Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P=8.4×10-14, odds ratio=0.86, 95%confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus.SNP rs11263763 genotypewas associatedwithHNF1BmRNAexpression butnotwithHNF1Bmethylationinendometrial tumor samples fromThe Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatinmarks extending fromtheminimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associatedwith endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.
Bibliographical noteFunding Information:
Fine-mapping analysis was supported by National Health and Medical Research Council (NHMRC) project grant (ID#1031333) to A.B.S., D.F.E. and A.M.D. Functional analysis was supported by NHMRC project grant (ID#1058415) to S.L.E., J.D.F. and A.M.D. A.B.S., P.M.W., G.W.M. and D.R.N. are supported by the NHMRC Fellowship scheme. D.F.E. is a Principal Research Fellow of Cancer Research UK. A.M.D. is supported by the Joseph Mitchell Trust. I.T. is supported by Cancer Research UK and the Oxford Comprehensive Biomedical Research Centre. Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007 and C5047/A10692), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112—the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. ANECS recruitment was supported by project grants from the NHMRC (ID#339435), the Cancer Council Queensland (ID#4196615) and Cancer Council Tasmania (ID#403031 and ID#457636). SEARCH recruitment was funded by a program grant from Cancer Research UK (C490/ A10124). Stage 1 and Stage 2 case genotyping was supported by the NHMRC (ID#552402, ID#1031333). Control data was generated by the Wellcome Trust Case Control Consortium (WTCCC), and a full list of the investigators who contributed to the generation of the data is available from the WTCCC website. We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02—funding for this project was provided by the Wellcome Trust under award 085475. NSECG was supported by the EU FP7 CHIBCHA grant and CORGI by Cancer Research UK. Recruitment of the QIMR Berghofer controls was supported by the NHMRC. The University of Newcastle, the Gladys M Brawn Senior Research Fellowship scheme, The Vincent Fairfax Family Foundation, the Hunter Medical Research Institute and the Hunter Area Pathology Service all contributed towards the costs of establishing the Hunter Community Study. The Bavarian Endometrial Cancer Study (BECS) was partly funded by the ELAN fund of the University of Erlangen. The Leuven Endometrium Study (LES) was supported by the Verelst Foundation for endometrial cancer. The Mayo Endometrial Cancer Study (MECS) and Mayo controls (MAY) were supported by grants from the National Cancer Institute of United States Public Health Service (R01 CA122443, U19 CA148112, P50 CA13 6393, and GAME-ON the NCI Cancer Post-GWAS Initiative U19 CA148112), the Fred C and Katherine B Andersen Foundation, the Mayo Foundation, and the Ovarian Cancer Research Fund with support of the Smith family, in memory of Kathryn Sladek Smith. MoMaTEC received financial support from a Helse Vest Grant, the University of Bergen, Melzer Foundation, The Norwegian Cancer Society (Harald Andersens legat), The Research Council of Norway and Haukeland University Hospital. The Newcastle Endometrial Cancer Study (NECS) acknowledges contributions from the University of Newcastle, The NBN Children’s Cancer Research Group, Ms Jennie Thomas and the Hunter Medical Research Institute. RENDOCAS was supported through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institu-tet (numbers: 20110222, 20110483, 20110141 and DF 07015), The Swedish Labor Market Insurance (number 100069) and The Swedish Cancer Society (number 11 0439). The Cancer Hormone Replacement Epidemiology in Sweden Study (CAHRES, formerly called The Singapore and Swedish Breast/Endometrial Cancer Study; SASBAC) was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institutes of Health and the Susan G. Komen Breast Cancer Foundation. The Shanghai Endometrial Cancer Genetic Study (SECGS) was supported by grants from the National Cancer Institute of United States Public Health Service (RO1 CA 092585 and R01 CA90899, R01 CA64277). The Breast Cancer Association Consortium (BCAC) is funded by Cancer Research UK (C1287/ A10118, C1287/A12014). The Ovarian Cancer Association Consortium (OCAC) is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07), and the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge. Additional funding for individual control groups is detailed in the Supplementary Information.
© The Author 2014.