Deciphering the genetics of hereditary non-syndromic colorectal cancer

• Published in: European journal of human genetics : EJHG Vol. 16; no. 12; pp. 1477 - 1486
• Main Authors: PAPAEMMANUIL, Eli, CARVAJAL-CARMONA, Luis, VIJAYAKRISHNAN, Jayaram, BRODERICK, Peter, GORMAN, Maggie, MARTIN, Lynn, LUCASSEN, Anneke, BISHOP, D. Timothy, EVANS, D. Gareth, MAHER, Eamonn R, STEINKE, Verena, RAHNER, Nils, SELLICK, Gabrielle S, SCHACKERT, Hans K, GOECKE, Timm O, HOLINSKI-FEDER, Elke, PROPPING, Peter, VAN WEZEL, Tom, WIJNEN, Juul, CAZIER, Jean-Baptiste, THOMAS, Huw, HOULSTON, Richard S, TOMLINSON, Ian, KEMP, Zoe, WEBB, Emily, SPAIN, Sarah, SULLIVAN, Kate, BARCLAY, Ella, LUBBE, Steven, JAEGER, Emma
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.12.2008
• Subjects: Adenoma - genetics; Alleles; Biological and medical sciences; Case-Control Studies; Chromosome 3; Chromosome 9; Chromosome Mapping; Chromosomes, Human, Pair 3; Classical genetics, quantitative genetics, hybrids; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Consortia; DNA Mutational Analysis; Familial adenomatous polyposis; Family; Family Health; Fundamental and applied biological sciences. Psychology; Gene Dosage; Gene mapping; General aspects. Genetic counseling; Genes; Genetic Linkage; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Genomes; Genotyping; Health risk assessment; Hospitals; Human; Humans; Laboratories; Linkage analysis; Linkage disequilibrium; Lod Score; Medical genetics; Medical research; Medical sciences; Molecular and cellular biology; Mutation; Polymorphism, Single Nucleotide; Population genetics; Rectum; Single-nucleotide polymorphism; Statistical analysis; Systematic review; Tumors; United Kingdom > UK; Germany; Genetic mapping; Rectal disease; Pathogenesis; Colorectal cancer; Chromosome; Malignant tumor; linkage; Hereditary; Genetic determinism; chromosome 3q22; Colonic disease; Genetic linkage; Digestive diseases; Intestinal disease; Genetics; Cancer
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2008.129

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.