Tetranucleotide Microsatellite Mutational Behavior Assessed in Real Time: Implications for Future Microsatellite Panels

Raeker, Maide Ö.; Pierre-Charles, Jovan; Carethers, John M.

doi:10.1016/j.jcmgh.2020.01.006

Cited by 8 publications

(6 citation statements)

References 43 publications

(100 reference statements)

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“…Positivity of a single marker was common in pancreatic cancers (48%, 15/31) using the EMAST marker panel, but less frequent (10%, 3/31) using the MSI marker panel. This highlights the possible differences between cancer types and the need to standardise EMAST marker panels and the nomenclature, possibly incorporating MSI and EMAST markers, as was suggested by Garcia et al [ 12 ] and Raeker et al [ 13 ].…”

Section: Discussionmentioning

confidence: 94%

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Tetranucleotide and Low Microsatellite Instability Are Inversely Associated with the CpG Island Methylator Phenotype in Colorectal Cancer

Meessen

Currey

Jahan

et al. 2021

Cancers

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MSH3 gene or protein deficiency or loss-of-function in colorectal cancer can cause a DNA mismatch repair defect known as “elevated microsatellite alterations at selected tetranucleotide repeats” (EMAST). A high percentage of MSI-H tumors exhibit EMAST, while MSI-L is also linked with EMAST. However, the distribution of CpG island methylator phenotype (CIMP) within the EMAST spectrum is not known. Five tetranucleotide repeat and five MSI markers were used to classify 100 sporadic colorectal tumours for EMAST, MSI-H and MSI-L according to the number of unstable markers detected. Promoter methylation was determined using methylation-specific PCR for MSH3, MCC, CDKN2A (p16) and five CIMP marker genes. EMAST was found in 55% of sporadic colorectal carcinomas. Carcinomas with only one positive marker (EMAST-1/5, 26%) were associated with advanced tumour stage, increased lymph node metastasis, MSI-L and lack of CIMP-H. EMAST-2/5 (16%) carcinomas displayed some methylation but MSI was rare. Carcinomas with ≥3 positive EMAST markers (13%) were more likely to have a proximal colon location and be MSI-H and CIMP-H. Our study suggests that EMAST/MSI-L is a valuable prognostic and predictive marker for colorectal carcinomas that do not display the high methylation phenotype CIMP-H.

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Section: Discussionmentioning

confidence: 94%

“…Similarly, MutLα dysfunction due to a MLH1 or PMS2 defect can cause both EMAST and MSI-H. Therefore, there is an obligatory overlap of tetranucleotide repeat instability and MSI-H colorectal cancers, but MSH3-related EMAST is linked with the MSI-L phenotype [ 4 , 6 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Tetranucleotide and Low Microsatellite Instability Are Inversely Associated with the CpG Island Methylator Phenotype in Colorectal Cancer

Meessen

Currey

Jahan

et al. 2021

Cancers

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“…A total of 304 cases of unselected sporadic CRC from North Carolina [ 9 , 10 ] were analyzed for MSI-H, MSI-L and EMAST [ 11 , 12 ]. The amount of Fn DNA per nanogram of tumor tissue DNA was also determined by qPCR (see Additional file 1 : Additional Materials and Methods).…”

Section: Main Textmentioning

confidence: 99%

Fusobacterium nucleatum infection correlates with two types of microsatellite alterations in colorectal cancer and triggers DNA damage

et al. 2020

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Fusobacterium nucleatum (Fn) is frequently found in colorectal cancers (CRCs). High loads of Fn DNA are detected in CRC tissues with microsatellite instability-high (MSI-H), or with the CpG island hypermethylation phenotype (CIMP). Fn infection is also associated with the inflammatory tumor microenvironment of CRC. A subtype of CRC exhibits inflammation-associated microsatellite alterations (IAMA), which are characterized by microsatellite instability-low (MSI-L) and/or an elevated level of microsatellite alterations at selected tetra-nucleotide repeats (EMAST). Here we describe two independent CRC cohorts in which heavy or moderate loads of Fn DNA are associated with MSI-H and L/E CRC respectively. We also show evidence that Fn produces factors that induce γ-H2AX, a hallmark of DNA double strand breaks (DSBs), in the infected cells.

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“…More recently, elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) has been observed among several cancers in relation to inflammation (4,(6)(7)(8). The detection of EMAST (in the absence of detection of MSI-High) corresponds to isolated MSH3 dysfunction, matching its expected MMR biochemical repair profile (4,(9)(10)(11). Additionally, MSI-Low, defined as one marker showing frameshift among the mono-and dinucleotide NCI consensus panel, correlates with isolated MSH3 dysfunction as well due to essentially all MSI-Low assays showing only dinucleotide frameshifts instead of any mononucleotide frameshifts (4,12,13).…”

mentioning

confidence: 99%

The Human DNA Mismatch Repair Protein MSH3 Contains Nuclear Localization and Export Signals That Enable Nuclear-Cytosolic Shuttling in Response to Inflammation

Tseng-Rogenski

Munakata

Choi

et al. 2020

Molecular and Cellular Biology

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Inactivation of DNA mismatch repair propels colorectal cancer (CRC) tumorigenesis. CRCs exhibiting elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) show reduced nuclear MutS homolog 3 (MSH3) expression with surrounding inflammation and portend poor patient outcomes. MSH3 reversibly exits from the nucleus to the cytosol in response to the proinflammatory cytokine interleukin-6 (IL-6), suggesting that MSH3 may be a shuttling protein. In this study, we manipulated three putative nuclear localization (NLS1 to -3) and two potential nuclear export signals (NES1 and -2) within MSH3. We found that both NLS1 and NLS2 possess nuclear import function, with NLS1 responsible for nuclear localization within full-length MSH3. We also found that NES1 and NES2 work synergistically to maximize nuclear export, with both being required for IL-6-induced MSH3 export. We examined a 27-bp deletion (Δ27bp) within the polymorphic exon 1 that occurs frequently in human CRC cells and neighbors NLS1. With oxidative stress, MSH3 with this deletion (Δ27bp MSH3) localizes to the cytoplasm, suggesting that NLS1 function in Δ27bp MSH3 is compromised. Overall, MSH3’s shuttling in response to inflammation enables accumulation in the cytoplasm; reduced nuclear MSH3 increases EMAST and DNA damage. We suggest that polymorphic sequences adjacent to NLS1 may enhance cytosolic retention, which has clinical implications for inflammation-associated neoplastic processes.

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Tetranucleotide Microsatellite Mutational Behavior Assessed in Real Time: Implications for Future Microsatellite Panels

Cited by 8 publications

References 43 publications

Tetranucleotide and Low Microsatellite Instability Are Inversely Associated with the CpG Island Methylator Phenotype in Colorectal Cancer

Tetranucleotide and Low Microsatellite Instability Are Inversely Associated with the CpG Island Methylator Phenotype in Colorectal Cancer

Fusobacterium nucleatum infection correlates with two types of microsatellite alterations in colorectal cancer and triggers DNA damage

The Human DNA Mismatch Repair Protein MSH3 Contains Nuclear Localization and Export Signals That Enable Nuclear-Cytosolic Shuttling in Response to Inflammation

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