Deciphering the genetics of hereditary non-syndromic colorectal cancer

CORGI Consortium

doi:10.1038/ejhg.2008.129

Deciphering the genetics of hereditary non-syndromic colorectal cancer

CORGI Consortium

Section of Cancer Genetics, Institute of Cancer Research and Royal Marsden Hospital, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.

Research output: Contribution to journal › Article › peer-review

29 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 language	English
Pages (from-to)	1477-86
Number of pages	10
Journal	European Journal of Human Genetics
Volume	16
Issue number	12
DOIs	https://doi.org/10.1038/ejhg.2008.129
Publication status	Published - Dec 2008

Keywords

Adenoma/genetics
Case-Control Studies
Chromosome Mapping
Chromosomes, Human, Pair 3
Colorectal Neoplasms/genetics
DNA Mutational Analysis
Family
Family Health
Gene Dosage
Genetic Linkage
Genome-Wide Association Study
Humans
Lod Score
Polymorphism, Single Nucleotide

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/ejhg.2008.129

Cite this

@article{b3398292195740a9a8b6895e43b7348f,

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.",

keywords = "Adenoma/genetics, Case-Control Studies, Chromosome Mapping, Chromosomes, Human, Pair 3, Colorectal Neoplasms/genetics, DNA Mutational Analysis, Family, Family Health, Gene Dosage, Genetic Linkage, Genome-Wide Association Study, Humans, Lod Score, Polymorphism, Single Nucleotide",

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

year = "2008",

month = dec,

doi = "10.1038/ejhg.2008.129",

language = "English",

volume = "16",

pages = "1477--86",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "Nature Publishing Group",

number = "12",

}

TY - JOUR

T1 - Deciphering the genetics of hereditary non-syndromic colorectal cancer

AU - CORGI Consortium

AU - Papaemmanuil, Eli

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 - Lucassen, Anneke

AU - Bishop, D Timothy

AU - Evans, D Gareth

AU - Maher, Eamonn R

AU - Steinke, Verena

AU - Rahner, Nils

AU - Schackert, Hans K

AU - Goecke, Timm O

AU - Holinski-Feder, Elke

AU - Propping, Peter

AU - Van Wezel, Tom

AU - Wijnen, Juul

AU - Cazier, Jean-Baptiste

AU - Thomas, Huw

AU - Houlston, Richard S

AU - Tomlinson, Ian

PY - 2008/12

Y1 - 2008/12

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.

KW - Adenoma/genetics

KW - Case-Control Studies

KW - Chromosome Mapping

KW - Chromosomes, Human, Pair 3

KW - Colorectal Neoplasms/genetics

KW - DNA Mutational Analysis

KW - Family

KW - Family Health

KW - Gene Dosage

KW - Genetic Linkage

KW - Genome-Wide Association Study

KW - Humans

KW - Lod Score

KW - Polymorphism, Single Nucleotide

U2 - 10.1038/ejhg.2008.129

DO - 10.1038/ejhg.2008.129

M3 - Article

C2 - 18628789

SN - 1018-4813

VL - 16

SP - 1477

EP - 1486

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 12

ER -

Deciphering the genetics of hereditary non-syndromic colorectal cancer

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this