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15 pages, 617 KiB

Open AccessArticle

MEM: An Algorithm for the Reliable Detection of Microsatellite Instability (MSI) on a Small NGS Panel in Colorectal Cancer

by Guillaume Herbreteau, Fabrice Airaud, Elise Pierre-Noël, Audrey Vallée, Stéphane Bézieau, Sandrine Théoleyre, Hélène Blons, Simon Garinet and Marc Guillaume Denis

Cancers 2021, 13(16), 4203; https://doi.org/10.3390/cancers13164203 - 20 Aug 2021

Cited by 3 | Viewed by 2880

Abstract

Purpose: MEM is an NGS algorithm that uses Expectation-Maximisation to detect the presence of unstable alleles from the NGS sequences of five microsatellites (BAT-25, BAT-26, NR-21, NR-24 and NR-27). The purpose of this study was to compare the MEM algorithm with a reference [...] Read more.

Purpose: MEM is an NGS algorithm that uses Expectation-Maximisation to detect the presence of unstable alleles from the NGS sequences of five microsatellites (BAT-25, BAT-26, NR-21, NR-24 and NR-27). The purpose of this study was to compare the MEM algorithm with a reference PCR method (MSI-PCR) and MisMatch Repair protein immunohistochemistry (MMR-IHC). Methods: FFPE colorectal cancer samples from 146 patients were analysed in parallel by MSI-PCR and NGS using the MEM algorithm. MMR-IHC results were available for 133 samples. Serial dilutions of an MSI positive control were performed to estimate the limit of detection. Results: the MEM algorithm was able to detect unstable alleles of each microsatellite with up to a 5% allelic fraction. Of the 146 samples, 28 (19.2%) were MSI in MSI-PCR. MEM algorithm results were in perfect agreement with those of MSI-PCR, at both MSI status and individual microsatellite level (Cohen’s kappa = 1). A high level of agreement was noted between MSI-PCR/MEM algorithm results and MMR-IHC results (Cohen’s kappa = 0.931). Conclusion: the MEM algorithm can determine the MSI status of colorectal cancer samples on a small NGS panel, using only five microsatellites approved by international guidelines, and can be combined with screening for targetable mutations. Full article

(This article belongs to the Special Issue Microsatellite Instability and Cancers)

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10 pages, 1031 KiB

Open AccessArticle

Expression of Mismatch Repair Proteins in Merkel Cell Carcinoma

by Thilo Gambichler, Nessr Abu Rached, Andrea Tannapfel, Jürgen C. Becker, Markus Vogt, Marina Skrygan, Ulrike Wieland, Steffi Silling, Laura Susok, Markus Stücker, Thomas Meyer, Eggert Stockfleth, Klaus Junker, Heiko U. Käfferlein, Thomas Brüning and Kerstin Lang

Cancers 2021, 13(11), 2524; https://doi.org/10.3390/cancers13112524 - 21 May 2021

Cited by 12 | Viewed by 2325

Abstract

We aimed to assess for the first time the mismatch repair (MMR) protein expression in Merkel cell carcinoma (MCC). Immunohistochemistry was performed for MLH1, MSH2, MSH6, and PMS2 on patients’ tumor tissue (n = 56), including neighbored healthy control tissue. In cases [...] Read more.

