Association Between Recurrent Metastasis From Stage II and III Primary Colorectal Tumors and Moderate Microsatellite Instability

Garcia, Melissa; Choi, Chan; Kim, Hyeong–Rok; Daoud, Yahya; Toiyama, Yuji; Takahashi, Masanobu; Goel, Ajay; Boland, C. Richard; Koi, Minoru

doi:10.1053/j.gastro.2012.03.034

Cited by 50 publications

(104 citation statements)

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“…Indeed, hMSH3 knockdown experiments utilizing cell models that can measure EMAST generation proved that hMSH3 deficiency drives EMAST formation (17,18). In contrast to classic MSI, patients with EMAST-positive tumors demonstrate shorter survival when compared to patients with EMAST-negative tumors (15,19). …”

Section: Introductionmentioning

confidence: 84%

“…EMAST is strongly associated with inflammation, and its presence is a biomarker for poor prognosis in patients with colorectal cancers (15,16,19). Non-cancer conditions, such as colitis in inflammatory bowel disease and pancreatitis, have been previously assessed for microsatellite instability, and are now known to be MSI-low.…”

Section: Discussionmentioning

confidence: 99%

“…Non-cancer conditions, such as colitis in inflammatory bowel disease and pancreatitis, have been previously assessed for microsatellite instability, and are now known to be MSI-low. One speculation is that MSI-low and EMAST represent the same or a spectrum biomarker of inflammation, as both EMAST and MSI-low often overlap in colon tumors (19,26,27). Given the consequence of metastasis and poor survival with EMAST-positive tumors, we need to understand how EMAST is generated and how it might impact or be modified by therapy.…”

Section: Discussionmentioning

confidence: 99%

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Interleukin 6 Alters Localization of hMSH3, Leading to DNA Mismatch Repair Defects in Colorectal Cancer Cells

et al. 2015

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Background & Aims Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is the most common DNA mismatch repair (MMR) defect in colorectal cancers, observed in ~60% of specimens. This acquired genotype correlates with metastasis and poor outcome of patients, and is associated with intra-epithelial inflammation and heterogenous nuclear levels of the MMR protein hMSH3. Inflammation and accompanying oxidative stress can cause hMSH3 to change its intracellular location, but little is known about the source of oxidative stress in cancer cells. We investigated whether cytokines mediate this process. Methods We analyzed levels of interleukin 6 (IL6) and its receptor (IL6R) in human colon and lung cancer cell lines by flow cytometry and ELISA; proteins were localized by immunofluorescence and immunoblot analyses. IL6 signaling was blocked with antibodies against IL6, soluble sgp130Fc fragments, and the STAT3 inhibitor NSC74859; a constitutively active form of STAT3 was expressed in colon and lung cancer cell lines to replicate IL6R signaling. EMAST was detected by DNA fragment analysis. Immunohistochemistry was used to examine levels of IL6 in 20 colorectal tumor and adjacent non-tumor tissues. Results Incubation of colon and lung cancer cell lines with IL6, but not other cytokines, caused hMSH3, but no other MMR proteins, to move from the nucleus to the cytosol after generation of oxidative stress; inhibition of IL6 signaling prevented this shift. Expression of constitutively active STAT3 also caused hMSH3 to translocate from the nucleus to the cytoplasm in cancer cell lines. Incubation of cells with IL6 led to tetranucleotide frameshifts, the signature for EMAST. EMAST-positive colorectal tumors had significantly higher levels of IL6 that EMAST-negative tumors. Conclusions IL6 signaling disrupts the nuclear localization of hMSH3 and DNA repair, leading to EMAST in cancer cell lines. Inflammatory cytokines might therefore promote genetic alterations in human cancer cells.

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Section: Introductionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Interleukin 6 Alters Localization of hMSH3, Leading to DNA Mismatch Repair Defects in Colorectal Cancer Cells

et al. 2015

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“…They reasoned that chemo-resistance is a major factor for recurrence and proved that Fn induces cancer cells’ chemo-resistance through activation of autophagy (44). We previously showed that stage II/III MSI-L/EMAST CRC exhibit a shorter RFS compared to MSI-H or non-MSI-H, non-MSI-L/EMAST CRC (79,80). Because MSI-L/EMAST CRCs are infected by Fn , it is tempting to speculate that a majority of Fn -associated CRCs that exhibit poor prognoses, especially shorter RFS, could be MSI-L/EMAST CRCs but not MSI-H CRCs.…”

Section: Possible Explanation Of Why Fusobacterium Infection Is Assocmentioning

confidence: 96%

<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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“…The presence of EMAST in primary CRCs predict advanced-stage disease in patients and is associated with poor survival over patients with EMAST negative CRC tumors. EMAST can modulate all 3 (MSI-H, CIN and CIMP) pathways in sporadic CRC tumorigenesis and is a biomarker linked to advanced, metastatic stage and poor survival in both groups, hypermutated and nonhypermutated sporadic colorectal cancer [15,16].…”

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confidence: 99%

Molecular stratification of sporadic and hereditary colorectal cancer – mini review

Kapitanović¹

2017

Medicina

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SummaryColorectal cancer (CRC) is one of the most common cancers and one of the leading causes of cancer death in the Western world. The disease arises from the accumulation of mutations in oncogenes, tumor suppressor genes and mismatch repair genes during progression from normal colon epithelium to adenoma and metastatic carcinoma. The majority of colorectal cancers arise in sporadic form. About one-third of patients with CRC have a family history of cancer and elevated risk for this malignant disease. However, only 5% of CRC arise from a germline mutation in high penetrant genes, adenomatous polyposis coli (APC) gene and DNA mismatch repair (MMR) genes. The most common hereditary CRC syndrome is Lynch syndrome defined by hereditary germline mutations in one the of MMR genes. The term hereditary non-polyposis colorectal cancer (HNPCC), previously used interchangeably with Lynch syndrome, now refers to a broader spectrum of familial CRC disorders that can mimic some clinical features of Lynch syndrome, but without germline mutations in MMR genes characteristic for Lynch syndrome. Distinguishing between the HNPCC disorders is important for clinicians, as the approach to surveillance for patients and their family members differs according to risk for CRC associated with each syndrome.This mini review will give some information about the most frequent molecular genetics changes in sporadic and hereditary colorectal cancer and its molecular stratification due to its heredity, somatic mutations and microsatellite instability.

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Association Between Recurrent Metastasis From Stage II and III Primary Colorectal Tumors and Moderate Microsatellite Instability

Cited by 50 publications

References 11 publications

Interleukin 6 Alters Localization of hMSH3, Leading to DNA Mismatch Repair Defects in Colorectal Cancer Cells

Interleukin 6 Alters Localization of hMSH3, Leading to DNA Mismatch Repair Defects in Colorectal Cancer Cells

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

Molecular stratification of sporadic and hereditary colorectal cancer – mini review

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