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EMAST is a Form of Microsatellite Instability That is Initiated by Inflammation and Modulates Colorectal Cancer Progression.

Carethers JM, Koi M, Tseng-Rogenski SS - Genes (Basel) (2015)

Bottom Line: MSI-H is highly correlated with loss of MMR protein expression, is commonly diploid, is often located in the right side of the colon, prognosticates good patient outcome, and predicts poor efficacy with 5-fluorouracil treatment.Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is another form of MSI at tetranucleotide repeats that has been observed in multiple cancers, but its etiology and clinical relevance to patient care has only been recently illuminated.Tumor hypoxia may also be a contributor.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Michigan, 3101 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. jcarethe@umich.edu.

ABSTRACT
DNA mismatch repair (MMR) function is critical for correcting errors coincident with polymerase-driven DNA replication, and its proteins are frequent targets for inactivation (germline or somatic), generating a hypermutable tumor that drives cancer progression. The biomarker for defective DNA MMR is microsatellite instability-high (MSI-H), observed in ~15% of colorectal cancers, and defined by mono- and dinucleotide microsatellite frameshift mutations. MSI-H is highly correlated with loss of MMR protein expression, is commonly diploid, is often located in the right side of the colon, prognosticates good patient outcome, and predicts poor efficacy with 5-fluorouracil treatment. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is another form of MSI at tetranucleotide repeats that has been observed in multiple cancers, but its etiology and clinical relevance to patient care has only been recently illuminated. Specifically, EMAST is an acquired somatic defect observed in up to 60% of colorectal cancers and caused by unique dysfunction of the DNA MMR protein MSH3 (and its DNA MMR complex MutSβ, a heterodimer of MSH2-MSH3), and in particular a loss-of-function phenotype due to a reversible shift from its normal nuclear location into the cytosol in response to oxidative stress and the pro-inflammatory cytokine interleukin-6. Tumor hypoxia may also be a contributor. Patients with EMAST colorectal cancers show diminished prognosis compared to patients without the presence of EMAST in their cancer. In addition to defective DNA MMR recognized by tetranucleotide (and di- and tri-nucleotide) frameshifts, loss of MSH3 also contributes to homologous recombination-mediated repair of DNA double stranded breaks, indicating the MSH3 dysfunction is a complex defect for cancer cells that generates not only EMAST but also may contribute to chromosomal instability and aneuploidy. Areas for future investigation for this most common DNA MMR defect among colorectal cancers include relationships between EMAST and chemotherapy response, patient outcome with aneuploid changes in colorectal cancers, target gene mutation analysis, and mechanisms related to inflammation-induced compartmentalization and inactivation for MSH3.

No MeSH data available.


Related in: MedlinePlus

Summary diagram relating colorectal pathogenesis that may be modulated by EMAST, affecting patient outcome. Colorectal cancers can be dichotomized into MSI-H and MSS, and previously MSI-L was lumped in with MSS cancers. EMAST, the biomarker for loss of MSH3 (MutSβ function), may modify the behavior of colorectal cancer, worsening patient survival. This is in contrast to patients with MSI-H colorectal cancers with the dominant genotype of loss of DNA mismatch repair and who have good survival outcome. Among EMAST cancers, a more balanced defect between moderate loss of mismatch repair and moderate loss of repair of double strand breaks may drive the overall worse behavior. Data indicates that there are racial differences for the prevalence of MSI-H and EMAST, as well as the type of inflammation associated with each biomarker.
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genes-06-00185-f004: Summary diagram relating colorectal pathogenesis that may be modulated by EMAST, affecting patient outcome. Colorectal cancers can be dichotomized into MSI-H and MSS, and previously MSI-L was lumped in with MSS cancers. EMAST, the biomarker for loss of MSH3 (MutSβ function), may modify the behavior of colorectal cancer, worsening patient survival. This is in contrast to patients with MSI-H colorectal cancers with the dominant genotype of loss of DNA mismatch repair and who have good survival outcome. Among EMAST cancers, a more balanced defect between moderate loss of mismatch repair and moderate loss of repair of double strand breaks may drive the overall worse behavior. Data indicates that there are racial differences for the prevalence of MSI-H and EMAST, as well as the type of inflammation associated with each biomarker.

Mentions: Although the EMAST biomarker is inclusive among MSI-H colorectal cancers due to the complete absence DNA mismatch repair, it, as a stand-alone biomarker with isolated MSH3 dysfunction, shows a different clinicopathogenic portfolio when compared to MSI-H cancers (Table 3). Unlike MSI-H colorectal cancers that generate neoantigens from frameshifted proteins that immunize the patient’s tumor and foretells an improved patient prognosis, EMAST cancers seem to develop as a consequence of inflammation (see Figure 3), modulating the baseline genomic instability of the tumor into one that is more aggressive and more likely to metastasize, and associated with poor patient survival (Figure 4). The source for the inciting inflammation for EMAST has not been investigated, but could involve the bowel contents including food debris, the microbiota and its fermentation or metabolic products, bile acids, as well as other metabolites [75,76,77]. Increased inflammation and EMAST is observed during the adenoma-carcinoma sequence [22], suggesting that the neoplasia or its morphology might perpetuate inflammation [22], and the role of immune cells needs to be examined [78]. Further exploration into the inciting and driving events that modify patient outcome as a result of EMAST and MSH3 dysfunction in colorectal cancers should yield potential approaches for primary or secondary intervention for patients [79,80].