We aimed to assess for the first time the mismatch repair (MMR) protein expression in Merkel cell carcinoma (MCC). Immunohistochemistry was performed for MLH1, MSH2, MSH6, and PMS2 on patients’ tumor tissue (n = 56), including neighbored healthy control tissue. In cases with low-level MMR expression (<10th percentile), we performed multiplex PCR in combination with high-resolution capillary electrophoresis in order to confirm microsatellite instability (MSI). Microscopic evaluation revealed a high median expression for all MMR proteins studied (91.6–96.3%). However, six patients (56/10.7%) had low-level MLH1 expression, six (55/10.9%) had low-level MSH2 expression, five (56/8.9%) had low-level MSH6 expression, and six (54/11.1%) had low-level PMS2 expression. Together, we observed nine (56/16.1%) patients who had low-level MMR expression of at least one protein. Of the patients with low-level MMR expression, MSI evaluation was possible in five cases, revealing one case with high-level MSI. In all MMR proteins assessed, low-level expression was significantly (p = 0.0004 to p < 0.0001) associated with a negative Merkel cell polyomavirus (MCPyV) status. However, the expression profiles of the MMR proteins did not correlate with clinical outcome measures such as disease relapse or death (p > 0.05). MCC appears to be a malignancy characterized by low-level MMR rather than completely deficient MMR in a subset of cases, predominantly affecting MCPyV-negative tumors. Future studies will establish whether this subset of MCC patients respond better to immune checkpoint inhibitor therapy. Full article

(This article belongs to the Special Issue Microsatellite Instability and Cancers)

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Review

Jump to: Research

15 pages, 348 KiB

Open AccessReview

Endoscopy to Diagnose and Prevent Digestive Cancers in Lynch Syndrome

by Raphael Olivier, Violaine Randrian, David Tougeron and Jean-Christophe Saurin

Cancers 2021, 13(14), 3505; https://doi.org/10.3390/cancers13143505 - 13 Jul 2021

Cited by 7 | Viewed by 2156

Abstract

Lynch syndrome patients could benefit from various recommendations to prevent digestive cancers. In this review, we summarize the criteria to identify Lynch syndrome in patients with digestive cancers. We detail endoscopic screening procedures in patients with Lynch syndrome for gastric, small bowel, pancreatic, [...] Read more.

Lynch syndrome patients could benefit from various recommendations to prevent digestive cancers. In this review, we summarize the criteria to identify Lynch syndrome in patients with digestive cancers. We detail endoscopic screening procedures in patients with Lynch syndrome for gastric, small bowel, pancreatic, and colorectal cancers. We review the precise modalities of endoscopic follow-up, particularly the discrepancies that exist between the guidelines of the various scientific societies. We discuss the treatment of colorectal cancers in Lynch syndrome cases and patient adherence to endoscopic follow-up programs. Full article

(This article belongs to the Special Issue Microsatellite Instability and Cancers)

18 pages, 1424 KiB

Open AccessReview

Microsatellite Instability in Colorectal Cancers: Carcinogenesis, Neo-Antigens, Immuno-Resistance and Emerging Therapies

by Violaine Randrian, Camille Evrard and David Tougeron

Cancers 2021, 13(12), 3063; https://doi.org/10.3390/cancers13123063 - 19 Jun 2021

Cited by 30 | Viewed by 5176

Abstract

A defect in the DNA repair system through a deficient mismatch repair system (dMMR) leads to microsatellite instability (MSI). Microsatellites are located in both coding and non-coding sequences and dMMR/MSI tumors are associated with a high mutation burden. Some of these mutations occur [...] Read more.

A defect in the DNA repair system through a deficient mismatch repair system (dMMR) leads to microsatellite instability (MSI). Microsatellites are located in both coding and non-coding sequences and dMMR/MSI tumors are associated with a high mutation burden. Some of these mutations occur in coding sequences and lead to the production of neo-antigens able to trigger an anti-tumoral immune response. This explains why non-metastatic MSI tumors are associated with high immune infiltrates and good prognosis. Metastatic MSI tumors result from tumor escape to the immune system and are associated with poor prognosis and chemoresistance. Consequently, immune checkpoint inhibitors (ICI) are highly effective and have recently been approved in dMMR/MSI metastatic colorectal cancers (mCRC). Nevertheless, some patients with dMMR/MSI mCRC have primary or secondary resistance to ICI. This review details carcinogenesis and the mechanisms through which MSI can activate the immune system. After which, we discuss mechanistic hypotheses in an attempt to explain primary and secondary resistances to ICI and emerging strategies being developed to overcome this phenomenon by targeting other immune checkpoints or through vaccination and modification of microbiota. Full article

