Microsatellite instability in endometrial cancer: New purpose for an old test

Kurnit, Katherine C.; Westin, Shannon N.; Coleman, Robert L.

doi:10.1002/cncr.32058

Cited by 23 publications

(14 citation statements)

References 64 publications

(131 reference statements)

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“…Microsatellite status is a strong prognostic marker in patients with colorectal cancer [ 39 , 40 ]. Lately, this biological feature has been used to define also a subgroup of endometrioid ECs [ 10 , 41 ], and its prognostic value has been evaluated extensively [ 42 , 43 ]. Some studies have shown better survival, others poor survival, whereas others again have found no association at all [ 43 , 44 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

“…Lately, this biological feature has been used to define also a subgroup of endometrioid ECs [ 10 , 41 ], and its prognostic value has been evaluated extensively [ 42 , 43 ]. Some studies have shown better survival, others poor survival, whereas others again have found no association at all [ 43 , 44 , 45 ]. In our series, MSI-H was found in 48% of ECs and present in patients with OS of 48.64 months (approximately four years; data updated to the year 2021; p -value = 0.85).…”

Section: Discussionmentioning

confidence: 99%

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Endometrial Carcinoma: Molecular Cytogenetics and Transcriptomic Profile

Brunetti

Panagopoulos

Vitelli

et al. 2022

Cancers

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Endometrial carcinomas (ECs) are histologically classified as endometrioid and nonendometrioid tumors, with each subgroup displaying different molecular profiles and clinical outcomes. Considerable biological and clinical heterogeneity exists within this scheme, however, reflecting its imperfection. We aimed to gather additional data that might help clarify the tumors’ pathogenesis and contribute toward a more meaningful classification scheme. In total, 33 ECs were examined for the presence of chromosomal aberrations, genomic imbalances, pathogenic variants, microsatellite instability, and expression profiles at both gene and miRNA levels. Chromosome 1 was the most frequently rearranged chromosome, showing a gain of all or part of the long arm. Pathogenic variants were found for PTEN (53%), PDGFRA (37%), PIK3CA (34%), and KIT (31%). High microsatellite instability was identified in 15 ECs. Comparing tumors and controls, we identified 23 differentially expressed genes of known importance in carcinogenesis, 15 genes involved in innate and adaptative immune responses, and altered expression of 7 miRNAs. miR-32-5p was the most upregulated. Our series showed a high degree of heterogeneity. Tumors were well-separated from controls, but there was no clear-cut separation between endometrioid and nonendometrioid ECs. Whether this means that the current phenotypic classification is of little relevance or if one still has not detected which genomic parameters to enter into correlation analyses remains unknown.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Endometrial Carcinoma: Molecular Cytogenetics and Transcriptomic Profile

Brunetti

Panagopoulos

Vitelli

et al. 2022

Cancers

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“…Our study also assumes that there is no testing for MMR deficiency in endometrial cancer in the no testing comparator. It may be that this testing is already being done, or will be done in the near future, to select patients for targeted immune therapies [72]. In this instance we would expect the cost-effectiveness of tumour testing-based strategies to be significantly improved for those patients as there would be zero incremental costs for those tests.…”

Section: Discussionmentioning

confidence: 99%

Cost-effectiveness analysis of reflex testing for Lynch syndrome in women with endometrial cancer in the UK setting

et al. 2019

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Background Lynch syndrome is a hereditary cancer syndrome caused by constitutional pathogenic variants in the DNA mismatch repair (MMR) system, leading to increased risk of colorectal, endometrial and other cancers. The study aimed to identify the incremental costs and consequences of strategies to identify Lynch syndrome in women with endometrial cancer. Methods A decision-analytic model was developed to evaluate the relative cost-effectiveness of reflex testing strategies for identifying Lynch syndrome in women with endometrial cancer taking the NHS perspective and a lifetime horizon. Model input parameters were sourced from various published sources. Consequences were measured using quality-adjusted life years (QALYs). A cost-effectiveness threshold of £20 000/QALY was used. Results Reflex testing for Lynch syndrome using MMR immunohistochemistry and MLH1 methylation testing was cost-effective versus no testing, costing £14 200 per QALY gained. There was uncertainty due to parameter imprecision, with an estimated 42% chance this strategy is not cost-effective compared with no testing. Age had a significant impact on cost-effectiveness, with testing not predicted to be cost-effective in patients aged 65 years and over. Conclusions Testing for Lynch syndrome in younger women with endometrial cancer using MMR immunohistochemistry and MLH1 methylation testing may be cost-effective. Age cut-offs may be controversial and adversely affect implementation.

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“…Several protocols exist to characterize MSI-H tumors: immunohistochemistry assay to quantify loss of MMR proteins such as MLH1, MSH2, PMS2 and MSH6, genomic PCR tests to measure MS length variability at the various MS loci and quantification of somatic MS variation from WES/WGS data acquired from matched tumor/normal DNA samples using next generation sequencing and computational tools to calculate standardized MSI-H metrics like the "MSI score" (40)(41)(42)(43)(44)(45). The strategies vary widely in terms of recall, sensitivity and specificity; thus, combining multiple protocols may increase the precision of the overall diagnosis (39,(46)(47)(48).…”

Section: Mmr Molecular Mechanism and Biomarker Strategiesmentioning

confidence: 99%

Lynch Syndrome and MSI-H Cancers: From Mechanisms to “Off-The-Shelf” Cancer Vaccines

et al. 2021

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Defective DNA mismatch repair (dMMR) is associated with many cancer types including colon, gastric, endometrial, ovarian, hepatobiliary tract, urinary tract, brain and skin cancers. Lynch syndrome – a hereditary cause of dMMR – confers increased lifetime risk of malignancy in different organs and tissues. These Lynch syndrome pathogenic alleles are widely present in humans at a 1:320 population frequency of a single allele and associated with an up to 80% risk of developing microsatellite unstable cancer (microsatellite instability – high, or MSI-H). Advanced MSI-H tumors can be effectively treated with checkpoint inhibitors (CPI), however, that has led to response rates of only 30-60% despite their high tumor mutational burden and favorable immune gene signatures in the tumor microenvironment (TME). We and others have characterized a subset of MSI-H associated highly recurrent frameshift mutations that yield shared immunogenic neoantigens. These frameshifts might serve as targets for off-the-shelf cancer vaccine designs. In this review we discuss the current state of research around MSI-H cancer vaccine development, its application to MSI-H and Lynch syndrome cancer patients and the utility of MSI-H as a biomarker for CPI therapy. We also summarize the tumor intrinsic mechanisms underlying the high occurrence rates of certain frameshifts in MSI-H. Finally, we provide an overview of pivotal clinical trials investigating MSI-H as a biomarker for CPI therapy and MSI-H vaccines. Overall, this review aims to inform the development of novel research paradigms and therapeutics.

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Microsatellite instability in endometrial cancer: New purpose for an old test

Abstract: Historically, microsatellite instability testing has been used to identify patients with endometrial cancer with Lynch syndrome. It currently is also being used to identify those individuals who may be candidates for immunotherapy.

Cited by 23 publications

References 64 publications

Endometrial Carcinoma: Molecular Cytogenetics and Transcriptomic Profile

Endometrial Carcinoma: Molecular Cytogenetics and Transcriptomic Profile

Cost-effectiveness analysis of reflex testing for Lynch syndrome in women with endometrial cancer in the UK setting

Lynch Syndrome and MSI-H Cancers: From Mechanisms to “Off-The-Shelf” Cancer Vaccines

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