MSH3-Deficiency Initiates EMAST without Oncogenic Transformation of Human Colon Epithelial Cells

Campregher, Christoph; Schmid, Gerald; Ferk, Franziska; Knasmüller, Siegfried; Khare, Vineeta; Kortüm, Benedikt; Dammann, Kyle; Lang, Michaela; Scharl, Theresa; Spittler, Andreas; Roig, Andres I.; Shay, Jerry W.; Gerner, Christopher; Gasché, Christoph

doi:10.1371/journal.pone.0050541

Cited by 50 publications

(58 citation statements)

References 60 publications

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“…The frequent incidence of EMAST in CRCs was confirmed by two other studies (34,35). The fact that EMAST is due to the loss of MSH3 was also proven by other studies using tissue cultured human cells (36,37). Later, Adam et al found patients with bi-allelic inactivation mutations at the MSH3 locus who suffered from colorectal adenoma polyposis syndrome.…”

Section: Characteristics Of Fusobacterium-associated Crcssupporting

confidence: 53%

<i>Fusobacterium nucleatum</i> Infection in Colorectal Cancer: Linking Inflammation, DNA Mismatch Repair and Genetic and Epigenetic Alterations

Koi

Okita

Carethers

2018

J Anus Rectum Colon

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It has been recently reported that the population of Fusobacterium, particularly Fusobacterium nucleatum (Fn), is overrepresented in colorectal cancers and adenomas. The promoting effects of Fn infection on adenoma and/or carcinoma formation have been shown in ApcMin/+mice. Characteristics of Fn-associated CRC were identified through studies using human CRC cohorts, and include right-sided colon location, CpG island methylation phenotype-high (CIMP-H), high level of microsatellite instability (MSI-H), and poor patient prognosis. A subset of Fn-associated CRC exhibits a low level of microsatellite instability (MSI-L) and elevated microsatellite alterations in selected tetra-nucleotide repeats (EMAST) induced by translocation of MSH3 from the nucleus to the cytoplasm in response to oxidative DNA damage or inflammatory signals. The association between CIMP/MSI-H and Fn-infection can be explained by the role of the mismatch repair (MMR) protein complex formed between MSH2 and MSH6 (MutSα) to repair aberrant bases generated by ROS to form 7,8-dihydro-8-oxo-guanine (8-oxoG). Clustered 8-oxoGs formed at CpG-rich regions including promoters by ROS is refractory to base excision repair (BER). Under these conditions, MutSα initiates repair in cooperation with DNA methyltransferases (DNMTs) and the polycomb repressive complex 4 (PRC4). DNMTs at damaged sites methylate CpG islands to repress transcription of target genes and promote repair reactions. Thus, continuous generation of ROS through chronic Fn infection may initiate 1) CIMP-positive adenoma and carcinoma in an MSH2/MSH6-dependent manner, and/or 2) MSI-L/EMAST CRC in an MSH3-dependent manner. The poor prognosis of Fn-associated CRC can be explained by Fn-induced immune-evasion and/or chemo-resistance.

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Section: Characteristics Of Fusobacterium-associated Crcssupporting

confidence: 53%

<i>Fusobacterium nucleatum</i> Infection in Colorectal Cancer: Linking Inflammation, DNA Mismatch Repair and Genetic and Epigenetic Alterations

Koi

Okita

Carethers

2018

J Anus Rectum Colon

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“…MSI-low, detected by generally 1 dinucleotide frameshift out of five mono- and di-nucleotide markers, is consistent with MSH3 dysfunction in the absence of any mononucleotide marker frameshifts;this hypothesis has been experimentally confirmed [3,10,11,13,14]. EMAST detection using tetranucloetide markers is consistent with isolated MSH3 dysfunction [3,6,11,13,14,16–18,].…”

Section: Generation Of Microsatellite Instability: Defective Dna Mismmentioning

confidence: 69%

Microsatellite Instability Pathway and EMAST in Colorectal Cancer

Carethers

2017

Curr Colorectal Cancer Rep

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Microsatellite instability (MSI) refers to the biochemical detection of frameshifted microsatellite sequences from genomic DNA. Genesis of MSI is due to defective DNA mismatch repair (MMR) that fails to correct post DNA replicative slippage mistakes at microsatellites. Most of the estimated 100,000 genomic microsatellites are non-coding; however, ~150–300 microsatellites are coding such that, when frameshifted during the pathogenesis of an MSI tumor, can generate immunogenic neopeptide antigens that limit the growth of tumor and prolong patient survival. In addition to the immune reaction and longer survival, patients with MSI colorectal cancers tend to have poorly differentiated tumors with mucinous features that are located in the right colon. Patients with MSI tumors are more resistant to 5-fluorouracil-based adjuvant chemotherapy but may be responsive to PD-1 immune checkpoint blockade. Specific defects of MMR function not only drive MSI but also elevate microsatellite alterations at selected tetranucleotide repeats that may further modify patient outcome.

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“…In CRC and human colon epithelial cells, MSH3-deficiency is associated with EMAST ([AAAG] n repeats) and MSI-L at dinucleotide repeats, and results in the formation of double strand breaks (DSBs) and significant changes in the proteome. 57; 65 …”

Section: Discussionmentioning

confidence: 99%

Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis

Adam

Spier

Zhao

et al. 2016

The American Journal of Human Genetics

209

161

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In around 30% of families with colorectal adenomatous polyposis, no germline mutation in the previously-implicated genes APC, MUTYH, POLE, POLD1, or NTHL1 can be identified, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis was performed. We identified two unrelated individuals with differing compound-heterozygous loss-of-function germline mutations in the mismatch repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319-1g>a, c.2760delC, c.3001-2a>c) was indicated on RNA and protein level. Analysis of the diseased individuals’ tumor tissue demonstrated high microsatellite instability of di- and tetranucleotides (EMAST) and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the loss-of-function effect and causal relevance of the mutations. The pedigrees, genotypes, and the frequency of MSH3 mutations in the general population are consistent with an autosomal recessive mode of inheritance. Both index persons had an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing Constitutional Mismatch Repair Deficiency Syndrome (CMMRD). Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study we describe biallelic germline mutations of MSH3 in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis.

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MSH3-Deficiency Initiates EMAST without Oncogenic Transformation of Human Colon Epithelial Cells

Cited by 50 publications

References 60 publications

<i>Fusobacterium nucleatum</i> Infection in Colorectal Cancer: Linking Inflammation, DNA Mismatch Repair and Genetic and Epigenetic Alterations

<i>Fusobacterium nucleatum</i> Infection in Colorectal Cancer: Linking Inflammation, DNA Mismatch Repair and Genetic and Epigenetic Alterations

Microsatellite Instability Pathway and EMAST in Colorectal Cancer

Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis

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