(This article belongs to the Special Issue Microsatellite Instability and Cancers)

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15 pages, 1419 KiB

Open AccessReview

Predictive and Prognostic Value of Microsatellite Instability in Gynecologic Cancer (Endometrial and Ovarian)

by Camille Evrard and Jérôme Alexandre

Cancers 2021, 13(10), 2434; https://doi.org/10.3390/cancers13102434 - 18 May 2021

Cited by 23 | Viewed by 3423

Abstract

For endometrial cancer, a new classification is now available from ESMO, ESGO, and ESTRO based on clinical and molecular characteristics to determine adjuvant therapy. The contribution of molecular biology is major for this pathology mainly by the intermediary of deficient mismatch repair/microsatellite instability. [...] Read more.

For endometrial cancer, a new classification is now available from ESMO, ESGO, and ESTRO based on clinical and molecular characteristics to determine adjuvant therapy. The contribution of molecular biology is major for this pathology mainly by the intermediary of deficient mismatch repair/microsatellite instability. Detection techniques for this phenotype have many peculiarities in gynecologic cancers (endometrial and ovarian) because it has been initially validated in colorectal cancer only. Endometrial cancer is the most common tumor with deficient mismatch repair, which is an important prognostic factor and a predictor of the benefit of adjuvant treatments. Concerning advanced stages, this phenotype is a theragnostic marker for using immunotherapy. Among ovarian cancer, microsatellite instability is less described in literature but exists, particularly in endometrioid type ovarian cancer. This review aims to provide an overview of the publications concerning deficient mismatch repair/microsatellite instability in endometrial and ovarian cancers, detection techniques, and clinical implications of these molecular characteristics. Full article

(This article belongs to the Special Issue Microsatellite Instability and Cancers)

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9 pages, 423 KiB

Open AccessEditor’s ChoiceReview

Immune Checkpoint Inhibition in Metastatic Colorectal Cancer Harboring Microsatellite Instability or Mismatch Repair Deficiency

by Romain Cohen, Raphaël Colle, Thomas Pudlarz, Maximilien Heran, Alex Duval, Magali Svrcek and Thierry André

Cancers 2021, 13(5), 1149; https://doi.org/10.3390/cancers13051149 - 8 Mar 2021

Cited by 32 | Viewed by 3519

Abstract

Microsatellite instability (MSI) is a tumor phenotype related to a deficient DNA mismatch repair system (dMMR). This phenotype, observed in 5% of metastatic mCRC but 10–18% of localized CRC, is associated with high tumor mutational burden with highly immunogenic neoantigens. It has emerged [...] Read more.

Microsatellite instability (MSI) is a tumor phenotype related to a deficient DNA mismatch repair system (dMMR). This phenotype, observed in 5% of metastatic mCRC but 10–18% of localized CRC, is associated with high tumor mutational burden with highly immunogenic neoantigens. It has emerged as a major predictive biomarker for the efficacy of ICIs. In this review, we will present a comprehensive overview of the literature concerning the efficacy of ICIs in MSI/dMMR mCRC, with a focus on new developments in first-line metastatic setting. Then, we will present current and future challenges of immuno-oncology for patients with MSI/dMMR metastatic CRC. Full article

(This article belongs to the Special Issue Microsatellite Instability and Cancers)

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21 pages, 416 KiB

Open AccessFeature PaperReview

Management of Non-Colorectal Digestive Cancers with Microsatellite Instability

by Mojun Zhu, Zhaohui Jin and Joleen M. Hubbard

Cancers 2021, 13(4), 651; https://doi.org/10.3390/cancers13040651 - 6 Feb 2021

Cited by 8 | Viewed by 2500

Abstract

Microsatellite instability (MSI) is a hallmark of genetic predisposition to DNA damage. It arises from either germline or somatic events leading to impaired function of the mismatch repair system. It can be detected via genetic sequencing or immunohistochemistry with relatively high concordance rates. [...] Read more.

