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Clinical characterization and the mutation spectrum in Swedish adenomatous polyposis families
Department of Molecular and Clinical Genetics, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
The Swedish Polyposis Registry, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
Department of Molecular and Clinical Genetics, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
Department of Molecular and Clinical Genetics, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
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2008 (English)In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 6, article id 6Article in journal (Refereed) Published
Abstract [en]

Background: The dominantly inherited condition familial adenomatous polyposis (FAP) is caused by germline mutations in the APC gene. Finding the causative mutations has great implications for the families. Correlating the genotypes to the phenotypes could help to improve the diagnosis and follow-up of patients.

Methods: Mutation screening of APCand the clinical characterization of 96 unrelated FAP patients from the Swedish Polyposis Registry was performed. In addition to generally used mutation screening methods, analyses of splicing-affecting mutations and investigations of the presence of low-frequency mutation alleles, indicating mosaics, have been performed, as well as quantitative real-time polymerase chain reaction to detect lowered expression of APC.

Results: Sixty-one different APC mutations in 81 of the 96 families were identified and 27 of those are novel. We have previously shown that 6 of the 96 patients carried biallelic MUTYH mutations. The 9 mutation-negative cases all display an attenuated or atypical phenotype. Probands with a genotype (codon 1250-1464) predicting a severe phenotype had a median age at diagnosis of 21.8 (range, 11-49) years compared with 34.4 (range, 14-57) years among those with mutations outside this region (P < 0.017). Dense polyposis (> 1000) occurred in 75% of the probands with a severe phenotype compared with 30% in those with mutations outside this region. The morbidity in colorectal cancer among probands was 25% at a mean age of 37.5 years and 29% at a mean age of 46.6 years.

Conclusion: Using a variety of mutation-detection techniques, we have achieved a 100% detection frequency in classical FAP. Probands with APC mutations outside codon 1250-1464, although exhibiting a less-severe phenotype, are at high risk of having a colorectal cancer at diagnosis indicating that age at diagnosis is as important as the severity of the disease for colorectal cancer morbidity. © 2008 Kanter-Smoler et al; licensee BioMed Central Ltd.

Place, publisher, year, edition, pages
BioMed Central, 2008. Vol. 6, article id 6
Keywords [en]
APC protein, DNA glycosylase MutY, DNA glycosyltransferase, adolescent, adult, age, aged, article, cancer risk, codon, colon polyposis, colorectal cancer, controlled study, disease severity, family, female, gene deletion, gene expression, gene mutation, genetic risk, genetic screening, genotype, high risk population, human, human tissue, ileorectal anastomosis, major clinical study, male, morbidity, mosaicism, mutational analysis, phenotype, prediction, quantitative analysis, real time polymerase chain reaction, school child, statistical significance, Sweden, total colon resection, colorectal tumor, gene frequency, genetics, nucleotide sequence, pathology, pathophysiology, tumor suppressor gene, Adenomatous Polyposis Coli, Colorectal Neoplasms, DNA Glycosylases, DNA Mutational Analysis, Genes, APC, Humans, Sequence Deletion
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:hj:diva-39622DOI: 10.1186/1741-7015-6-10ISI: 000256299900001PubMedID: 18433509Scopus ID: 2-s2.0-44049105290OAI: oai:DiVA.org:hj-39622DiVA, id: diva2:1211800
Available from: 2018-05-31 Created: 2018-05-31 Last updated: 2018-05-31Bibliographically approved

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