Abstract
BackgroundFamilial 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.MethodsEighty-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).ResultsAPC 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).ConclusionThe 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.
Highlights
Familial adenomatous polyposis (FAP) is an autosomal dominant-inherited colorectal cancer syndrome, caused by germline mutations in the adenomatous polyposis coli (APC) gene
MUTYH analysis is recommended for all APC-negative families, even if a recessive inheritance is not confirmed
The genetic basis of most cases of FAP is a germline mutation of the adenomatous polyposis coli (APC) gene (5q21), which encodes a tumor suppressor protein involved in regulation of cell proliferation and chromosome segregation [3]
Summary
Familial adenomatous polyposis (FAP) is an autosomal dominant-inherited colorectal cancer syndrome, caused by germline mutations in the APC gene. Familial adenomatous polyposis (FAP; OMIM#175100) is a rare autosomal dominant colorectal cancer predisposition syndrome, characterised by the presence of hundreds to thousands of adenomatous polyps in the colon and rectum from an early age. In the absence of prophylactic surgery, colorectal cancer (CRC) is the inevitable consequence of FAP. Attenuated FAP (AFAP) is a clinical variant characterised by the presence of fewer than 100 colonic polyps, and often has a later age of onset of polyposis and CRC [2]. The genetic basis of most cases of FAP is a germline mutation of the adenomatous polyposis coli (APC) gene (5q21), which encodes a tumor suppressor protein involved in regulation of cell proliferation and chromosome segregation [3]. In AFAP, germline mutations have been generally detected either in exon 9 or the 5' and 3' ends of the gene [5]
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