Abstract 3765: APC and MUTYH mutation spectrum in Brazil: First genotype characterization of brazilian FAP and AFAP patients identifies 6 novel mutations
Authors: Torrezan Giovana T. , da Silva Felipe Cavalcanti Carneiro , Gomy Israel , Santos Erika Maria Monteiro , Rossi Benedito Mauro , Carraro Dirce Maria 
Published: June 2012

Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited colorectal cancer predisposing syndrome caused by mutations in the adenomatous polyposis coli (APC) gene. The most prominent clinical manifestation is the presence of hundreds to thousands of colorectal polyps. A milder phenotype is found in patients affected with attenuated FAP (AFAP), which can be caused by mutations in the untranslated region or the alternative spliced exon 9 of APC, or by biallelic mutations in the base-excision repair gene MUTYH. Characterization of causative mutations in these genes allows presymptomatic diagnosis, close follow-up and prophylactic intervention in affected families. We scanned the APC and MUTYH genes for disease-causing mutations in 16 unrelated Brazilian probands affected by classical or attenuated FAP. We performed DNA sequencing of the complete coding region of both genes, as well as long range PCR and allele specific PCR for confirmation of mutations. Patients with classical FAP (11) were first screened for APC mutations while patients with the attenuated phenotype or indicative of recessive heritance (5) were first screened for MUTYH mutations. We identified a specific mutation in 15 of the 16 probands (93,75%) – 11 in APC gene and 4 in MUTYH; 5 are novel germline pathogenic mutations, 9 are previously described mutations and one is a novel sequence variant in exon 15 of APC with unknown significance. This variant was classified by prediction programs SIFT and Polyhen as being tolerable and possibly damaging, respectively. In APC, most mutations resulted in premature truncation of translation caused by non-sense (36%) or change in reading frame (54%) due to small deletions (4), insertions (1) or duplications (1). The majority of mutations were located in exon 15 (64%), 2 in exon 8 and 1 in exon 4. Biallelic germline mutations in MUTYH were identified in 4 of the 16 patients (25%). Two patients presented the hotspot missense mutation p.Tyr179Cys accompanied by a truncation mutation (one deletion and one duplication). The biallelic nature of the mutations was confirmed by allele specific PCR and segregation analysis in unaffected relatives. One patient was homozygote by common origin for the missense mutation p.Arg241Trp and one was homozygote for a deletion of exons 4-15, identified by long range PCR. Finally, one patient had no mutation by the methods previously described and will be further screened by deep-sequencing of whole exonic regions. Analysis of the genotype/phenotype correlations showed similar results to those observed in other populations. This is the first comprehensive report of APC and MUTYH germline mutation spectrum in Brazil.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3765. doi:10.1158/1538-7445.AM2011-3765