title: Disease severity and genetic pathways in attenuated familial adenomatous polyposis vary greatly but depend on the site of the germline mutation.
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.
  
  
  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.
authors.affiliation: Molecular and Population Genetics Laboratory, Cancer Research UK, London Research Institute, London, UK.
authors.forename: O M
authors.initials: OM
authors.lastname: Sieber
authors.forename: S
authors.initials: S
authors.lastname: Segditsas
authors.forename: A L
authors.initials: AL
authors.lastname: Knudsen
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Luz
authors.forename: A J
authors.initials: AJ
authors.lastname: Rowan
authors.forename: S L
authors.initials: SL
authors.lastname: Spain
authors.forename: C
authors.initials: C
authors.lastname: Thirlwell
authors.forename: K M
authors.initials: KM
authors.lastname: Howarth
authors.forename: E E M
authors.initials: EE
authors.lastname: Jaeger
authors.forename: J
authors.initials: J
authors.lastname: Robinson
authors.forename: E
authors.initials: E
authors.lastname: Volikos
authors.forename: A
authors.initials: A
authors.lastname: Silver
authors.forename: G
authors.initials: G
authors.lastname: Kelly
authors.forename: S
authors.initials: S
authors.lastname: Aretz
authors.forename: I
authors.initials: I
authors.lastname: Frayling
authors.forename: P
authors.initials: P
authors.lastname: Hutter
authors.forename: M
authors.initials: M
authors.lastname: Dunlop
authors.forename: T
authors.initials: T
authors.lastname: Guenther
authors.forename: K
authors.initials: K
authors.lastname: Neale
authors.forename: R
authors.initials: R
authors.lastname: Phillips
authors.forename: K
authors.initials: K
authors.lastname: Heinimann
authors.forename: I P M
authors.initials: IP
authors.lastname: Tomlinson
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D025601:Adenomatous Polyposis Coli Protein