1. ¹Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK
2. ²Molecular and Population Genetics Laboratory, Cancer Research UK, London, UK
3. ³Colorectal Cancer Unit, Cancer Research UK, St Mark's Hospital, Harrow, UK
4. ⁴Medical Genetics, St Mary's Hospital, Manchester, UK
5. ⁵Department of Medical and Molecular Genetics, University of Birmingham School of Medicine and West Midlands Genetics Service, Birmingham Women's Hospital, Edgbaston, Birmingham, UK
6. ⁶Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK
7. ⁷Genetic Epidemiology Laboratory, Cancer Research UK, St James's University Hospital, Leeds, UK
8. ⁸Institute of Human Genetics, University of Bonn, Bonn, Germany
9. ⁹Department of Surgical Research, Technische Universität Dresden, Dresden, Germany
10. ¹⁰Institute of Human Genetics, University of Düsseldorf, Germany
11. ¹¹Department of Pathology, Leiden Medical Centre, Leiden, The Netherlands
12. ¹²Bioinformatics and Biostatistics, London Research Institute, Cancer Research UK, London, UK

Correspondence: Dr Professor R Houlston, Section of Cancer Genetics, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5 NG, UK. Tel: +44 208 722 4175; Fax: +44 208 722 4359; E-mail: richard.houlston@icr.ac.uk; Professor I Tomlinson, Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, UK. Tel: +44 207 269 2884; Fax: +44 207 269 3093; E-mail: ian.tomlinson@cancer.org.uk

¹³These authors contributed equally to this work

¹⁴These authors have joint PI status

Received 26 March 2008; Revised 29 May 2008; Accepted 29 May 2008; Published online 16 July 2008.

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.