B Rivera1, S González2, E Sánchez-Tomé3, I Blanco4, F Mercadillo3, R Letón5, J Benítez1, M Robledo6, G Capellá7, M Urioste8. 1. Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Valencia; Human Genetics Group, Human Cancer genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid. 2. Molecular Diagnosis Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona. 3. Human Genetics Group, Human Cancer genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid. 4. Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL and FIGTP-Catalan Institute of Oncology, Barcelona. 5. Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, CNIO, Madrid. 6. Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Valencia; Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, CNIO, Madrid. 7. Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain. 8. Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Valencia; Human Genetics Group, Human Cancer genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid. Electronic address: murioste@cnio.es.
Abstract
BACKGROUND: Classical familial adenomatous polyposis (FAP) is characterized by the appearance of >100 colorectal adenomas. PATIENTS AND METHODS: We screened the APC and MUTYH genes for mutations and evaluated the genotype-phenotype correlation in 136 Spanish classical FAP families. RESULTS: APC/MUTYH mutations were detected in 107 families. Sixty-four distinct APC point mutations were detected in 95 families of which all were truncating mutations. A significant proportion (39.6%) had not been previously reported. Mutations were spread over the entire coding region and great rearrangements were identified in six families. Another six families exhibited biallelic MUTYH mutations. No APC or MUTYH mutations were detected in 29 families. These APC/MUTYH-negative families showed clinical differences with the APC-positive families. A poor correlation between phenotype and mutation site was observed. CONCLUSIONS: Our results highlight that a broad approach in the genetic study must be considered for classical FAP due to involvement of both APC and MUTYH and the heterogeneous spectrum of APC mutations observed in this Spanish population. The scarcely consistent genotype-phenotype correlation does not allow making specific recommendations regarding screening and management. Differences observed in APC/MUTYH-negative families may reflect a genetic basis other than mutations in APC and MUTYH genes for FAP predisposition.
BACKGROUND:Classical familial adenomatous polyposis (FAP) is characterized by the appearance of >100 colorectal adenomas. PATIENTS AND METHODS: We screened the APC and MUTYH genes for mutations and evaluated the genotype-phenotype correlation in 136 Spanish classical FAP families. RESULTS:APC/MUTYH mutations were detected in 107 families. Sixty-four distinct APC point mutations were detected in 95 families of which all were truncating mutations. A significant proportion (39.6%) had not been previously reported. Mutations were spread over the entire coding region and great rearrangements were identified in six families. Another six families exhibited biallelic MUTYH mutations. No APC or MUTYH mutations were detected in 29 families. These APC/MUTYH-negative families showed clinical differences with the APC-positive families. A poor correlation between phenotype and mutation site was observed. CONCLUSIONS: Our results highlight that a broad approach in the genetic study must be considered for classical FAP due to involvement of both APC and MUTYH and the heterogeneous spectrum of APC mutations observed in this Spanish population. The scarcely consistent genotype-phenotype correlation does not allow making specific recommendations regarding screening and management. Differences observed in APC/MUTYH-negative families may reflect a genetic basis other than mutations in APC and MUTYH genes for FAP predisposition.
Authors: Frederik J Hes; Dina Ruano; Marry Nieuwenhuis; Carli M Tops; Melanie Schrumpf; Maartje Nielsen; Petra E A Huijts; Juul T Wijnen; Anja Wagner; Encarna B Gómez García; Rolf H Sijmons; Fred H Menko; Tom G W Letteboer; Nicoline Hoogerbrugge; Jan Harryvan; Ellen Kampman; Hans Morreau; Hans F A Vasen; Tom van Wezel Journal: J Med Genet Date: 2013-11-19 Impact factor: 6.318