title: Heterogeneous molecular mechanisms underlie attenuated familial adenomatous polyposis.
abstract: OBJECTIVE
  Familial adenomatous polyposis is a phenotypically heterogeneous disease predisposing to colorectal cancer. It is dominantly transmitted, when associated with the APC gene, and recessively inherited, when associated with MUTYH gene. We searched for APC and MUTYH germline alterations in Italian and Greek patients with attenuated polyposis, a phenotypic variant whose genetic cause remains unknown in many cases.
  
  
  METHODS
  We studied 26 unrelated patients (and 16 relatives) with multiple colorectal adenomas (3-100, by endoscopic analysis) that had screened APC mutation-negative by protein truncation test. We searched for APC rearrangements by multiplex ligation-dependent probe amplification and for MUTYH mutations by sequencing. We performed a screening of five MUTYH recurrent pathogenic mutations in 501 Italian and 144 Greek controls.
  
  
  RESULTS
  One patient proved to carry an APC whole-gene deletion; 4 of 25 (16%) patients showed biallelic and 3 of 25 (12%) monoallelic MUTYH mutations. In the three heterozygous subjects no pathogenetic variants were found in OGG1, MTH1, APE1, MSH2, and MSH6 genes. Frequency assessment of MUTYH mutations in healthy subjects showed that only Y165C and G382D reach a subpolymorphic frequency.
  
  
  CONCLUSIONS
  Attenuated polyposis patients without "conventional" APC mutations are genetically heterogeneous, and the phenotype is not directly related to the germline defect. Therefore, the families' appropriate management requires an accurate genetic and clinical investigation.
authors: Department of Genetics and Microbiology, University of Pavia, Pavia, Italy.
authors: Francesca
authors: F
authors: Cattaneo
authors: Sara
authors: S
authors: Molatore
authors: Markos
authors: M
authors: Mihalatos
authors: Angela
authors: A
authors: Apessos
authors: Tiziana
authors: T
authors: Venesio
authors: Silvia
authors: S
authors: Bione
authors: Pierangela
authors: P
authors: Grignani
authors: Georgios
authors: G
authors: Nasioulas
authors: Guglielmina Nadia
authors: GN
authors: Ranzani
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D045647:DNA Glycosylases / Q000235:genetics; D005260:Female; D017491:Genes, APC; D018740:Genetic Heterogeneity; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase