Detection of coding microsatellite frameshift mutations in DNA mismatch repair-deficient mouse intestinal tumors

Stefan M. Woerner, Elena Tosti, Yan P. Yuan, Matthias Kloor, Peer Bork, Winfried Edelmann, Johannes Gebert

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Different DNA mismatch repair (MMR)-deficient mouse strains have been developed as models for the inherited cancer predisposing Lynch syndrome. It is completely unresolved, whether coding mononucleotide repeat (cMNR) gene mutations in these mice can contribute to intestinal tumorigenesis and whether MMR-deficient mice are a suitable molecular model of human microsatellite instability (MSI)-associated intestinal tumorigenesis. A proof-of-principle study was performed to identify mouse cMNR-harboring genes affected by insertion/deletion mutations in MSI murine intestinal tumors. Bioinformatic algorithms were developed to establish a database of mouse cMNR-harboring genes. A panel of five mouse noncoding mononucleotide markers was used for MSI classification of intestinal matched normal/tumor tissues from MMR-deficient (Mlh1-/-, Msh2-/-, Msh2LoxP/LoxP) mice. cMNR frameshift mutations of candidate genes were determined by DNA fragment analysis. Murine MSI intestinal tumors but not normal tissues from MMR-deficient mice showed cMNR frameshift mutations in six candidate genes (Elavl3, Tmem107, Glis2, Sdccag1, Senp6, Rfc3). cMNRs of mouse Rfc3 and Elavl3 are conserved in type and length in their human orthologs that are known to be mutated in human MSI colorectal, endometrial and gastric cancer. We provide evidence for the utility of a mononucleotide marker panel for detection of MSI in murine tumors, the existence of cMNR instability in MSI murine tumors, the utility of mouse subspecies DNA for identification of polymorphic repeats, and repeat conservation among some orthologous human/mouse genes, two of them showing instability in human and mouse MSI intestinal tumors. MMR-deficient mice hence are a useful molecular model system for analyzing MSI intestinal carcinogenesis.

Original languageEnglish (US)
Pages (from-to)1376-1386
Number of pages11
JournalMolecular Carcinogenesis
Volume54
Issue number11
DOIs
StatePublished - Nov 1 2015

Fingerprint

Frameshift Mutation
DNA Mismatch Repair
Microsatellite Repeats
Microsatellite Instability
Neoplasms
Carcinogenesis
Molecular Models
Genes
INDEL Mutation
Hereditary Nonpolyposis Colorectal Neoplasms
Insertional Mutagenesis
DNA
Endometrial Neoplasms
Computational Biology
Stomach Neoplasms
Colorectal Neoplasms

Keywords

  • Coding microsatellite instability
  • MMR-deficient mice
  • MSI intestinal carcinogenesis
  • MSI target genes

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

Detection of coding microsatellite frameshift mutations in DNA mismatch repair-deficient mouse intestinal tumors. / Woerner, Stefan M.; Tosti, Elena; Yuan, Yan P.; Kloor, Matthias; Bork, Peer; Edelmann, Winfried; Gebert, Johannes.

In: Molecular Carcinogenesis, Vol. 54, No. 11, 01.11.2015, p. 1376-1386.

Research output: Contribution to journalArticle

Woerner, Stefan M. ; Tosti, Elena ; Yuan, Yan P. ; Kloor, Matthias ; Bork, Peer ; Edelmann, Winfried ; Gebert, Johannes. / Detection of coding microsatellite frameshift mutations in DNA mismatch repair-deficient mouse intestinal tumors. In: Molecular Carcinogenesis. 2015 ; Vol. 54, No. 11. pp. 1376-1386.
@article{3905005ed2db44bea0ae0fc5db931bf5,
title = "Detection of coding microsatellite frameshift mutations in DNA mismatch repair-deficient mouse intestinal tumors",
abstract = "Different DNA mismatch repair (MMR)-deficient mouse strains have been developed as models for the inherited cancer predisposing Lynch syndrome. It is completely unresolved, whether coding mononucleotide repeat (cMNR) gene mutations in these mice can contribute to intestinal tumorigenesis and whether MMR-deficient mice are a suitable molecular model of human microsatellite instability (MSI)-associated intestinal tumorigenesis. A proof-of-principle study was performed to identify mouse cMNR-harboring genes affected by insertion/deletion mutations in MSI murine intestinal tumors. Bioinformatic algorithms were developed to establish a database of mouse cMNR-harboring genes. A panel of five mouse noncoding mononucleotide markers was used for MSI classification of intestinal matched normal/tumor tissues from MMR-deficient (Mlh1-/-, Msh2-/-, Msh2LoxP/LoxP) mice. cMNR frameshift mutations of candidate genes were determined by DNA fragment analysis. Murine MSI intestinal tumors but not normal tissues from MMR-deficient mice showed cMNR frameshift mutations in six candidate genes (Elavl3, Tmem107, Glis2, Sdccag1, Senp6, Rfc3). cMNRs of mouse Rfc3 and Elavl3 are conserved in type and length in their human orthologs that are known to be mutated in human MSI colorectal, endometrial and gastric cancer. We provide evidence for the utility of a mononucleotide marker panel for detection of MSI in murine tumors, the existence of cMNR instability in MSI murine tumors, the utility of mouse subspecies DNA for identification of polymorphic repeats, and repeat conservation among some orthologous human/mouse genes, two of them showing instability in human and mouse MSI intestinal tumors. MMR-deficient mice hence are a useful molecular model system for analyzing MSI intestinal carcinogenesis.",
keywords = "Coding microsatellite instability, MMR-deficient mice, MSI intestinal carcinogenesis, MSI target genes",
author = "Woerner, {Stefan M.} and Elena Tosti and Yuan, {Yan P.} and Matthias Kloor and Peer Bork and Winfried Edelmann and Johannes Gebert",
year = "2015",
month = "11",
day = "1",
doi = "10.1002/mc.22213",
language = "English (US)",
volume = "54",
pages = "1376--1386",
journal = "Molecular Carcinogenesis",
issn = "0899-1987",
publisher = "Wiley-Liss Inc.",
number = "11",

