title: Reduced expression of APC-1B but not APC-1A by the deletion of promoter 1B is responsible for familial adenomatous polyposis.
abstract: Germline mutations in the tumor suppressor gene APC are associated with familial adenomatous polyposis (FAP). Here we applied whole-genome sequencing (WGS) to the DNA of a sporadic FAP patient in which we did not find any pathological APC mutations by direct sequencing. WGS identified a promoter deletion of approximately 10 kb encompassing promoter 1B and exon1B of APC. Additional allele-specific expression analysis by deep cDNA sequencing revealed that the deletion reduced the expression of the mutated APC allele to as low as 11.2% in the total APC transcripts, suggesting that the residual mutant transcripts were driven by other promoter(s). Furthermore, cap analysis of gene expression (CAGE) demonstrated that the deleted promoter 1B region is responsible for the great majority of APC transcription in many tissues except the brain. The deletion decreased the transcripts of APC-1B to 39-45% in the patient compared to the healthy controls, but it did not decrease those of APC-1A. Different deletions including promoter 1B have been reported in FAP patients. Taken together, our results strengthen the evidence that analysis of structural variations in promoter 1B should be considered for the FAP patients whose pathological mutations are not identified by conventional direct sequencing.
authors.affiliation: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Gastroenterology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nagayama
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, 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 108-8639, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Komura
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Rui
authors.initials: R
authors.lastname: Yamaguchi
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shibuya
authors.affiliation: Department of Clinical Genetic Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Arai
authors.affiliation: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, 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 108-8639, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Ikenoue
authors.affiliation: Gastroenterology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ueno
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.|Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.|Division of Health Medical Computational Science, Health Intelligence Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Division of Health Medical Data Science, Health Intelligence Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Seiya
authors.initials: S
authors.lastname: Imoto
authors.affiliation: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, 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; D005786:Gene Expression Regulation; D018095:Germ-Line Mutation / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D009928:Organ Specificity / Q000235:genetics; D010375:Pedigree; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000073336:Whole Genome Sequencing / Q000379:methods*
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D020033:Protein Isoforms; D025521:Tumor Suppressor Proteins