title: Somatic APC mosaicism: a frequent cause of familial adenomatous polyposis (FAP).
abstract: Somatic mutational mosaicism presents a challenge for both molecular and clinical diagnostics and may contribute to deviations from predicted genotype-phenotype correlations. During APC mutation screening in 1,248 unrelated patients with familial adenomatous polyposis (FAP), we identified 75 cases with an assumed or confirmed de novo mutation. Prescreening methods (protein truncation test [PTT], DHPLC) indicated the presence of somatic mosaicism in eight cases (11%). Sequencing of the corresponding fragments revealed very weak mutation signals, pointing to the presence of either nonsense or frameshift mutations at low level. All mutations were confirmed and quantified by SNaPshot analysis: in leukocyte DNA from the eight patients, the percentage of mosaicism varied between 5.5% and 77%, while the proportion of the mutation in DNA extracted from adenomas of the respective patient was consistently higher. The eight mutations identified as mosaic are localized within codons 216-1464 of the APC gene. According to the known genotype-phenotype correlation, patients with mutations in this region exhibit typical or severe FAP. However, six of the eight patients presented with an attenuated or atypical polyposis phenotype. Our data demonstrate that in a fraction of FAP patients the causative APC mutation may not be detected due to weak signals or somatic mosaicism that is restricted to tissues other than blood. SNaPshot analysis was proven to be an easy, rapid, and reliable method of confirming low-level mutations and evaluating the degree of mosaicism. Some of the deviations from the expected phenotype in FAP can be explained by the presence of somatic mosaicism.
authors.affiliation: Institute of Human Genetics, University Hospital of Bonn, Bonn, Germany. Stefan.Aretz@ukb.uni-bonn.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Aretz
authors.forename: Dietlinde
authors.initials: D
authors.lastname: Stienen
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Friedrichs
authors.forename: Susanne
authors.initials: S
authors.lastname: Stemmler
authors.forename: Siegfried
authors.initials: S
authors.lastname: Uhlhaas
authors.forename: Nils
authors.initials: N
authors.lastname: Rahner
authors.forename: Peter
authors.initials: P
authors.lastname: Propping
authors.forename: Waltraut
authors.initials: W
authors.lastname: Friedl
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism; D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D001483:Base Sequence; D003062:Codon; D004247:DNA / Q000378:metabolism; D017491:Genes, APC; D005838:Genotype; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D019656:Loss of Heterozygosity; D008969:Molecular Sequence Data; D009030:Mosaicism; D009154:Mutation; D010641:Phenotype; D014018:Tissue Distribution
chemical_list: D003062:Codon; D004247:DNA