EMAST is a Form of Microsatellite Instability That is Initiated by Inflammation and Modulates Colorectal Cancer Progression.

Carethers JM, Koi M, Tseng-Rogenski SS - Genes (Basel) (2015)

Summary diagram relating colorectal pathogenesis that may be modulated by EMAST, affecting patient outcome. Colorectal cancers can be dichotomized into MSI-H and MSS, and previously MSI-L was lumped in with MSS cancers. EMAST, the biomarker for loss of MSH3 (MutSβ function), may modify the behavior of colorectal cancer, worsening patient survival. This is in contrast to patients with MSI-H colorectal cancers with the dominant genotype of loss of DNA mismatch repair and who have good survival outcome. Among EMAST cancers, a more balanced defect between moderate loss of mismatch repair and moderate loss of repair of double strand breaks may drive the overall worse behavior. Data indicates that there are racial differences for the prevalence of MSI-H and EMAST, as well as the type of inflammation associated with each biomarker.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4488660&req=5

genes-06-00185-f004: Summary diagram relating colorectal pathogenesis that may be modulated by EMAST, affecting patient outcome. Colorectal cancers can be dichotomized into MSI-H and MSS, and previously MSI-L was lumped in with MSS cancers. EMAST, the biomarker for loss of MSH3 (MutSβ function), may modify the behavior of colorectal cancer, worsening patient survival. This is in contrast to patients with MSI-H colorectal cancers with the dominant genotype of loss of DNA mismatch repair and who have good survival outcome. Among EMAST cancers, a more balanced defect between moderate loss of mismatch repair and moderate loss of repair of double strand breaks may drive the overall worse behavior. Data indicates that there are racial differences for the prevalence of MSI-H and EMAST, as well as the type of inflammation associated with each biomarker.
Mentions: Although the EMAST biomarker is inclusive among MSI-H colorectal cancers due to the complete absence DNA mismatch repair, it, as a stand-alone biomarker with isolated MSH3 dysfunction, shows a different clinicopathogenic portfolio when compared to MSI-H cancers (Table 3). Unlike MSI-H colorectal cancers that generate neoantigens from frameshifted proteins that immunize the patient’s tumor and foretells an improved patient prognosis, EMAST cancers seem to develop as a consequence of inflammation (see Figure 3), modulating the baseline genomic instability of the tumor into one that is more aggressive and more likely to metastasize, and associated with poor patient survival (Figure 4). The source for the inciting inflammation for EMAST has not been investigated, but could involve the bowel contents including food debris, the microbiota and its fermentation or metabolic products, bile acids, as well as other metabolites [75,76,77]. Increased inflammation and EMAST is observed during the adenoma-carcinoma sequence [22], suggesting that the neoplasia or its morphology might perpetuate inflammation [22], and the role of immune cells needs to be examined [78]. Further exploration into the inciting and driving events that modify patient outcome as a result of EMAST and MSH3 dysfunction in colorectal cancers should yield potential approaches for primary or secondary intervention for patients [79,80].

Bottom Line: MSI-H is highly correlated with loss of MMR protein expression, is commonly diploid, is often located in the right side of the colon, prognosticates good patient outcome, and predicts poor efficacy with 5-fluorouracil treatment.Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is another form of MSI at tetranucleotide repeats that has been observed in multiple cancers, but its etiology and clinical relevance to patient care has only been recently illuminated.Tumor hypoxia may also be a contributor.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Michigan, 3101 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. jcarethe@umich.edu.

ABSTRACT
DNA mismatch repair (MMR) function is critical for correcting errors coincident with polymerase-driven DNA replication, and its proteins are frequent targets for inactivation (germline or somatic), generating a hypermutable tumor that drives cancer progression. The biomarker for defective DNA MMR is microsatellite instability-high (MSI-H), observed in ~15% of colorectal cancers, and defined by mono- and dinucleotide microsatellite frameshift mutations. MSI-H is highly correlated with loss of MMR protein expression, is commonly diploid, is often located in the right side of the colon, prognosticates good patient outcome, and predicts poor efficacy with 5-fluorouracil treatment. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is another form of MSI at tetranucleotide repeats that has been observed in multiple cancers, but its etiology and clinical relevance to patient care has only been recently illuminated. Specifically, EMAST is an acquired somatic defect observed in up to 60% of colorectal cancers and caused by unique dysfunction of the DNA MMR protein MSH3 (and its DNA MMR complex MutSβ, a heterodimer of MSH2-MSH3), and in particular a loss-of-function phenotype due to a reversible shift from its normal nuclear location into the cytosol in response to oxidative stress and the pro-inflammatory cytokine interleukin-6. Tumor hypoxia may also be a contributor. Patients with EMAST colorectal cancers show diminished prognosis compared to patients without the presence of EMAST in their cancer. In addition to defective DNA MMR recognized by tetranucleotide (and di- and tri-nucleotide) frameshifts, loss of MSH3 also contributes to homologous recombination-mediated repair of DNA double stranded breaks, indicating the MSH3 dysfunction is a complex defect for cancer cells that generates not only EMAST but also may contribute to chromosomal instability and aneuploidy. Areas for future investigation for this most common DNA MMR defect among colorectal cancers include relationships between EMAST and chemotherapy response, patient outcome with aneuploid changes in colorectal cancers, target gene mutation analysis, and mechanisms related to inflammation-induced compartmentalization and inactivation for MSH3.

No MeSH data available.


Related in: MedlinePlus