title: Deciphering the genetics of hereditary non-syndromic colorectal cancer.
abstract: Previously we have localized to chromosome 3q21-q24, a predisposition locus for colorectal cancer (CRC), through a genome-wide linkage screen (GWLS) of 69 families without familial adenomatous polyposis or hereditary non-polyposis CRC. To further investigate Mendelian susceptibility to CRC, we extended our screen to include a further GWLS of an additional 34 CRC families. We also searched for a disease gene at 3q21-q24 by linkage disequilibrium mapping in 620 familial CRC cases and 960 controls by genotyping 1676 tagging SNPs and sequencing 30 candidate genes from the region. Linkage analysis was conducted using the Affymetrix 10K SNP array. Data from both GWLSs were pooled and multipoint linkage statistics computed. The maximum NPL score (3.01; P=0.0013) across all families was at 3q22, maximal evidence for linkage coming from families segregating rectal CRC. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a dominant model (HLOD=2.79; P=0.00034), with an estimated 43% of families linked. In the case-control analysis, the strongest association was obtained at rs698675 (P=0.0029), but this was not significant after adjusting for multiple testing. Analysis of candidate gene mapping to the region of maximal linkage on 3q22 failed to identify a causal mutation. There was no evidence for linkage to the previously reported 9q CRC locus (NPL=0.95, P=0.23; HLOD(dominant)=0.40, HLOD(recessive)=0.20). Our findings are consistent with the hypothesis that variation at 3q22 contributes to the risk of CRC, but this is unlikely to be mediated through a restricted set of alleles.
authors.affiliation: Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Eli
authors.initials: E
authors.lastname: Papaemmanuil
authors.forename: Luis
authors.initials: L
authors.lastname: Carvajal-Carmona
authors.forename: Gabrielle S
authors.initials: GS
authors.lastname: Sellick
authors.forename: Zoe
authors.initials: Z
authors.lastname: Kemp
authors.forename: Emily
authors.initials: E
authors.lastname: Webb
authors.forename: Sarah
authors.initials: S
authors.lastname: Spain
authors.forename: Kate
authors.initials: K
authors.lastname: Sullivan
authors.forename: Ella
authors.initials: E
authors.lastname: Barclay
authors.forename: Steven
authors.initials: S
authors.lastname: Lubbe
authors.forename: Emma
authors.initials: E
authors.lastname: Jaeger
authors.forename: Jayaram
authors.initials: J
authors.lastname: Vijayakrishnan
authors.forename: Peter
authors.initials: P
authors.lastname: Broderick
authors.forename: Maggie
authors.initials: M
authors.lastname: Gorman
authors.forename: Lynn
authors.initials: L
authors.lastname: Martin
authors.forename: Anneke
authors.initials: A
authors.lastname: Lucassen
authors.forename: D Timothy
authors.initials: DT
authors.lastname: Bishop
authors.forename: D Gareth
authors.initials: DG
authors.lastname: Evans
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.forename: Verena
authors.initials: V
authors.lastname: Steinke
authors.forename: Nils
authors.initials: N
authors.lastname: Rahner
authors.forename: Hans K
authors.initials: HK
authors.lastname: Schackert
authors.forename: Timm O
authors.initials: TO
authors.lastname: Goecke
authors.forename: Elke
authors.initials: E
authors.lastname: Holinski-Feder
authors.forename: Peter
authors.initials: P
authors.lastname: Propping
authors.forename: Tom
authors.initials: T
authors.lastname: Van Wezel
authors.forename: Juul
authors.initials: J
authors.lastname: Wijnen
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Cazier
authors.forename: Huw
authors.initials: H
authors.lastname: Thomas
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
mesh_terms: D000236:Adenoma / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3; D015179:Colorectal Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D005190:Family; D005192:Family Health; D018628:Gene Dosage; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D006801:Humans; D008126:Lod Score; D020641:Polymorphism, Single Nucleotide