MSI‐L/EMAST is a predictive biomarker for metastasis in colorectal cancer patients

Esfahani, Amir Torshizi; Seyedna, Seyed Yoosef; Nazemalhosseini‐Mojarad, Ehsan; Majd, Ahmad; Aghdaei, Hamid Asadzadeh

doi:10.1002/jcp.27983

Cited by 35 publications

(27 citation statements)

References 59 publications

(138 reference statements)

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“…EMAST CRCs have been suggested to portray a distinct clinicopathological profile, and some studies have found associations between EMAST and a higher histological state, chronic inflammation, and poor prognosis 15,20,26 . Hence, EMAST has been suggested to be a biomarker in CRC 16,17,27 . In our study, which to our knowledge is the first genome‐wide study focusing on tetranucleotide instability, we found no evidence for EMAST as a separate entity.…”

Section: Discussioncontrasting

confidence: 60%

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No evidence of EMAST in whole genome sequencing data from 248 colorectal cancers

Kondelin

Martin

Katainen

et al. 2021

Genes Chromosomes & Cancer

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Microsatellite instability (MSI) is caused by defective DNA mismatch repair (MMR), and manifests as accumulation of small insertions and deletions (indels) in short tandem repeats of the genome. Another form of repeat instability, elevated microsatellite alterations at selected tetranucleotide repeats (EMAST), has been suggested to occur in 50% to 60% of colorectal cancer (CRC), of which approximately one quarter are accounted for by MSI. Unlike for MSI, the criteria for defining EMAST is not consensual. EMAST CRCs have been suggested to form a distinct subset of CRCs that has been linked to a higher tumor stage, chronic inflammation, and poor prognosis. EMAST CRCs not exhibiting MSI have been proposed to show instability of di‐ and trinucleotide repeats in addition to tetranucleotide repeats, but lack instability of mononucleotide repeats. However, previous studies on EMAST have been based on targeted analysis of small sets of marker repeats, often in relatively few samples. To gain insight into tetranucleotide instability on a genome‐wide level, we utilized whole genome sequencing data from 227 microsatellite stable (MSS) CRCs, 18 MSI CRCs, 3 POLE‐mutated CRCs, and their corresponding normal samples. As expected, we observed tetranucleotide instability in all MSI CRCs, accompanied by instability of mono‐, di‐, and trinucleotide repeats. Among MSS CRCs, some tumors displayed more microsatellite mutations than others as a continuum, and no distinct subset of tumors with the previously proposed molecular characters of EMAST could be observed. Our results suggest that tetranucleotide repeat mutations in non‐MSI CRCs represent stochastic mutation events rather than define a distinct CRC subclass.

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Section: Discussioncontrasting

confidence: 60%

“…EMAST has been suggested to relate to exposure to environmental carcinogens 17 . It has also been proposed to show potential for serving as a prognostic or preventive biomarker 16,17,27 …”

Section: Introductionmentioning

confidence: 99%

No evidence of EMAST in whole genome sequencing data from 248 colorectal cancers

Kondelin

Martin

Katainen

et al. 2021

Genes Chromosomes & Cancer

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“…We previously reported in another cohort that CDKN2A (p16) methylation was significantly less frequent in MSI-L colon tumours compared to MSI-H or MSS tumours and that MSI-L tumours were associated with poor survival [ 31 ]. Since then, evidence has been strengthening that both MSI-L or EMAST/non-MSI-H are markers of poor prognosis in colorectal carcinoma and share a mechanistic basis [ 7 , 12 , 37 , 38 ]. Here, we show that the poor prognosis is likely due to increased lymph node metastasis, which is associated with the presence of one positive EMAST or MSI marker.…”

Section: Discussionmentioning

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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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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“…Thus, MSI‐H and MSI‐L had distinct clinicopathologic features, prognosis and chemotherapy response. Amir et al suggested that MSI‐L was associated with advanced stage and inferior prognosis compared with MSI‐H and MSS in colorectal cancers . In DLBCLs, the underlying mechanisms of MSI‐H and MSI‐L needed further investigations.…”

Section: Discussionmentioning

confidence: 99%

Microsatellite instability and its associations with the clinicopathologic characteristics of diffuse large B‐cell lymphoma

Tian

Xue

et al. 2020

Cancer Medicine

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Microsatellite instability (MSI) has been investigated as a prognostic and predictive factor for chemotherapy in colorectal cancer and has recently been demonstrated to be predictive of the PD‐1/PD‐L1 checkpoint blockade response in various solid tumors. However, MSI status in diffuse large B‐cell lymphomas (DLBCLs) has not been thoroughly explored. This study investigated MSI status in DLBCLs and analyzed the associations between MSI and clinicopathologic characteristics and clinical outcomes. Ninety‐two cases of primary DLBCLs treated with R‐CHOP/CHOP chemotherapy between 2009 and 2017 were collected. MSI detection was performed by the Promega MSI Analysis System. The protein expression of MLH1, MSH2, MSH6, and PMS2 was detected by immunohistochemistry. The associations of MSI‐H and MSI‐L with progression‐free survival (PFS) and overall survival (OS) were assessed by COX models and Kaplan–Meier curves. The correlations of complete response (CR) after R‐CHOP/CHOP chemotherapy with MSI‐H and MSI‐L were examined by univariate and multivariate logistic regression analyses, respectively. 3 of 92 cases (3.2%) were high MSI (MSI‐H), and 9 cases (9/92, 9.8%) exhibited low MSI (MSI‐L). One case with MSI‐H showed negative expression of MSH2 and MSH6. Univariate analysis indicated that MSI‐L was correlated with poor response to R‐CHOP/CHOP chemotherapy in DLBCLs (OR, 0.178; 95% CI, 0.041‐0.776; P = .022). Multivariate analysis showed that MSI‐L was an independent predictive factor for non‐CR to R‐CHOP/CHOP chemotherapy (OR, 0.144; 95% CI, 0.027‐0.761; P = .023). Kaplan‐Meier curves showed that there was a trend that MSI‐H patients had favorable PFS (P = .36) and OS (P = .48), which did not have statistical significance and MSI‐L was not significantly correlated with PFS (P = .24) and OS (P = .52).Our study indicated that there existed MSI‐H and MSI‐L in DLBCLs. MSI‐L could be an independent predictive factor for the chemotherapy response in DLBCLs.

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MSI‐L/EMAST is a predictive biomarker for metastasis in colorectal cancer patients

Cited by 35 publications

References 59 publications

No evidence of EMAST in whole genome sequencing data from 248 colorectal cancers

No evidence of EMAST in whole genome sequencing data from 248 colorectal cancers

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

Microsatellite instability and its associations with the clinicopathologic characteristics of diffuse large B‐cell lymphoma

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