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.
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Acknowledgements
We are grateful to the patients, their families and their clinicians for their participation in this study. The CORGI Consortium comprised Lucy Side, Lucy Curtis and Peter Risby (Oxford Regional Genetics Service, Churchill Hospital, Oxford, UK), Carole Cummings and Angela Brady (North-West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, UK), Joan Paterson (Anglia Regional Genetics Service, Addenbrooke's Hospital, Cambridge, UK), Shirley Hodgson and Tessa Homfray (South-West Thames Regional Genetics Service, St George's Hospital, Tooting, London, UK), Louise Izatt (South-East Thames Regional Genetics Service, Guy's Hospital, London, UK), Alan Donaldson (South-West Regional Genetics Service, Bristol, UK), Patrick Morrison (Northern Ireland Regional Genetics Service, City Hospital, Belfast, UK), Carole Brewer (South-West Regional Genetics Service, Royal Devon and Exeter Hospital, Exeter, UK), John Burn and Alison Trainer (Northern Regional Genetics Service, International Centre for Life, Newcastle, UK), Rosemarie Davidson and Victoria Murday (West of Scotland Regional Genetics Service, Yorkhill Hospital, Glasgow, UK), Jaqueline Cook (Sheffield Regional Genetics Service, Children's Hospital, Sheffield, UK), Neva Haites (North of Scotland Regional Genetics Service, Foresterhill Hospital, Aberdeen, UK), Eamonn Sheridan (Yorkshire Regional Genetics Service, St James's Hospital, Leeds, UK), Andrew Green (Republic of Ireland Genetics Service, Our Lady's Hospital for Sick Children, Dublin, Republic of Ireland) and Susan Ritchie (Nottingham Centre for Medical Genetics, City Hospital, Nottingham, UK), who should be regarded as co-authors of this work. The work was supported by grants from Cancer Research UK. ZK was funded by the EU, GS by Leukemia Research, EP by the Institute of Cancer Research and SS by CORE. Finally, work of the German HNPCC consortium is supported by German Cancer Aid.
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URLs for programs and data presented herein are as follows:
Online Mendelian Inheritance in Man (OMIM): http://www.ncbi.nlm.nih.gov/sites/entrez
SUSPECTS: http://www.genetics.med.ed.ac.uk/suspects/
dbSNP: http://www.ncbi.nlm.nih.gov/sites/entrez
UCSC Human Genome browser, http://genome.ucsc.edu/cgi-bin/hgGateway
Affymetrix NetAffx: http://www.affymetrix.com/analysis/index.affx
Illumina: http://www.illumina.com/
SNPLINK: http://www.icr.ac.uk/cancgen/molgen/MolPopGen_Bioinformatics.htm
R suite of programs: http://www.r-project.org/
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Supplementary Information accompanies the paper on European Journal of Human Genetics website (http://www.nature.com/ejhg)
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Papaemmanuil, E., Carvajal-Carmona, L., Sellick, G. et al. Deciphering the genetics of hereditary non-syndromic colorectal cancer. Eur J Hum Genet 16, 1477–1486 (2008). https://doi.org/10.1038/ejhg.2008.129
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DOI: https://doi.org/10.1038/ejhg.2008.129
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