title: Detection of APC mosaicism by next-generation sequencing in an FAP patient.
abstract: Familial adenomatous polyposis (FAP) of the colon is characterized by multiple polyps in the intestine and extra-colonic manifestations. Most FAP cases are caused by a germline mutation in the tumor-suppressor gene APC, but some cases of adenomatous polyposis result from germline mutations in MUTYH, POLD1 or POLE. Although sequence analysis of APC by the Sanger method is routinely performed for genetic testing, there remain cases whose mutations are not detected by the analysis. Next-generation sequencing has enabled us to analyze the comprehensive human genome, improving the chance of identifying disease causative variants. In this study, we conducted whole-genome sequencing of a sporadic FAP patient in which we did not find any pathogenic APC mutations by the conventional Sanger sequencing. Whole-genome sequencing and subsequent deep sequencing identified a mosaic mutation of c.3175G>T, p.E1059X in ~12% of his peripheral leukocytes. Additional deep sequencing of his buccal mucosa, hair follicles, non-cancerous mucosa of the stomach and colon disclosed that these tissues harbored the APC mutation at different frequencies. Our data implied that genetic analysis by next-generation sequencing is an effective strategy to identify genetic mosaicism in hereditary diseases.
authors.affiliation: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Komura
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Rui
authors.initials: R
authors.lastname: Yamaguchi
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Seiya
authors.initials: S
authors.lastname: Imoto
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Eigo
authors.initials: E
authors.lastname: Shimizu
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kasuya
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shibuya
authors.affiliation: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Seira
authors.initials: S
authors.lastname: Hatakeyama
authors.affiliation: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Ikenoue
authors.affiliation: Department of Surgery, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hata
authors.affiliation: Department of Surgery, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Giichiro
authors.initials: G
authors.lastname: Tsurita
authors.affiliation: Department of Surgery, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Shinozaki
authors.affiliation: Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Laboratory of Functional Genomics, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Sumio
authors.initials: S
authors.lastname: Sugano
authors.affiliation: 1] Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan [2] Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Furukawa
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000328:Adult; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009030:Mosaicism
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein