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, Gareth Evans, Anneke Lucassen, D Timothy Bishop, Eamonn R Maher, Verena Steinke, Nils RahnerTimm O Goecke, Hans K Schackert, Elke Holinski-Feder, Peter Propping, Tom Van Wezel, Juul Wijnen, Jean-Baptiste Cazier, Huw Thomas, Richard S Houlston, Ian Tomlinson, Neva Elizabeth Haites, CORGI Consortium

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; 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.
Original languageEnglish
Pages (from-to)1477-1486
Number of pages10
JournalEJHG : European journal of human genetics : the official journal of the European Society of Human Genetics.
Volume16
Issue number12
Early online date16 Jul 2008
DOIs
Publication statusPublished - Dec 2008

Fingerprint

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

Keywords

  • Adenoma
  • Case-Control Studies
  • Chromosome Mapping
  • Chromosomes, Human, Pair 3
  • Colorectal Neoplasms
  • DNA Mutational Analysis
  • Family
  • Family Health
  • Gene Dosage
  • Genome-Wide Association Study
  • Humans
  • Linkage (Genetics)
  • Lod Score
  • Polymorphism, Single Nucleotide
  • colorectal cancer
  • linkage
  • chromosome 3q22

Cite this

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; Evans, Gareth ; Lucassen, Anneke; Bishop, D Timothy; Maher, Eamonn R; Steinke, Verena; Rahner, Nils; Goecke, Timm O; Schackert, Hans K; Holinski-Feder, Elke; Propping, Peter; Van Wezel, Tom; Wijnen, Juul; Cazier, Jean-Baptiste; Thomas, Huw; Houlston, Richard S; Tomlinson, Ian; Haites, Neva Elizabeth; CORGI Consortium.

In: EJHG : European journal of human genetics : the official journal of the European Society of Human Genetics. , Vol. 16, No. 12, 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, Evans, G, Lucassen, A, Bishop, DT, Maher, ER, Steinke, V, Rahner, N, Goecke, TO, Schackert, HK, Holinski-Feder, E, Propping, P, Van Wezel, T, Wijnen, J, Cazier, J-B, Thomas, H, Houlston, RS, Tomlinson, I, Haites, NE & CORGI Consortium 2008, 'Deciphering the genetics of hereditary non-syndromic colorectal cancer', EJHG : European journal of human genetics : the official journal of the European Society 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 ; Evans, Gareth ; Lucassen, Anneke ; Bishop, D Timothy ; Maher, Eamonn R ; Steinke, Verena ; Rahner, Nils ; Goecke, Timm O ; Schackert, Hans K ; Holinski-Feder, Elke ; Propping, Peter ; Van Wezel, Tom ; Wijnen, Juul ; Cazier, Jean-Baptiste ; Thomas, Huw ; Houlston, Richard S ; Tomlinson, Ian ; Haites, Neva Elizabeth ; CORGI Consortium. / Deciphering the genetics of hereditary non-syndromic colorectal cancer. In: EJHG : European journal of human genetics : the official journal of the European Society of Human Genetics. . 2008 ; Vol. 16, No. 12. pp. 1477-1486.
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T1 - Deciphering the genetics of hereditary non-syndromic colorectal cancer

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AU - Carvajal-Carmona, Luis

AU - Sellick, Gabrielle S

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 - Evans, Gareth

AU - Lucassen, Anneke

AU - Bishop, D Timothy

AU - Maher, Eamonn R

AU - Steinke, Verena

AU - Rahner, Nils

AU - Goecke, Timm O

AU - Schackert, Hans K

AU - Holinski-Feder, Elke

AU - Propping, Peter

AU - Van Wezel, Tom

AU - Wijnen, Juul

AU - Cazier, Jean-Baptiste

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AU - Tomlinson, Ian

AU - Haites, Neva Elizabeth

AU - CORGI Consortium

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N2 - 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.

AB - 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.

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KW - Case-Control Studies

KW - Chromosome Mapping

KW - Chromosomes, Human, Pair 3

KW - Colorectal Neoplasms

KW - DNA Mutational Analysis

KW - Family

KW - Family Health

KW - Gene Dosage

KW - Genome-Wide Association Study

KW - Humans

KW - Linkage (Genetics)

KW - Lod Score

KW - Polymorphism, Single Nucleotide

KW - colorectal cancer

KW - linkage

KW - chromosome 3q22

U2 - 10.1038/ejhg.2008.129

DO - 10.1038/ejhg.2008.129

M3 - Article

C2 - 18628789

VL - 16

SP - 1477

EP - 1486

JO - EJHG : European journal of human genetics : the official journal of the European Society of Human Genetics.

JF - EJHG : European journal of human genetics : the official journal of the European Society of Human Genetics.

SN - 1018-4813

IS - 12

ER -