Purpose: 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 ligationdependent 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. Conclusion: 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. Genet Med 2007:9(12):836 -841.
Key Words: polyposis, colorectal cancer, phenotype, germline mutations, molecular mechanismsFamilial adenomatous polyposis (FAP) is an inherited syndrome conferring a very high risk of colorectal cancer through the formation of multiple colorectal adenomas. The number of adenomas, the age of onset of adenomatosis and carcinoma, and the possible presence of extracolonic manifestations, vary both between and within the affected families. In the "classic" disease, the number of adenomas ranges from a hundred to thousands and polyps usually emerge during the second-third decade of life. 1 On the other hand, the so-called "attenuated" polyposis (Ͻ100 adenomas) is characterized by a milder course of the disease, a later onset of adenomatosis, and a reduced expression of the extracolonic manifestations; the average age of colon cancer is 50 -55 years, which is about 10 -15 years later than the age found for classic disease. 2 Although diagnostic criteria are consistent with the above characteristics, attenuated polyposis is not a well-defined entity and can either mimic the typical disease or resemble sporadic adenomas and colorectal cancer.Both classic and attenuated polyposis can be associated with germline mutations of either APC tumor suppressor gene 3,4 or MUTYH base excision repair gene. 5,6 Classic (FAP) and attenuated (AFAP) polyposis linked to APC gene follow a dominant mode of inheritance, whereas the MUTYH-associated disease (MAP) is recessively transmitted. The great majority of APC ...