RESUMEN
Two main colorectal polyposis syndromes have been described, familial adenomatous polyposis and MUTYH-associated polyposis syndromes. Some polyposis remains unexplained: 20% of adenomatous polyposis and serrated polyposis. The aim of this study was to evaluate in a cohort of patients with unexplained polyposis whether a genetic defect could be detected. Individuals presenting polyposis with more than 40 adenomas or more than 20 serrated polyps (hyperplastic, sessile serrated and mixed), without causative mutation identified, were included. Complementary explorations on APC or MUTYH were performed: search for APC mosaicism, splicing-affecting mutations, large genomic rearrangement of MUTYH. Four genes of Wnt pathway (AXIN2, PPP2R1B, WIF1, SFRP1) and two genes of transforming growth factor-ß (TGF-ß) pathway (SMAD4, BMPR1A) were screened for germline mutation. Twenty-five patients had an unexplained adenomatous polyposis (familial or sporadic). Five pathogenic mutations were found: four in APC gene (with one case of mosaicism) and one in BMPR1A gene. The exploration of APC mosaicism was better performed from adenoma DNA with high-resolution melting. The screening of the candidate genes did not find any causative mutation. Thirteen individuals had an unexplained serrated polyposis and a frameshift on SMAD4 gene was identified. All mutations were identified in familial cases of polyposis. After new pathological examination, both BMPR1A and SMAD4 cases were found to be associated with a juvenile polyposis while the polyposis was initially described as adenomatous or undetermined. In 17% (6/38) of the patients the causative mutation of the polyposis was identified. Genetic causes were heterogeneous. Sporadic polyposis patients must be considered as potential APC mosaicism. The histological classification of polyposis is strongly important in direct genetic exploration.
Asunto(s)
Poliposis Adenomatosa del Colon/diagnóstico , Poliposis Adenomatosa del Colon/genética , Poliposis Adenomatosa del Colon/patología , Proteína de la Poliposis Adenomatosa del Colon/genética , Adulto , Anciano , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Estudios de Cohortes , ADN Glicosilasas/genética , Análisis Mutacional de ADN , Mutación del Sistema de Lectura , Enfermedades Gastrointestinales/diagnóstico , Enfermedades Gastrointestinales/genética , Enfermedades Gastrointestinales/patología , Pruebas Genéticas , Mutación de Línea Germinal , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Mosaicismo , Desnaturalización de Ácido Nucleico , Mutación Puntual , Proteína Smad4/genética , Vía de Señalización Wnt/genéticaRESUMEN
OBJECTIVES: Sporadic colorectal cancer is influenced by numerous single nucleotide polymorphisms (SNPs), each with minor effects on the cancer risk. This study seeks to determine whether there is any association of the I1307K, E1317Q and D1822V variants within the Adenomatous polyposis coli gene (APC) and risk to develop colorectal cancer in Tunisian population. METHODS: Direct sequencing was used to investigate three SNPs in the APC in 48 Tunisian sporadic colorectal cancer cases and 63 controls. RESULTS: There was no statistically significant association between the I1307K, E1317Q and D1822V variants investigated and colorectal cancer risk. CONCLUSION: The lack of association may show that these variants selected for this study are not involved in the colorectal carcinogenic process. Otherwise, the eventual biological effect is so little to go undetected, unless increasing the sample size.