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Journal of human genetics
Aug, 2019;64 (8): 729-740.

Development of an MSI-positive colon tumor with aberrant DNA methylation in a PPAP patient.

Kiyoshi Yamaguchi, Eigo Shimizu, Rui Yamaguchi, Seiya Imoto, Mitsuhiro Komura, Seira Hatakeyama, Rei Noguchi, Kiyoko Takane, Tsuneo Ikenoue, Yoshimasa Gohda, Hideaki Yano, Satoru Miyano, Yoichi Furukawa
Author Information
  1. Kiyoshi Yamaguchi: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan. ORCID
  2. Eigo Shimizu: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
  3. Rui Yamaguchi: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
  4. Seiya Imoto: Division of Health Medical Data Science, Health Intelligence Center, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan. ORCID
  5. Mitsuhiro Komura: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
  6. Seira Hatakeyama: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
  7. Rei Noguchi: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
  8. Kiyoko Takane: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
  9. Tsuneo Ikenoue: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
  10. Yoshimasa Gohda: Department of Surgery, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan.
  11. Hideaki Yano: Department of Surgery, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan.
  12. Satoru Miyano: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
  13. Yoichi Furukawa: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan. furukawa@ims.u-tokyo.ac.jp. ORCID
PMID: 31089268 DOI: 10.1038/s10038-019-0611-7

Abstract

Polymerase proofreading-associated polyposis (PPAP) is a disease caused by germline variations in the POLE and POLD1 genes that encode catalytic subunits of DNA polymerases. Studies of cancer genomes have identified somatic mutations in these genes, suggesting the importance of polymerase proofreading of DNA replication in suppressing tumorigenesis. Here, we identified a germline frameshift variation in the POLE gene (c.4191_4192delCT, p.Tyr1398*) in a case with multiple adenomatous polyps and three synchronous colon cancers. Interestingly, one of the colon cancers showed microsatellite instability-high (MSI-H) and another microsatellite stable. Immunohistochemical staining revealed that the MSI-H tumor cells lost the expression of MLH1 protein. Whole genome sequencing of the MSI-H tumor did not find pathogenic somatic mutations in mismatch repair genes but found frameshift mutations in the TET genes that catalyze 5-methylcytosine hydroxylation. Bisulfite sequencing of the tumor corroborated an increase in the number of hypermethylated regions including the MLH1 promoter. These data indicate that PPAP patients might develop MSI-positive tumors through epigenetic silencing of MLH1. These findings will contribute to comprehensive understanding of the molecular basis of tumors that involve deficiency of proofreading activity of DNA polymerases.

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Grants

  1. 16H01569/MEXT | Japan Society for the Promotion of Science (JSPS)
  2. Center of Innovation program/MEXT | Japan Science and Technology Agency (JST)

MeSH Term

Aged
Alleles
Colonic Neoplasms
Colorectal Neoplasms, Hereditary Nonpolyposis
DNA Methylation
DNA Mutational Analysis
DNA Polymerase II
Female
Frameshift Mutation
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genetic Association Studies
Genetic Predisposition to Disease
Genotype
Germ-Line Mutation
Humans
Immunohistochemistry
Male
Microsatellite Instability
Neoplasm Staging
Pedigree
Phenotype
Poly-ADP-Ribose Binding Proteins
Repressor Proteins
Whole Genome Sequencing

Chemicals

Poly-ADP-Ribose Binding Proteins
Repressor Proteins
tetracycline resistance-encoding transposon repressor protein
DNA Polymerase II
POLE protein, human
Case Reports Journal Article
Article has an altmetric score of 4

Word Cloud

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