Tags

Type your tag names separated by a space and hit enter

Contribution of APC and MUTYH mutations to familial adenomatous polyposis susceptibility in Hungary.
Fam Cancer. 2016 Jan; 15(1):85-97.FC

Abstract

Familial adenomatous polyposis (FAP) is a colorectal cancer predisposition syndrome with considerable genetic and phenotypic heterogeneity, defined by the development of multiple adenomas throughout the colorectum. FAP is caused either by monoallelic mutations in the adenomatous polyposis coli gene APC, or by biallelic germline mutations of MUTYH, this latter usually presenting with milder phenotype. The aim of the present study was to characterize the genotype and phenotype of Hungarian FAP patients. Mutation screening of 87 unrelated probands from FAP families (21 of them presented as the attenuated variant of the disease, showing <100 polyps) was performed using DNA sequencing and multiplex ligation-dependent probe amplification. Twenty-four different pathogenic mutations in APC were identified in 65 patients (75 %), including nine cases (37.5 %) with large genomic alterations. Twelve of the point mutations were novel. In addition, APC-negative samples were also tested for MUTYH mutations and we were able to identify biallelic pathogenic mutations in 23 % of these cases (5/22). Correlations between the localization of APC mutations and the clinical manifestations of the disease were observed, cases with a mutation in the codon 1200-1400 region showing earlier age of disease onset (p < 0.003). There were only a few, but definitive dissimilarities between APC- and MUTYH-associated FAP in our cohort: the age at onset of polyposis was significantly delayed for biallelic MUTYH mutation carriers as compared to patients with an APC mutation. Our data represent the first comprehensive study delineating the mutation spectra of both APC and MUTYH in Hungarian FAP families, and underscore the overlap between the clinical characteristics of APC- and MUTYH-associated phenotypes, necessitating a more appropriate clinical characterization of FAP families.

Authors+Show Affiliations

Department of Molecular Genetics, National Institute of Oncology, Rath Gy. u. 7-9, Budapest, 1122, Hungary.Department of Molecular Genetics, National Institute of Oncology, Rath Gy. u. 7-9, Budapest, 1122, Hungary. Hamon Center for Therapeutic Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.Department of General Surgery, National Institute of Oncology, Budapest, Hungary.Department of Clinical Central Laboratory, National Institute of Oncology, Budapest, Hungary.Multidisciplinary Centre of Head and Neck Oncology, National Institute of Oncology, Budapest, Hungary.Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.Department of Molecular Genetics, National Institute of Oncology, Rath Gy. u. 7-9, Budapest, 1122, Hungary. e.olah@oncol.hu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26446593

Citation

Papp, Janos, et al. "Contribution of APC and MUTYH Mutations to Familial Adenomatous Polyposis Susceptibility in Hungary." Familial Cancer, vol. 15, no. 1, 2016, pp. 85-97.
Papp J, Kovacs ME, Matrai Z, et al. Contribution of APC and MUTYH mutations to familial adenomatous polyposis susceptibility in Hungary. Fam Cancer. 2016;15(1):85-97.
Papp, J., Kovacs, M. E., Matrai, Z., Orosz, E., Kásler, M., Børresen-Dale, A. L., & Olah, E. (2016). Contribution of APC and MUTYH mutations to familial adenomatous polyposis susceptibility in Hungary. Familial Cancer, 15(1), 85-97. https://doi.org/10.1007/s10689-015-9845-5
Papp J, et al. Contribution of APC and MUTYH Mutations to Familial Adenomatous Polyposis Susceptibility in Hungary. Fam Cancer. 2016;15(1):85-97. PubMed PMID: 26446593.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Contribution of APC and MUTYH mutations to familial adenomatous polyposis susceptibility in Hungary. AU - Papp,Janos, AU - Kovacs,Marietta Eva, AU - Matrai,Zoltan, AU - Orosz,Enikő, AU - Kásler,Miklós, AU - Børresen-Dale,Anne-Lise, AU - Olah,Edith, PY - 2015/10/9/entrez PY - 2015/10/9/pubmed PY - 2016/10/7/medline KW - APC KW - Colorectal cancer KW - Familial adenomatous polyposis KW - Genotype–phenotype correlations KW - Germline mutations KW - MUTYH SP - 85 EP - 97 JF - Familial cancer JO - Fam. Cancer VL - 15 IS - 1 N2 - Familial adenomatous polyposis (FAP) is a colorectal cancer predisposition syndrome with considerable genetic and phenotypic heterogeneity, defined by the development of multiple adenomas throughout the colorectum. FAP is caused either by monoallelic mutations in the adenomatous polyposis coli gene APC, or by biallelic germline mutations of MUTYH, this latter usually presenting with milder phenotype. The aim of the present study was to characterize the genotype and phenotype of Hungarian FAP patients. Mutation screening of 87 unrelated probands from FAP families (21 of them presented as the attenuated variant of the disease, showing <100 polyps) was performed using DNA sequencing and multiplex ligation-dependent probe amplification. Twenty-four different pathogenic mutations in APC were identified in 65 patients (75 %), including nine cases (37.5 %) with large genomic alterations. Twelve of the point mutations were novel. In addition, APC-negative samples were also tested for MUTYH mutations and we were able to identify biallelic pathogenic mutations in 23 % of these cases (5/22). Correlations between the localization of APC mutations and the clinical manifestations of the disease were observed, cases with a mutation in the codon 1200-1400 region showing earlier age of disease onset (p < 0.003). There were only a few, but definitive dissimilarities between APC- and MUTYH-associated FAP in our cohort: the age at onset of polyposis was significantly delayed for biallelic MUTYH mutation carriers as compared to patients with an APC mutation. Our data represent the first comprehensive study delineating the mutation spectra of both APC and MUTYH in Hungarian FAP families, and underscore the overlap between the clinical characteristics of APC- and MUTYH-associated phenotypes, necessitating a more appropriate clinical characterization of FAP families. SN - 1573-7292 UR - https://www.unboundmedicine.com/medline/citation/26446593/Contribution_of_APC_and_MUTYH_mutations_to_familial_adenomatous_polyposis_susceptibility_in_Hungary_ L2 - https://doi.org/10.1007/s10689-015-9845-5 DB - PRIME DP - Unbound Medicine ER -