Mutational spectrum of APC and genotype-phenotype correlations in Greek FAP patients

Abstract

Background: Familial adenomatous polyposis, an autosomal dominant inherited disease caused by germline mutations within the APC gene, is characterized by early onset colorectal cancer as a consequence of the intrinsic phenotypic feature of multiple colorectal adenomatic polyps. The genetic investigation of Greek adenomatous polyposis families was performed in respects to APC and MUTYH germline mutations. Additionally, all available published mutations were considered in order to define the APC mutation spectrum in Greece.

Methods: A cohort of 25 unrelated adenomatous polyposis families of Greek origin has been selected. Genetic testing included direct sequencing of APC and MUTYH genes. APC gene was also checked for large genomic rearrangements by MLPA.

Results: Analysis of the APC gene performed in a Greek cohort of twenty five FAP families revealed eighteen different germline mutations in twenty families (80%), four of which novel. Mutations were scattered between exon 3 and codon 1503 of exon 15, while no large genomic rearrangements were identified.

Conclusion: This concise report describes the spectrum of all APC mutations identified in Greek FAP families, including four novel mutations. It is concluded that the Greek population is characterized by genetic heterogeneity, low incidence of genomic rearrangements in APC gene and lack of founder mutation in FAP syndrome.

Figure 1

The mutational spectrum of APC germline mutations identified in 35 unrelated Greek families. Each bullet represents a carrier family of an APC germline mutation. Black bullets represent mutations identified by our group, whereas grey bullets represent mutations identified by others in Greek families. * [29], ° [30], ^ [31]

Figure 2

Characterization of the intonic base substitution causing alternative splicing. (A) DNA sequence of intron 7-exon 8 boundaries, where the AG acceptor site is highlighted in the dotted box in both the wild type and the mutant DNA and the premature termination codon is coloured in red. (B) The 7-bp insertion upstream of exon 8 on cDNA from the patient is coloured in grey.