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Disease severity and genetic pathways in attenuated familial adenomatous polyposis vary greatly but depend on the site of the germline mutation

¹ Molecular and Population Genetics Laboratory, Cancer Research UK, London Research Institute, London, UK
² The Danish Polyposis Register, Department of Surgical Gastroenterology, Hvidovre University Hospital, Hvidovre, Denmark
³ Research Group Human Genetics, Department of Research DKBW, University of Basel, Basel, Switzerland
⁴ Colorectal Cancer Unit, Cancer Research UK, London Research Institute, London, UK
⁵ Computational Genome Analysis Laboratory, Cancer Research UK, London Research Institute, London, UK
⁶ Institute of Human Genetics, University of Bonn, Wilhelmstrasse, Bonn, Germany
⁷ Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK
⁸ Institut Central des Hôpitaux Valaisans, Sion, Switzerland
⁹ Colon Cancer Genetics Group, MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK
¹⁰ Academic Department of Histopatholgy, Cancer Research UK, London Research Institute, London, UK
¹¹ Polyposis Registry, Cancer Research UK, St Mark’s Hospital, Harrow, UK
¹² Molecular and Population Genetics Laboratory, Cancer Research UK, London Research Institute, London, UK, and Colorectal Cancer Unit, Cancer Research UK, London Research Institute, London, UK

Correspondence to:
Correspondence to:
Dr I Tomlinson
Molecular and Population Genetics Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK; ian.tomlinson{at}cancer.org.uk

ABSTRACT
Background: Attenuated familial adenomatous polyposis (AFAP) is associated with germline mutations in the 5', 3', and exon 9 of the adenomatous polyposis coli (APC) gene. These mutations probably encode a limited amount of functional APC protein.

Methods and results: We found that colonic polyp number varied greatly among AFAP patients but members of the same family tended to have more similar disease severity. 5' Mutants generally had more polyps than other patients. We analysed somatic APC mutations/loss of heterozygosity (LOH) in 235 tumours from 35 patients (16 families) with a variety of AFAP associated germline mutations. In common with two previous studies of individual kindreds, we found biallelic changes ("third hits") in some polyps. We found that the "third hit" probably initiated tumorigenesis. Somatic mutation spectra were similar in 5' and 3' mutant patients, often resembling classical FAP. In exon 9 mutants, in contrast, "third hits" were more common. Most "third hits" left three 20 amino acid repeats (20AARs) on the germline mutant APC allele, with LOH (or proximal somatic mutation) of the wild-type allele; but some polyps had loss of the germline mutant with mutation leaving one 20AAR on the wild-type allele.

Conclusions: We propose that mutations, such as nt4661insA, that leave three 20AARs are preferentially selected in cis with some AFAP mutations because the residual protein function is near optimal for tumorigenesis. Not all AFAP polyps appear to need "three hits" however. AFAP is phenotypically and genetically heterogeneous. In addition to effects of different germline mutations, modifier genes may be acting on the AFAP phenotype, perhaps influencing the quantity of functional protein produced by the germline mutant allele.

Abbreviations: FAP, familial adenomatous polyposis; AFAP, attenuated familial adenomatous polyposis; 20AAR, 20 amino acid beta-catenin binding and degradation repeats; MLPA, multiplex ligation dependent probe amplification analysis; RQM-PCR, real time quantitative multiplex polymerase chain reaction; LOH, loss of heterozygosity; APC, adenomatous polyposis coli; SSCP, single strand conformational polymorphism; SNP, single nucleotide polymorphism; IQR, interquartile range; IRES, internal ribosome entry site

Keywords: genetic pathways; familial adenomatous polyposis; germline mutation

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