}

TY - JOUR

T1 - Detection of coding microsatellite frameshift mutations in DNA mismatch repair-deficient mouse intestinal tumors

AU - Woerner, Stefan M.

AU - Tosti, Elena

AU - Yuan, Yan P.

AU - Kloor, Matthias

AU - Bork, Peer

AU - Edelmann, Winfried

AU - Gebert, Johannes

PY - 2015/11/1

Y1 - 2015/11/1

N2 - Different DNA mismatch repair (MMR)-deficient mouse strains have been developed as models for the inherited cancer predisposing Lynch syndrome. It is completely unresolved, whether coding mononucleotide repeat (cMNR) gene mutations in these mice can contribute to intestinal tumorigenesis and whether MMR-deficient mice are a suitable molecular model of human microsatellite instability (MSI)-associated intestinal tumorigenesis. A proof-of-principle study was performed to identify mouse cMNR-harboring genes affected by insertion/deletion mutations in MSI murine intestinal tumors. Bioinformatic algorithms were developed to establish a database of mouse cMNR-harboring genes. A panel of five mouse noncoding mononucleotide markers was used for MSI classification of intestinal matched normal/tumor tissues from MMR-deficient (Mlh1-/-, Msh2-/-, Msh2LoxP/LoxP) mice. cMNR frameshift mutations of candidate genes were determined by DNA fragment analysis. Murine MSI intestinal tumors but not normal tissues from MMR-deficient mice showed cMNR frameshift mutations in six candidate genes (Elavl3, Tmem107, Glis2, Sdccag1, Senp6, Rfc3). cMNRs of mouse Rfc3 and Elavl3 are conserved in type and length in their human orthologs that are known to be mutated in human MSI colorectal, endometrial and gastric cancer. We provide evidence for the utility of a mononucleotide marker panel for detection of MSI in murine tumors, the existence of cMNR instability in MSI murine tumors, the utility of mouse subspecies DNA for identification of polymorphic repeats, and repeat conservation among some orthologous human/mouse genes, two of them showing instability in human and mouse MSI intestinal tumors. MMR-deficient mice hence are a useful molecular model system for analyzing MSI intestinal carcinogenesis.

AB - Different DNA mismatch repair (MMR)-deficient mouse strains have been developed as models for the inherited cancer predisposing Lynch syndrome. It is completely unresolved, whether coding mononucleotide repeat (cMNR) gene mutations in these mice can contribute to intestinal tumorigenesis and whether MMR-deficient mice are a suitable molecular model of human microsatellite instability (MSI)-associated intestinal tumorigenesis. A proof-of-principle study was performed to identify mouse cMNR-harboring genes affected by insertion/deletion mutations in MSI murine intestinal tumors. Bioinformatic algorithms were developed to establish a database of mouse cMNR-harboring genes. A panel of five mouse noncoding mononucleotide markers was used for MSI classification of intestinal matched normal/tumor tissues from MMR-deficient (Mlh1-/-, Msh2-/-, Msh2LoxP/LoxP) mice. cMNR frameshift mutations of candidate genes were determined by DNA fragment analysis. Murine MSI intestinal tumors but not normal tissues from MMR-deficient mice showed cMNR frameshift mutations in six candidate genes (Elavl3, Tmem107, Glis2, Sdccag1, Senp6, Rfc3). cMNRs of mouse Rfc3 and Elavl3 are conserved in type and length in their human orthologs that are known to be mutated in human MSI colorectal, endometrial and gastric cancer. We provide evidence for the utility of a mononucleotide marker panel for detection of MSI in murine tumors, the existence of cMNR instability in MSI murine tumors, the utility of mouse subspecies DNA for identification of polymorphic repeats, and repeat conservation among some orthologous human/mouse genes, two of them showing instability in human and mouse MSI intestinal tumors. MMR-deficient mice hence are a useful molecular model system for analyzing MSI intestinal carcinogenesis.

KW - Coding microsatellite instability

KW - MMR-deficient mice

KW - MSI intestinal carcinogenesis

KW - MSI target genes

UR - http://www.scopus.com/inward/record.url?scp=84945437544&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84945437544&partnerID=8YFLogxK

U2 - 10.1002/mc.22213

DO - 10.1002/mc.22213

M3 - Article

C2 - 25213383

AN - SCOPUS:84945437544

VL - 54

SP - 1376

EP - 1386

JO - Molecular Carcinogenesis

JF - Molecular Carcinogenesis

SN - 0899-1987

IS - 11

ER -