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Human Molecular Genetics, 2000, Vol. 9, No. 15 2215-2221
© 2000 Oxford University Press

Germline APC variants in patients with multiple colorectal adenomas, with evidence for the particular importance of E1317Q

Hanan Lamlum1, Nada Al Tassan2, Emma Jaeger1, Ian Frayling3,6, Oliver Sieber1, Faisal Bin Reza1, Maria Eckert1, Andrew Rowan1, Ella Barclay1, Wendy Atkin3, Christopher Williams4, John Gilbert7, Jeremy Cheadle2, Jennie Bell5, Richard Houlston8, Walter Bodmer9, Julian Sampson2 and Ian Tomlinson1,+

1Molecular and Population Genetics Laboratory, Imperial Cancer Research Fund, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK, 2Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff CF4 4XN, UK, 3ICRF Colorectal Unit, 4Wolfson Endoscopy Unit and 5Kennedy-Galton Centre, St Mark’s and Northwick Park Hospitals, Watford Road, Harrow HA1 3UJ, UK, 6Department of Medical Genetics, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK, 7Department of Surgery, Wexham Park Hospital, Slough SL2 4HL, UK, 8Section of Cancer Genetics, Haddow Laboratories, Institute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, UK and 9Cancer and Immunogenetics Laboratory, Imperial Cancer Research Fund, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK

Mendelian tumour syndromes are caused by rare mutations, which usually lead to protein inactivation. Few studies have determined whether or not the same genes harbour other, more common variants, which might have a lower penetrance and/or cause mild disease, perhaps indistinguishable from sporadic disease and accounting for a considerable proportion of the unexplained inherited risk of tumours in the general population. Germline variants at the APC locus are excellent candidates for explaining why some individuals are predisposed to colorectal adenomas, but do not have the florid phenotype of familial adenomatous polyposis. We have screened 164 unrelated patients with ‘multiple’ (3–100) colorectal adenomas for germline variants throughout the APC gene, including promoter mutations. In addition to three Ashkenazi patients with I1307K, we found seven patients with the E1317Q variant. E1317Q is significantly associated with multiple colorectal adenomas (OR = 11.17, 95% CI = 2.30–54.3, p < 0.001), accounting for ~4% of all patients with multiple colorectal adenomas. In addition, four patients with truncating APC variants in exon 9 or in the 3' part of the gene were identified. Germline APC variants account for ~10% of patients with multiple adenomas. Unidentified predisposition genes almost certainly exist. We argue that it is worthwhile to screen multiple adenoma patients for a restricted number of germline APC variants, namely the missense changes E1317Q and I1307K (if of Ashkenazi descent), and, if there is a family history of colorectal tumours, for truncating mutations 5' to exon 5, in exon 9 and 3' to codon 1580.

+ To whom correspondence should be addressed. Tel: +44 207 269 2884, Fax: +44 207 269 2885; Email: i.tomlinson@icrf.icnet.uk


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