Detecting mismatch repair deficiency in solid neoplasms: immunohistochemistry, microsatellite instability, or both?

Wang, Chiyun; Zhang, Liying; Vakiani, Efsevia; Shia, Jinru

doi:10.1038/s41379-022-01109-4

Cited by 25 publications

(47 citation statements)

References 77 publications

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“…Many sporadic tumors exhibit MSI due to the somatic inactivation of MMR machinery. Importantly, earlier studies aimed at developing reliable MSI assays focused mainly on MSI detection in colorectal tumors [ 10 ]. These tumors are characterized by a high rate of cell proliferation, and the concordance of the MSI testing by a conventional five-marker panel versus MLH1/MSH2/MSH6/PMS2 IHC is close to 100% [ 11 ].…”

Section: Microsatellite Instabilitymentioning

confidence: 99%

“…These tumors are characterized by a high rate of cell proliferation, and the concordance of the MSI testing by a conventional five-marker panel versus MLH1/MSH2/MSH6/PMS2 IHC is close to 100% [ 11 ]. Furthermore, almost all colorectal tumors arising in patients with Lynch syndrome are microsatellite unstable and have high TMB, and the same is true for sporadic CRCs arising due to MLH1 promoter hypermethylation [ 8 , 10 , 12 ].…”

Section: Microsatellite Instabilitymentioning

confidence: 99%

“…It was revealed that the standard PCR panels often fail to reliably detect MSI in non-colorectal tumors, for example, in endometrial carcinomas, which are characterized by a particularly high rate of microsatellite instability [ 13 ]. Furthermore, there are instances of tumors with well-proven MMR-D status, often linked to Lynch syndrome, which do not accumulate a high number of mutations in microsatellites, possibly due to low proliferation rates [ 8 , 10 , 14 , 15 , 16 ]. Therefore, distinct criteria may be applied to the pre-screening test for hereditary cancer and to the assay aimed at the selection of patients for immunotherapy.…”

Section: Microsatellite Instabilitymentioning

confidence: 99%

“…PCR is generally cheaper and has a lower turn-around time as compared to NGS; therefore, the development of an “agnostic” PCR test is an attractive goal. There are several commercial PCR platforms (e.g., OncoMate TM MSI Dx Analysis System (Promega) or Idylla TM MSI Assay (Biocartis)) as well as a multitude of laboratory-developed tests [ 10 ]. It has been reported that the standard five-marker panel (BAT25, BAT26, NR21, NR24, NR27 (MONO27)) may produce false-negative results in non-colorectal tumors, hence additional microsatellites are probably required for reliable MSI analysis in other cancer types.…”

Section: Microsatellite Instabilitymentioning

confidence: 99%

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Integrative Genomic Tests in Clinical Oncology

Imyanitov

Sokolenko

2022

IJMS

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Many clinical decisions in oncology practice rely on the presence or absence of an alteration in a single genetic locus, be it a pathogenic variant in a hereditary cancer gene or activating mutation in a drug target. In addition, there are integrative tests that produce continuous variables and evaluate complex characteristics of the entire tumor genome. Microsatellite instability (MSI) analysis identifies tumors with the accumulation of mutations in short repetitive nucleotide sequences. This procedure is utilized in Lynch syndrome diagnostic pipelines and for the selection of patients for immunotherapy. MSI analysis is well-established for colorectal malignancies, but its applications in other cancer types lack standardization and require additional research. Homologous repair deficiency (HRD) indicates tumor sensitivity to PARP inhibitors and some cytotoxic drugs. HRD-related “genomic scars” are manifested by a characteristic pattern of allelic imbalances, accumulation of deletions with flanking homology, and specific mutation signatures. The detection of the genetic consequences of HRD is particularly sophisticated and expensive, as it involves either whole genome sequencing (WGS) or the utilization of large next-generation sequencing (NGS) panels. Tumor mutation burden (TMB) can be determined by whole exome sequencing (WES) or middle-throughput NGS multigene testing. Although TMB is regarded as an agnostic indicator of tumor sensitivity to immunotherapy, the clinical utility of this test is proven only for a few cancer types.

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Section: Microsatellite Instabilitymentioning

confidence: 99%

Section: Microsatellite Instabilitymentioning

confidence: 99%

Section: Microsatellite Instabilitymentioning

confidence: 99%

Section: Microsatellite Instabilitymentioning

confidence: 99%

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Integrative Genomic Tests in Clinical Oncology

Imyanitov

Sokolenko

2022

IJMS

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“…Считается, что инактивация белков системы MMR сопровождается выраженной микросателлитной нестабильностью только в опухолях с высоким индексом пролиферации. В то же время новообразования, возникающие на фоне синдрома Линча или в результате соматической инактивации генов MMR, для которых характерна низкая скорость деления клеток, могут демонстрировать dMMR в отсутствие MSI, при этом они отличаются низкой мутационной нагрузкой и отсутствием чувствительности к иммунотерапии [20][21][22][23][24]. Действительно, зависимость между совокупным количеством мутаций и выраженностью ответа опухоли на ингибиторы контрольных точек иммунного ответа отмечается даже для MSI-позитивных опухолей [25], при этом dMMR-карциномы с сохранным статусом микросателлитов демонстрируют, в целом, заметно меньшее количество изменений нуклеотидной последовательности по сравнению с микросателлит-нестабильными неоплазмами [23].…”

