title: CHEK2, MGMT, SULT1E1 and SULT1A1 polymorphisms and endometrial cancer risk.
abstract: Several single nucleotide polymorphisms (SNPs) in candidate genes of DNA repair and hormone pathways have been reported to be associated with endometrial cancer risk. We sought to confirm these associations in two endometrial cancer case-control sample sets and used additional data from an existing genome-wide association study to prioritize an additional SNP for further study. Five SNPs from the CHEK2, MGMT, SULT1E1 and SULT1A1 genes, genotyped in a total of 1597 cases and 1507 controls from two case-control studies, the Australian National Endometrial Cancer Study and the Polish Endometrial Cancer Study, were assessed for association with endometrial cancer risk using logistic regression analysis. Imputed data was drawn for CHEK2 rs8135424 for 666 cases from the Study of Epidemiology and Risk factors in Cancer Heredity study and 5190 controls from the Wellcome Trust Case Control Consortium. We observed no association between SNPs in the MGMT, SULT1E1 and SULT1A1 genes and endometrial cancer risk. The A allele of the rs8135424 CHEK2 SNP was associated with decreased risk of endometrial cancer (adjusted per-allele OR 0.83; 95%CI 0.70-0.98; p = .03) however this finding was opposite to that previously published. Imputed data for CHEK2 rs8135424 supported the direction of effect reported in this study (OR 0.85; 95% CI 0.65-1.10). Previously reported endometrial cancer risk associations with SNPs from in genes involved in estrogen metabolism and DNA repair were not replicated in our larger study population. This study highlights the need for replication of candidate gene SNP studies using large sample groups, to confirm risk associations and better prioritize downstream studies to assess the causal relationship between genetic variants and cancer risk. Our findings suggest that the CHEK2 SNP rs8135424 be prioritized for further study as a genetic factor associated with risk of endometrial cancer.
authors.affiliation: Hormone Dependent Cancer Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Australia.
authors.forename: Tracy A
authors.initials: TA
authors.lastname: O'Mara
authors.forename: Kaltin
authors.initials: K
authors.lastname: Ferguson
authors.forename: Paul
authors.initials: P
authors.lastname: Fahey
authors.forename: Louise
authors.initials: L
authors.lastname: Marquart
authors.forename: Hannah P
authors.initials: HP
authors.lastname: Yang
authors.forename: Jolanta
authors.initials: J
authors.lastname: Lissowska
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Thompson
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Healey
authors.forename: Alison M
authors.initials: AM
authors.lastname: Dunning
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.forename: Penelope M
authors.initials: PM
authors.lastname: Webb
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Spurdle
mesh_terms: D015239:Arylsulfotransferase / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics; D016022:Case-Control Studies; D064447:Checkpoint Kinase 2; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D004717:Endometrium / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012307:Risk Factors; D015238:Sulfotransferases / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D015238:Sulfotransferases; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human; C020122:estrone sulfotransferase; D045643:DNA Repair Enzymes