Comparative analysis of microsatellite instability by next-generation sequencing, MSI PCR and MMR immunohistochemistry in 1942 solid cancers

Kang, So Young; Kim, Deok Geun; Ahn, Soomin; Ha, Sang Yun; Kim, Kyoung‐Mee

doi:10.1016/j.prp.2022.153874

Cited by 18 publications

(11 citation statements)

References 32 publications

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“…MSI status was determined by interrogation of 130 homopolymer MSI marker sites. MSI-H status was defined as ≥ 20%, MSI-low (MSI-L) as 20–1% and MS-stable (MSS) as < 1%, based on previous studies 51 .…”

Section: Methodsmentioning

confidence: 99%

Novel, clinically relevant genomic patterns identified by comprehensive genomic profiling in ATRX-deficient IDH-wildtype adult high-grade gliomas

Bedics,

Szőke,

Bátai

et al. 2023

Sci Rep

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Glioblastomas are the most common IDH-wildtype adult high-grade gliomas, frequently harboring mutations in the TERT gene promoter (pTERT) and utilizing the subsequent telomerase overexpression for telomere length maintenance. However, some rare cases show loss of ATRX and use alternative mechanisms of telomere lengthening. In this study, we performed the first complex genomic analysis specifically concentrating on the latter subgroup. Comprehensive genomic profiling of 12 ATRX-deficient and 13 ATRX-intact IDH-wildtype adult high-grade gliomas revealed that ATRX and pTERT mutations are mutually exclusive. DNMT3A alterations were confined to ATRX-deficient, while PTEN mutations to ATRX-intact cases. RAS–MAPK pathway alterations, including NF1 mutations, were more characteristic in the ATRX-deficient group. Variants of genes related to homologous recombination repair showed different patterns of affected genes. Two ATRX-deficient tumors with high tumor mutational burden and mismatch repair deficiency were found. One of these contained a novel fusion involving the NTRK2 and LRRFIP2 genes, while the other showed loss of MSH2 and MSH6 without genetic alterations in the encoding genes suggesting an epigenetic background. Genetic characteristics of ATRX-deficient IDH-wildtype adult high-grade gliomas suggest that these tumors are particularly intriguing targets of potential future therapeutic interventions including immunotherapies combined with MAPK pathway inhibition and DNA repair inhibitors.

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Section: Methodsmentioning

confidence: 99%

Novel, clinically relevant genomic patterns identified by comprehensive genomic profiling in ATRX-deficient IDH-wildtype adult high-grade gliomas

Bedics,

Szőke,

Bátai

et al. 2023

Sci Rep

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“…MLH1 promoter methylation testing (or BRAF mutation testing for CRC; [ 33 ]) and NGS analysis of the tumor may be useful in clarifying the MMR gene mutation status. However, microsatellite analysis by NGS should be validated for each organ system against MMR-IHC and MSI-PCR as the reference method [ 10 , 11 , 28 ].…”

Section: Update On Step-by-step Assessment Of Mmr-ihcmentioning

confidence: 99%

Testing for deficient mismatch repair and microsatellite instability

Rüschoff,

Schildhaus,

Rüschoff

et al. 2023

Pathologie

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Testing to detect mismatch repair deficiency (dMMR) and high-grade microsatellite instability (MSI-H) has become an integral part of the routine diagnostic workup for colorectal cancer (CRC). While MSI was initially considered to be a possible indicator of a hereditary disposition to cancer (Lynch syndrome, LS), today the prediction of the therapy response to immune checkpoint inhibitors (ICI) is in the foreground. Corresponding recommendations and testing algorithms are available for use in primary diagnosis (reviewed in: Rüschoff et al. 2021).Given the increasing importance for routine use and the expanding indication spectrum of ICI therapies for non-CRCs, such as endometrial, small intestinal, gastric, and biliary tract cancers, an updated review of dMMR/MSI testing is presented. The focus is on the challenges in the assessment of immunohistochemical stains and the value of PCR-based procedures, considering the expanded ICI indication spectrum. A practice-oriented flowchart for everyday diagnostic decision-making is provided that considers new data on the frequency and type of discordances between MMR-IHC and MSI-PCR findings, and the possible role of Next Generation Sequencing in clarifying them. Reference is made to the significance of systematic quality assurance measures (e.g., QuIP MSI portal and multicenter proficiency testing), including regular continued training and education.

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“… 86 Conversely, those with more comprehensive insurance may find the spectrum of cancers that undergo MMR testing is broader than currently seen in the United Kingdom. 87 Whether someone can access PGD is also determined by their level of insurance cover.…”

Section: The Global Perspectivementioning

confidence: 99%

A Focused Clinical Review of Lynch Syndrome

Georgiou¹,

Monje-Garcia²,

Miles³

et al. 2023

CMAR

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Lynch syndrome (LS) is an autosomal dominant condition that increases an individual’s risk of a constellation of cancers. LS is defined when an individual has inherited pathogenic variants in the mismatch repair genes. Currently, most people with LS are undiagnosed. Early detection of LS is vital as those with LS can be enrolled in cancer reduction strategies through chemoprophylaxis, risk reducing surgery and cancer surveillance. However, these interventions are often invasive and require refinement. Furthermore, not all LS associated cancers are currently amenable to surveillance. Historically only those with a strong family history suggestive of LS were offered testing; this has proved far too restrictive. New criteria for testing have recently been introduced including the universal screening for LS in associated cancers. This has increased the number of people being diagnosed with LS but has also brought about unique challenges such as when to consent for germline testing and questions over how and who should carry out the consent. The results of germline testing for LS can be complicated and the diagnostic pathway is not always clear. Furthermore, by testing only those with cancer for LS we fail to identify these individuals before they develop potentially fatal pathology. This review will outline these challenges and explore solutions. Furthermore, we consider the potential future of LS care and the related treatments and interventions which are the current focus of research.

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Comparative analysis of microsatellite instability by next-generation sequencing, MSI PCR and MMR immunohistochemistry in 1942 solid cancers

Cited by 18 publications

References 32 publications

Novel, clinically relevant genomic patterns identified by comprehensive genomic profiling in ATRX-deficient IDH-wildtype adult high-grade gliomas

Novel, clinically relevant genomic patterns identified by comprehensive genomic profiling in ATRX-deficient IDH-wildtype adult high-grade gliomas

Testing for deficient mismatch repair and microsatellite instability

A Focused Clinical Review of Lynch Syndrome

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