title: Genome-wide analysis associates familial colorectal cancer with increases in copy number variations and a rare structural variation at 12p12.3.
abstract: Colorectal cancer (CRC) is one of the most common cancer worldwide. However, a large number of genetic risk factors involved in CRC have not been understood. Copy number variations (CNVs) might partly contribute to the 'missing heritability' of CRC. An increased overall burden of CNV has been identified in several complex diseases, whereas the association between the overall CNV burden and CRC risk is largely unknown. We performed a genome-wide investigation of CNVs on genomic DNA from 384 familial CRC cases and 1285 healthy controls by the Affymetrix 6.0 array. An increase of overall CNV burden was observed in familial CRC patients compared with healthy controls, especially for CNVs larger than 50kb (case/control ratio = 1.66, P = 0.025). In addition, we discovered for the first time a novel structural variation at 12p12.3 and determined the breakpoints by strategic PCR and sequencing. This 12p12.3 structural variation was found in four of 2862 CRC cases but not in 6243 healthy controls (P = 0.0098). RERGL gene (RERG/RAS-like), the only gene influenced by the 12p12.3 structural variation, sharing most of the conserved regions with its close family member RERG tumor suppressor gene (RAS-like, estrogen-regulated, growth inhibitor), might be a novel CRC-related gene. In conclusion, this is the first study to reveal the contribution of the overall burden of CNVs to familial CRC risk and identify a novel rare structural variation at 12p12.3 containing RERGL gene to be associated with CRC.
authors.affiliation: Molecular Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Rongxi
authors.initials: R
authors.lastname: Yang
authors.forename: Bowang
authors.initials: B
authors.lastname: Chen
authors.forename: Katrin
authors.initials: K
authors.lastname: Pfütze
authors.forename: Stephan
authors.initials: S
authors.lastname: Buch
authors.forename: Verena
authors.initials: V
authors.lastname: Steinke
authors.forename: Elke
authors.initials: E
authors.lastname: Holinski-Feder
authors.forename: Sarah
authors.initials: S
authors.lastname: Stöcker
authors.forename: Witigo
authors.initials: W
authors.lastname: von Schönfels
authors.forename: Thomas
authors.initials: T
authors.lastname: Becker
authors.forename: Hans K
authors.initials: HK
authors.lastname: Schackert
authors.forename: Brigitte
authors.initials: B
authors.lastname: Royer-Pokora
authors.forename: Matthias
authors.initials: M
authors.lastname: Kloor
authors.forename: Wolff H
authors.initials: WH
authors.lastname: Schmiegel
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.forename: Christoph
authors.initials: C
authors.lastname: Engel
authors.forename: Jesus
authors.initials: J
authors.lastname: Lascorz Puertolas
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
authors.forename: Nelli
authors.initials: N
authors.lastname: Kunkel
authors.forename: Peter
authors.initials: P
authors.lastname: Bugert
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Michael
authors.initials: M
authors.lastname: Krawczak
authors.forename: Clemens
authors.initials: C
authors.lastname: Schafmayer
authors.forename: Peter
authors.initials: P
authors.lastname: Propping
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D002881:Chromosomes, Human, Pair 12 / Q000737:chemistry* / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D056915:DNA Copy Number Variations; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D015321:Gene Rearrangement; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D020558:GTP Phosphohydrolases; C529586:RERG protein, human