title: Molecular analysis of the APC and MUTYH genes in Galician and Catalonian FAP families: a different spectrum of mutations?
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Fundación Pública Galega de Medicina Xenómica, Grupo de Medicina Xenómica-USC, CIBERER, Santiago de Compostela, Galicia, Spain. nuria.gomez@usc.es
authors.forename: Nuria
authors.initials: N
authors.lastname: Gómez-Fernández
authors.forename: Sergi
authors.initials: S
authors.lastname: Castellví-Bel
authors.forename: Ceres
authors.initials: C
authors.lastname: Fernández-Rozadilla
authors.forename: Francesc
authors.initials: F
authors.lastname: Balaguer
authors.forename: Jenifer
authors.initials: J
authors.lastname: Muñoz
authors.forename: Irene
authors.initials: I
authors.lastname: Madrigal
authors.forename: Montserrat
authors.initials: M
authors.lastname: Milà
authors.forename: Begoña
authors.initials: B
authors.lastname: Graña
authors.forename: Ana
authors.initials: A
authors.lastname: Vega
authors.forename: Antoni
authors.initials: A
authors.lastname: Castells
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.forename: Clara
authors.initials: C
authors.lastname: Ruiz-Ponte
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D045647:DNA Glycosylases / Q000235:genetics*; D005006:Ethnicity; D005260:Female; D005787:Gene Frequency; D017491:Genes, APC; D018095:Germ-Line Mutation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D021141:Nucleic Acid Amplification Techniques; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D013030:Spain; D055815:Young Adult
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase