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Identification and replication of the interplay of four genetic high-risk variants for urinary bladder cancer.

About this Publication
Title
Identification and replication of the interplay of four genetic high-risk variants for urinary bladder cancer.
Pubmed ID
29028944 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Carcinogenesis. 2017 Dec 7; Volume 38 (Issue 12): Pages 1167-1179
Authors
Selinski S, Blaszkewicz M, Ickstadt K, Gerullis H, Otto T, Roth E, Volkert F, Ovsiannikov D, Moormann O, Banfi G, Nyirady P, Vermeulen SH, Garcia-Closas M, Figueroa JD, Johnson A, Karagas MR, Kogevinas M, Malats N, Schwenn M, Silverman DT, ...show more Koutros S, Rothman N, Kiemeney LA, Hengstler JG, Golka K
Affiliations
  • Systems Toxicology, Leibniz-Institut für Arbeitsforschung an der TU Dortmund, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Germany.
  • Faculty of Statistics, TU Dortmund University, Germany.
  • Department of Urology, Lukasklinik Neuss, Germany.
  • Department of Urology, Evangelic Hospital, Paul Gerhardt Foundation, Germany.
  • Department of Urology, St.-Josefs-Hospital, Germany.
  • Department of Urology, Semmelweis University Budapest, Hungary.
  • Department for Health Evidence (133 HEV) and Department of Urology (659 URO), Radboud University Medical Center (Radboudumc), The Netherlands.
  • Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute (NCI), National Institutes of Health (NIH), USA.
  • Usher Institute of Population Health Sciences and Informatics, CRUK Edinburgh Centre, University of Edinburgh, UK.
  • Vermont Department of Health, Vermont Cancer Registry, USA.
...show more
  • Department of Epidemiology, Geisel School of Medicine at Dartmouth, USA.
  • Cancer Program, ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Spain.
  • Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), Spain.
  • Maine Department of Health and Human Services, Maine Cancer Registry, USA.
Abstract

Little is known whether genetic variants identified in genome-wide association studies interact to increase bladder cancer risk. Recently, we identified two- and three-variant combinations associated with a particular increase of bladder cancer risk in a urinary bladder cancer case-control series (Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), 1501 cases, 1565 controls). In an independent case-control series (Nijmegen Bladder Cancer Study, NBCS, 1468 cases, 1720 controls) we confirmed these two- and three-variant combinations. Pooled analysis of the two studies as discovery group (IfADo-NBCS) resulted in sufficient statistical power to test up to four-variant combinations by a logistic regression approach. The New England and Spanish Bladder Cancer Studies (2080 cases and 2167 controls) were used as a replication series. Twelve previously identified risk variants were considered. The strongest four-variant combination was obtained in never smokers. The combination of rs1014971[AA] near apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A (APOBEC3A) and chromobox homolog 6 (CBX6), solute carrier family 1s4 (urea transporter), member 1 (Kidd blood group) (SLC14A1) exon single nucleotide polymorphism (SNP) rs1058396[AG, GG], UDP glucuronosyltransferase 1 family, polypeptide A complex locus (UGT1A) intron SNP rs11892031[AA] and rs8102137[CC, CT] near cyclin E1 (CCNE1) resulted in an unadjusted odds ratio (OR) of 2.59 (95% CI = 1.93-3.47; P = 1.87 × 10-10), while the individual variant ORs ranged only between 1.11 and 1.30. The combination replicated in the New England and Spanish Bladder Cancer Studies (ORunadjusted = 1.60, 95% CI = 1.10-2.33; P = 0.013). The four-variant combination is relatively frequent, with 25% in never smoking cases and 11% in never smoking controls (total study group: 19% cases, 14% controls). In conclusion, we show that four high-risk variants can statistically interact to confer increased bladder cancer risk particularly in never smokers.

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