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Background  Familial adenomatous polyposis (FAP) is an autosomal dominant-inherited colorectal cancer syndrome, caused by germline mutations in the  APC  gene. Recently, biallelic mutations in  MUTYH  have also been identified in patients with multiple colorectal adenomas and in  APC -negative patients with FAP. The aim of this work is therefore to determine the frequency of  APC  and  MUTYH  mutations among FAP families from two Spanish populations.    Methods  Eighty-two unrelated patients with classical or attenuated FAP were screened for  APC  germline mutations.  MUTYH  analysis was then conducted in those  APC -negative families and in 9 additional patients from a previous study. Direct sequencing, SSCP analysis and TaqMan genotyping were used to identify point and frameshift mutations, meanwhile large rearrangements in the  APC  gene were screened by multiplex ligation-dependent probe amplification (MLPA).    Results   APC  germline mutations were found in 39% of the patients and, despite the great number of genetic variants described so far in this gene, seven new mutations were identified. The two hotspots at codons 1061 and 1309 of the  APC  gene accounted for 9,4% of the  APC -positive families, although they were underrepresented in Galician samples. The deletion at codon 1061 was not found in 19  APC -positive Galician patients but represented 23% of the Catalonian positive families (p = 0,058). The same trend was observed at codon 1309, even though statistical analysis showed no significance between populations. Twenty-four percent of the  APC -negative patients carried biallelic  MUTYH  germline mutations, and showed an attenuated polyposis phenotype generally without extracolonic manifestations. New genetic variants were found, as well as the two hotspots already reported (p.Tyr165Cys and p.Gly382Asp).    Conclusion  The results we present indicate that in Galician patients the frequency of the hotspot at codon 1061 in  APC  differs significantly from the Catalonian and also other Caucasian populations. Similar results had already been obtained in a previous study and could be due to the genetic isolation of the Galician population.  MUTYH  analysis is also recommended for all  APC -negative families, even if a recessive inheritance is not confirmed.

Molecular analysis of the APC and MUTYH genes in Galician and Catalonian FAP families: a different spectrum of mutations?