Development of an MSI-positive colon tumor with aberrant DNA methylation in a PPAP patient.
Aged
Alleles
Colonic Neoplasms
/ diagnosis
Colorectal Neoplasms, Hereditary Nonpolyposis
/ diagnosis
DNA Methylation
DNA Mutational Analysis
DNA Polymerase II
/ genetics
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
/ genetics
Repressor Proteins
/ genetics
Whole Genome Sequencing
Journal
Journal of human genetics
ISSN: 1435-232X
Titre abrégé: J Hum Genet
Pays: England
ID NLM: 9808008
Informations de publication
Date de publication:
Aug 2019
Aug 2019
Historique:
received:
24
10
2018
accepted:
19
04
2019
revised:
18
03
2019
pubmed:
16
5
2019
medline:
18
12
2019
entrez:
16
5
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31089268
doi: 10.1038/s10038-019-0611-7
pii: 10.1038/s10038-019-0611-7
doi:
Substances chimiques
Poly-ADP-Ribose Binding Proteins
0
Repressor Proteins
0
tetracycline resistance-encoding transposon repressor protein
0
DNA Polymerase II
EC 2.7.7.7
POLE protein, human
EC 2.7.7.7
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
729-740Subventions
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 16H01569
Organisme : MEXT | Japan Science and Technology Agency (JST)
ID : Center of Innovation program
Commentaires et corrections
Type : CommentIn
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