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Microsatellite Instability: Laboratory Diagnostic Nuances (Position Statement of the Russian Interregional Organization of Molecular Geneticists in Oncology and Oncohematology)

Demidova¹,

Филипенко²,

Цуканов³

et al. 2023

Voprosy Onkologii

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Микросателлитной нестабильностью (microsatellite instability, MSI) называется феномен накопления мутаций (делеций и инсерций) в коротких повторяющихся последовательностях ДНК. Наиболее частой причиной MSI является дефект системы репарации неспаренных оснований ДНК (mismatch repair deficiency, dMMR). Анализ MSI/dMMR используется при диагностике синдрома Линча, а также для отбора пациентов на терапию ингибиторами контрольных точек иммунного ответа. Тестирование MSI подразумевает анализ длины нескольких информативных микросателлитных маркеров при помощи ПЦР или NGS, а выявление dMMR основывается на иммуногистохимическом анализе экспрессии белков MLH1, MSH2, MSH6 и PMS2. Эти методы можно считать взаимозаменяемыми в случае колоректального рака, поэтому при анализе карцином толстой кишки выбор между тестированием MSI и dMMR может определяться организационными и экономическими предпочтениями. Карциномы с низкой пролиферативной активностью, в т.ч. ассоциированные с синдромом Линча, могут демонстрировать dMMR в отсутствие MSI, при этом они отличаются низкой мутационной нагрузкой и отсутствием чувствительности к иммунотерапии. Процедуры выявления микросателлитной нестабильности в неколоректальных опухолях остаются недостаточно стандартизованными и нуждаются в дальнейшем совершенствовании.

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Lynch Syndrome and Somatic Mismatch Repair Variants in Pancreas Cancer

O’Connor,

Harrold,

Lin

et al. 2024

JAMA Oncol

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ImportanceMicrosatellite (MS) instability (MSI-H) occurs frequently in Lynch syndrome (LS)–associated tumors and is associated with response to immune checkpoint blockade (ICB) therapy. MSI-H is conferred by germline or somatic variants in mismatch repair genes. The contribution of somatic oncogenesis to MSI-H in pancreatic cancer (PC) is unknown.ObjectiveTo evaluate an LS-related PC cohort to define clinicogenomic features, describe somatic MSI-H cases (germline negative), characterize response to ICB, and guide preferred MS testing methods.Design, Setting, and ParticipantsThis single-institution, retrospective analysis was conducted from March 2012 to July 2023 at Memorial Sloan Kettering Cancer Center and included 55 patients with PC and either an LS germline pathogenic variant (gPV) or somatic mismatch repair (MMR) variant.Main Outcomes and MeasuresComposite MMR and MS status determined using orthogonal methods. An artificial intelligence classifier was used to account for low-cellularity specimens. Demographic and clinical data were abstracted from medical record. Zygosity status and somatic comutation landscape analyzed.ResultsFifty-five patients (23 women [42%]) had PC and an MMR variant: 32 (58%) had LS (LS cohort) and 23 (42%) had a somatic MMR variant (no germline pathogenic variant, somatic MMR cohort). In the LS cohort, 10 (31%) had gMSH2, 9 (28%) gMSH6, 8 (25%) gPMS2, 4 (13%) gMLH1, 1 (3%) gEPCAM. The median age at diagnosis was 68 years (range, 45-88 years). For composite MS status, 17 (59%) were MSI-H, 12 (41%) MS stable, and 3 MS unknown. Five cases were reclassified as MSI-H by the artificial intelligence classifier. In the somatic MMR cohort, 11 (48%) had MSH6, 7 (30%) MLH1, 3 (13%) MSH2, and 2 (9%) PMS2. The median age at diagnosis was 72 years (range, 66-85 years). For composite MS status, 10 (43%) were MSI-H, 11 (48%) MS stable, and 2 (9%) MS indeterminate. Six cases were reclassified as MSI-H by the artificial intelligence classifier. For the LS and somatic MMR cohorts, 20 received ICB (n = 17 MSI-H). The median ICB duration was 27.7 months (95% CI, 11.5 to not reached); the disease control rate was 80%.ConclusionThe results of this cross-sectional study suggest that MSI-H occurs due to LS or somatic oncogenesis in PC. Orthogonal MS testing is key in PC; the artificial intelligence classifier reclassified approximately 20% of cases, most of which were low cellularity. ICB for patients with LS or somatic MSI-H PC provided significant benefit.

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Detecting mismatch repair deficiency in solid neoplasms: immunohistochemistry, microsatellite instability, or both?

Cited by 25 publications

References 77 publications

Integrative Genomic Tests in Clinical Oncology

Integrative Genomic Tests in Clinical Oncology

Microsatellite Instability: Laboratory Diagnostic Nuances (Position Statement of the Russian Interregional Organization of Molecular Geneticists in Oncology and Oncohematology)

Lynch Syndrome and Somatic Mismatch Repair Variants in Pancreas Cancer

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