mutation.


RESULTS
The variant allele homozygote genotype for the DeltaDNMT3B -283T>C polymorphism was associated with a decreased risk for CIMP+ CRC (OR: 0.31, 95%CI: 0.09-0.73, p=0.009). Individuals with TS 3R/3R had an increased risk of CIMP- CRC (OR: 2.21, 95%CI: 1.23-4.91, p=0.01). Moreover, the carriers of 3R allele had an increased risk of CIMP- CRC (OR: 1.45, 95%CI: 1.10-2.13, p=0.01).


CONCLUSIONS
This study provides support to the hypothesis that methyl-group metabolism plays a role in the etiology of both CIMP+ and CIMP- colorectal cancers but has a different impact on a distinct molecular subgroups of colorectal cancer.
Karpinski
Pawel
P
Department of Genetics, Wroclaw Medical University, ul. Marcinkowskiego 1, Wroclaw, Poland. polemiraza@poczta.fm
Myszka
Aleksander
A
Ramsey
David
D
Misiak
Blazej
B
Gil
Justyna
J
Laczmanska
Izabela
I
Grzebieniak
Zygmunt
Z
Sebzda
Tadeusz
T
Smigiel
Robert
R
Stembalska
Agnieszka
A
Sasiadek
Maria M
MM
D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013940:Thymidylate Synthase / Q000235:genetics*; D000097584:DNA Methyltransferase 3B
D014408:Biomarkers, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D000097584:DNA Methyltransferase 3B