title: Association of familial colorectal cancer with variants in the E-cadherin (CDH1) and cyclin D1 (CCND1) genes.
abstract: BACKGROUND
  About 20% of colorectal cancer (CRC) patients show some kind of familiarity, which might be caused by yet unknown combinations of low penetrance susceptibility genes. We aimed to identify genetic factors for familial CRC (fCRC) in a unique study design that includes phenotypic extremes as represented by fCRC cases and 'hyper-normal' controls without CRC history and no adenomatous polyps on colonoscopy.
  
  
  METHODS
  Candidate gene variants were determined by allele-specific amplification (SLC10A2 c.169C>T and c.171G>T) and restriction fragment length polymorphism assays (CCND1 c.870A>G; CDH1 -160C>A; TP53 R72P; VDR T2M). In total, 98 patients with fCRC, 96 patients with sporadic CRC, and 220 hyper-normal controls were included.
  
  
  RESULTS
  The minor allele of the CDH1 -160C>A polymorphism occurred significantly more often in controls compared to fCRC cases (OR = 0.664; p = 0.042). Homozygosity of the minor allele was significantly associated with affiliation to the control group (OR = 0.577; p = 0.029), indicating that both heterozygous and homozygous carriers of the common allele are at-risk for CRC. With respect to the CCND1 c.870A>G mutation, comparison of fCRC and sporadic CRC cases showed that A/A homozygosity was more common than G/G homozygosity among fCRC patients compared to controls (OR = 2.119; p = 0.045). However, no differences in allele or genotype frequencies were detected between sporadic CRC cases and controls, and no associations were observed for SLC10A2, TP53, and VDR polymorphisms.
  
  
  CONCLUSIONS
  We report a potential association of variants in the CCND1 and CDH1 genes with fCRC using a unique study design with phenotypic extremes.
authors.affiliation: Department of Internal Medicine I, University Hospital Bonn, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. frank.gruenhage@ukb.uni-bonn.de
authors.forename: Frank
authors.initials: F
authors.lastname: Grünhage
authors.forename: Matthias
authors.initials: M
authors.lastname: Jungck
authors.forename: Christoph
authors.initials: C
authors.lastname: Lamberti
authors.forename: Christine
authors.initials: C
authors.lastname: Berg
authors.forename: Ursula
authors.initials: U
authors.lastname: Becker
authors.forename: Hildegard
authors.initials: H
authors.lastname: Schulte-Witte
authors.forename: Dominik
authors.initials: D
authors.lastname: Plassmann
authors.forename: Nils
authors.initials: N
authors.lastname: Rahner
authors.forename: Stefan
authors.initials: S
authors.lastname: Aretz
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Friedrichs
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.forename: Frank
authors.initials: F
authors.lastname: Lammert
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics*; D016022:Case-Control Studies; D003113:Colonoscopy; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D018570:Risk Assessment
chemical_list: D015703:Antigens, CD; C530104:CCND1 protein, human; C513384:CDH1 protein, human; D015820:Cadherins; D019938:Cyclin D1