Heterogeneous molecular mechanisms underlie attenuated familial adenomatous polyposis.
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.
Cattaneo
Francesca
F
Department of Genetics and Microbiology, University of Pavia, Pavia, Italy.
Molatore
Sara
S
Mihalatos
Markos
M
Apessos
Angela
A
Venesio
Tiziana
T
Bione
Silvia
S
Grignani
Pierangela
P
Nasioulas
Georgios
G
Ranzani
Guglielmina Nadia
GN
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
D045647:DNA Glycosylases; C061738:mutY adenine glycosylase