Deciphering the genetics of hereditary non-syndromic colorectal cancer

Eli Papaemmanuil, Luis Carvajal-Carmona, Gabrielle S. Sellick, Zoe Kemp, Emily Webb, Sarah Spain, Kate Sullivan, Ella Barclay, Steven Lubbe, Emma Jaeger, Jayaram Vijayakrishnan, Peter Broderick, Maggie Gorman, Lynn Martin, Anneke Lucassen, D. Timothy Bishop, D. Gareth Evans, Eamonn R. Maher, Verena Steinke, Nils Rahner & 10 others Hans K. Schackert, Timm O. Goecke, Elke Holinski-Feder, Peter Propping, Tom Van Wezel, Juul Wijnen, Jean Baptiste Cazier, Huw Thomas, Richard S. Houlston, Ian Tomlinson

Research output: Contribution to journalArticle

25 Citations (Scopus)

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; HLODdominant = 0.40, HLODrecessive = 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.

Original languageEnglish (US)
Pages (from-to)1477-1486
Number of pages10
JournalEuropean Journal of Human Genetics
Volume16
Issue number12
DOIs
StatePublished - 2008
Externally publishedYes

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Colorectal Neoplasms
Chromosome Mapping
Single Nucleotide Polymorphism
Genome
Adenomatous Polyposis Coli
Linkage Disequilibrium
Rectal Neoplasms
Genes
Chromosomes
Alleles
Mutation

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Papaemmanuil, E., Carvajal-Carmona, L., Sellick, G. S., Kemp, Z., Webb, E., Spain, S., ... Tomlinson, I. (2008). Deciphering the genetics of hereditary non-syndromic colorectal cancer. European Journal of Human Genetics, 16(12), 1477-1486. https://doi.org/10.1038/ejhg.2008.129

Deciphering the genetics of hereditary non-syndromic colorectal cancer. / Papaemmanuil, Eli; Carvajal-Carmona, Luis; Sellick, Gabrielle S.; Kemp, Zoe; Webb, Emily; Spain, Sarah; Sullivan, Kate; Barclay, Ella; Lubbe, Steven; Jaeger, Emma; Vijayakrishnan, Jayaram; Broderick, Peter; Gorman, Maggie; Martin, Lynn; Lucassen, Anneke; Bishop, D. Timothy; Evans, D. Gareth; Maher, Eamonn R.; Steinke, Verena; Rahner, Nils; 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.

In: European Journal of Human Genetics, Vol. 16, No. 12, 2008, p. 1477-1486.

Research output: Contribution to journalArticle

Papaemmanuil, E, Carvajal-Carmona, L, Sellick, GS, Kemp, Z, Webb, E, Spain, S, Sullivan, K, Barclay, E, Lubbe, S, Jaeger, E, Vijayakrishnan, J, Broderick, P, Gorman, M, Martin, L, Lucassen, A, Bishop, DT, Evans, DG, Maher, ER, Steinke, V, Rahner, N, Schackert, HK, Goecke, TO, Holinski-Feder, E, Propping, P, Van Wezel, T, Wijnen, J, Cazier, JB, Thomas, H, Houlston, RS & Tomlinson, I 2008, 'Deciphering the genetics of hereditary non-syndromic colorectal cancer', European Journal of Human Genetics, vol. 16, no. 12, pp. 1477-1486. https://doi.org/10.1038/ejhg.2008.129
Papaemmanuil, Eli ; Carvajal-Carmona, Luis ; Sellick, Gabrielle S. ; Kemp, Zoe ; Webb, Emily ; Spain, Sarah ; Sullivan, Kate ; Barclay, Ella ; Lubbe, Steven ; Jaeger, Emma ; Vijayakrishnan, Jayaram ; Broderick, Peter ; Gorman, Maggie ; Martin, Lynn ; Lucassen, Anneke ; Bishop, D. Timothy ; Evans, D. Gareth ; Maher, Eamonn R. ; Steinke, Verena ; Rahner, Nils ; 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. / Deciphering the genetics of hereditary non-syndromic colorectal cancer. In: European Journal of Human Genetics. 2008 ; Vol. 16, No. 12. pp. 1477-1486.
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AU - Carvajal-Carmona, Luis

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AU - Kemp, Zoe

AU - Webb, Emily

AU - Spain, Sarah

AU - Sullivan, Kate

AU - Barclay, Ella

AU - Lubbe, Steven

AU - Jaeger, Emma

AU - Vijayakrishnan, Jayaram

AU - Broderick, Peter

AU - Gorman, Maggie

AU - Martin, Lynn

AU - Lucassen, Anneke

AU - Bishop, D. Timothy

AU - Evans, D. Gareth

AU - Maher, Eamonn R.

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AU - Rahner, Nils

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AU - Propping, Peter

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AU - Houlston, Richard S.

AU - Tomlinson, Ian

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