title: Variants in the netrin-1 receptor UNC5C prevent apoptosis and increase risk of familial colorectal cancer.
abstract: OBJECTIVE
  Expression of the netrin-1 dependence receptor UNC5C is reduced in many colorectal tumors; mice with the UNC5C mutations have increased progression of intestinal tumors. We investigated whether specific variants in UNC5C increase risk of colorectal cancer (CRC).
  
  
  METHODS
  We analyzed the sequence of UNC5C in blood samples from 1801 patients with CRC and 4152 controls from 3 cohorts (France, United States, and Finland). Almost all cases from France and the United States had familial CRC; of the Finnish cases, 92 of 984 were familial. We analyzed whether CRC segregates with the UNC5C variant A628K in 3 families with histories of CRC. We also performed haplotype analysis to determine the origin of this variant.
  
  
  RESULTS
  Of 817 patients with familial CRC, 14 had 1 of 4 different, unreported missense variants in UNC5C. The variants p.Asp353Asn (encodes D353N), p.Arg603Cys (encodes R603C), and p.Gln630Glu (encodes Q630E) did not occur significantly more often in cases than controls. The variant p.Ala628Lys (A628K) was detected in 3 families in the French cohort (odds ratio, 8.8; Wald's 95% confidence interval, 1.47-52.93; P = .03) and in 2 families in the US cohort (odds ratio, 1.9; P = .6) but was not detected in the Finnish cohort; UNC5C A628K segregated with CRC in families. Three families with A628K had a 109-kilobase identical haplotype that spanned most of UNC5C, indicating recent origin of this variant in white subjects (14 generations; 95% confidence interval, 6-36 generations). Transfection of HEK293T cells with UNC5C-A628K significantly reduced apoptosis compared with wild-type UNC5C, measured in an assay of active caspase-3.
  
  
  CONCLUSIONS
  Inherited mutations in UNC5C prevent apoptosis and increase risk of CRC.
authors: Apoptosis, Cancer and Development Laboratory - Equipe Labellisée 'La Ligue,' UMR INSERM 1052 - CNRS 5286, University of Lyon, Lyon, France.
authors: Marie-May
authors: MM
authors: Coissieux
authors: Jerneja
authors: J
authors: Tomsic
authors: Marie
authors: M
authors: Castets
authors: Heather
authors: H
authors: Hampel
authors: Sari
authors: S
authors: Tuupanen
authors: Nadine
authors: N
authors: Andrieu
authors: Ilene
authors: I
authors: Comeras
authors: Youenn
authors: Y
authors: Drouet
authors: Christine
authors: C
authors: Lasset
authors: Sandya
authors: S
authors: Liyanarachchi
authors: Laetitia
authors: L
authors: Mazelin
authors: Alain
authors: A
authors: Puisieux
authors: Jean-Christophe
authors: JC
authors: Saurin
authors: Jean-Yves
authors: JY
authors: Scoazec
authors: Qing
authors: Q
authors: Wang
authors: Lauri
authors: L
authors: Aaltonen
authors: Stephan M
authors: SM
authors: Tanner
authors: Albert
authors: A
authors: de la Chapelle
authors: Agnès
authors: A
authors: Bernet
authors: Patrick
authors: P
authors: Mehlen
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000097:blood / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020125:Mutation, Missense / Q000235:genetics*; D000075386:Netrin Receptors; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000097:blood / Q000235:genetics*; D012307:Risk Factors
chemical_list: D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; C115727:UNC5C protein, human