Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk
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Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk. / Painter, Jodie N; O'Mara, Tracy A; Batra, Jyotsna; Cheng, Timothy; Lose, Felicity A; Dennis, Joe; Michailidou, Kyriaki; Tyrer, Jonathan P; Ahmed, Shahana; Ferguson, Kaltin; Healey, Catherine S; Kaufmann, Susanne; Hillman, Kristine M; Walpole, Carina; Moya, Leire; Pollock, Pamela; Jones, Angela; Howarth, Kimberley; Martin, Lynn; Gorman, Maggie; Hodgson, Shirley; De Polanco, Ma Magdalena Echeverry; Sans, Monica; Carracedo, Angel; Castellvi-Bel, Sergi; Rojas-Martinez, Augusto; Santos, Erika; Teixeira, Manuel R; Carvajal-Carmona, Luis; Shu, Xiao-Ou; Long, Jirong; Zheng, Wei; Xiang, Yong-Bing; Montgomery, Grant W; Webb, Penelope M; Scott, Rodney J; McEvoy, Mark; Attia, John; Holliday, Elizabeth; Martin, Nicholas G; Nyholt, Dale R; Henders, Anjali K; Fasching, Peter A; Hein, Alexander; Beckmann, Matthias W; Renner, Stefan P; Dörk, Thilo; Hillemanns, Peter; Dürst, Matthias; Runnebaum, Ingo; Lambrechts, Diether; Coenegrachts, Lieve; Schrauwen, Stefanie; Amant, Frederic; Winterhoff, Boris; Dowdy, Sean C; Goode, Ellen L; Teoman, Attila; Salvesen, Helga B; Trovik, Jone; Njolstad, Tormund S; Werner, Henrica M J; Ashton, Katie; Proietto, Tony; Otton, Geoffrey; Tzortzatos, Gerasimos; Mints, Miriam; Tham, Emma; Hall, Per; Czene, Kamila; Liu, Jianjun; Li, Jingmei; Hopper, John L; Southey, Melissa C; Ekici, Arif B; Ruebner, Matthias; Johnson, Nicola; Peto, Julian; Burwinkel, Barbara; Marme, Frederik; Brenner, Hermann; Dieffenbach, Aida K; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Depreeuw, Jeroen; Moisse, Matthieu; Chang-Claude, Jenny; Rudolph, Anja; Couch, Fergus J; Olson, Janet E; Giles, Graham G; Bruinsma, Fiona; Cunningham, Julie M; Fridley, Brooke L; Børresen-Dale, Anne-Lise; Kristensen, Vessela N; Cox, Angela; Swerdlow, Anthony J; Orr, Nicholas; Bolla, Manjeet K; Wang, Qin; Weber, Rachel Palmieri; Chen, Zhihua; Shah, Mitul; French, Juliet D; Pharoah, Paul D P; Dunning, Alison M; Tomlinson, Ian; Easton, Douglas F; Edwards, Stacey L; Thompson, Deborah J; Spurdle, Amanda B; National Study of Endometrial Cancer Genetics Group (NSECG).
in: HUM MOL GENET, Jahrgang 24, Nr. 5, 01.03.2015, S. 1478-92.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk
AU - Painter, Jodie N
AU - O'Mara, Tracy A
AU - Batra, Jyotsna
AU - Cheng, Timothy
AU - Lose, Felicity A
AU - Dennis, Joe
AU - Michailidou, Kyriaki
AU - Tyrer, Jonathan P
AU - Ahmed, Shahana
AU - Ferguson, Kaltin
AU - Healey, Catherine S
AU - Kaufmann, Susanne
AU - Hillman, Kristine M
AU - Walpole, Carina
AU - Moya, Leire
AU - Pollock, Pamela
AU - Jones, Angela
AU - Howarth, Kimberley
AU - Martin, Lynn
AU - Gorman, Maggie
AU - Hodgson, Shirley
AU - De Polanco, Ma Magdalena Echeverry
AU - Sans, Monica
AU - Carracedo, Angel
AU - Castellvi-Bel, Sergi
AU - Rojas-Martinez, Augusto
AU - Santos, Erika
AU - Teixeira, Manuel R
AU - Carvajal-Carmona, Luis
AU - Shu, Xiao-Ou
AU - Long, Jirong
AU - Zheng, Wei
AU - Xiang, Yong-Bing
AU - Montgomery, Grant W
AU - Webb, Penelope M
AU - Scott, Rodney J
AU - McEvoy, Mark
AU - Attia, John
AU - Holliday, Elizabeth
AU - Martin, Nicholas G
AU - Nyholt, Dale R
AU - Henders, Anjali K
AU - Fasching, Peter A
AU - Hein, Alexander
AU - Beckmann, Matthias W
AU - Renner, Stefan P
AU - Dörk, Thilo
AU - Hillemanns, Peter
AU - Dürst, Matthias
AU - Runnebaum, Ingo
AU - Lambrechts, Diether
AU - Coenegrachts, Lieve
AU - Schrauwen, Stefanie
AU - Amant, Frederic
AU - Winterhoff, Boris
AU - Dowdy, Sean C
AU - Goode, Ellen L
AU - Teoman, Attila
AU - Salvesen, Helga B
AU - Trovik, Jone
AU - Njolstad, Tormund S
AU - Werner, Henrica M J
AU - Ashton, Katie
AU - Proietto, Tony
AU - Otton, Geoffrey
AU - Tzortzatos, Gerasimos
AU - Mints, Miriam
AU - Tham, Emma
AU - Hall, Per
AU - Czene, Kamila
AU - Liu, Jianjun
AU - Li, Jingmei
AU - Hopper, John L
AU - Southey, Melissa C
AU - Ekici, Arif B
AU - Ruebner, Matthias
AU - Johnson, Nicola
AU - Peto, Julian
AU - Burwinkel, Barbara
AU - Marme, Frederik
AU - Brenner, Hermann
AU - Dieffenbach, Aida K
AU - Meindl, Alfons
AU - Brauch, Hiltrud
AU - Lindblom, Annika
AU - Depreeuw, Jeroen
AU - Moisse, Matthieu
AU - Chang-Claude, Jenny
AU - Rudolph, Anja
AU - Couch, Fergus J
AU - Olson, Janet E
AU - Giles, Graham G
AU - Bruinsma, Fiona
AU - Cunningham, Julie M
AU - Fridley, Brooke L
AU - Børresen-Dale, Anne-Lise
AU - Kristensen, Vessela N
AU - Cox, Angela
AU - Swerdlow, Anthony J
AU - Orr, Nicholas
AU - Bolla, Manjeet K
AU - Wang, Qin
AU - Weber, Rachel Palmieri
AU - Chen, Zhihua
AU - Shah, Mitul
AU - French, Juliet D
AU - Pharoah, Paul D P
AU - Dunning, Alison M
AU - Tomlinson, Ian
AU - Easton, Douglas F
AU - Edwards, Stacey L
AU - Thompson, Deborah J
AU - Spurdle, Amanda B
AU - National Study of Endometrial Cancer Genetics Group (NSECG)
AU - Harth, Volker
N1 - © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
PY - 2015/3/1
Y1 - 2015/3/1
N2 - 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 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The 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 chromatin marks extending from the minimal 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 associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.
AB - 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 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The 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 chromatin marks extending from the minimal 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 associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.
U2 - 10.1093/hmg/ddu552
DO - 10.1093/hmg/ddu552
M3 - SCORING: Journal article
C2 - 25378557
VL - 24
SP - 1478
EP - 1492
JO - HUM MOL GENET
JF - HUM MOL GENET
SN - 0964-6906
IS - 5
ER -