Microsatellite instability (MSI) is a hallmark of genetic predisposition to DNA damage. It arises from either germline or somatic events leading to impaired function of the mismatch repair system. It can be detected via genetic sequencing or immunohistochemistry with relatively high concordance rates. The presence of MSI in a tumor reflects a high neoantigen load and predicts favorable treatment response to immune checkpoint inhibitors (ICIs). In gastrointestinal cancers, MSI is a predictive biomarker for ICIs with potential prognostic impact but its clinical utility varies widely depending on tumor type. This may be explained by the complexity of tumor microenvironment as highlighted by recent translational studies. In this review, we will discuss the predictive and prognostic value of MSI status in non-colorectal cancers of the digestive system, important clinical trials involving ICIs and potential strategies to overcome resistance to immunotherapy. Full article

(This article belongs to the Special Issue Microsatellite Instability and Cancers)

33 pages, 1258 KiB

Open AccessReview

Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors

by Julie Leclerc, Catherine Vermaut and Marie-Pierre Buisine

Cancers 2021, 13(3), 467; https://doi.org/10.3390/cancers13030467 - 26 Jan 2021

Cited by 46 | Viewed by 8921

Abstract

Microsatellite instability (MSI) is a hallmark of Lynch syndrome (LS)-related tumors but is not specific to it, as approximately 80% of MSI/mismatch repair-deficient (dMMR) tumors are sporadic. Methods leading to the diagnosis of LS have considerably evolved in recent years and so have [...] Read more.

Microsatellite instability (MSI) is a hallmark of Lynch syndrome (LS)-related tumors but is not specific to it, as approximately 80% of MSI/mismatch repair-deficient (dMMR) tumors are sporadic. Methods leading to the diagnosis of LS have considerably evolved in recent years and so have tumoral tests for LS screening and for the discrimination of LS-related to MSI-sporadic tumors. In this review, we address the hallmarks of LS, including the clinical, histopathological, and molecular features. We present recent advances in diagnostic and screening strategies to identify LS patients. We also discuss the pitfalls associated with the current strategies, which should be taken into account to improve the diagnosis of LS and avoid inappropriate clinical management. Full article

(This article belongs to the Special Issue Microsatellite Instability and Cancers)

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16 pages, 319 KiB

Open AccessEditor’s ChoiceReview

Prognostic and Predictive Values of Mismatch Repair Deficiency in Non-Metastatic Colorectal Cancer

by Zhaohui Jin and Frank A. Sinicrope

Cancers 2021, 13(2), 300; https://doi.org/10.3390/cancers13020300 - 15 Jan 2021

Cited by 38 | Viewed by 3179

Abstract

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Universal MMR/MSI testing is standard of care for all patients with newly diagnosed CRC based on multi-society guidelines in the United States. Such testing is intended to identify patients with Lynch Syndrome [...] Read more.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Universal MMR/MSI testing is standard of care for all patients with newly diagnosed CRC based on multi-society guidelines in the United States. Such testing is intended to identify patients with Lynch Syndrome due to a germline mutation in an MMR gene, but also detects those with sporadic dMMR/MSI-high CRCs. The prognostic utility of MMR/MSI status in non-metastatic colorectal cancer has been studied extensively, yet more limited data are available for its predictive utility. Results have not been entirely consistent due to potential stage-related differences and limited numbers of dMMR/MSI-H patients included in the studies. In this review, we summarize the current evidence for the prognostic and predictive value of dMMR/MSI-H in non-metastatic CRC, and discuss the use of this biomarker for patient management and treatment decisions in clinical practice. Full article

(This article belongs to the Special Issue Microsatellite Instability and Cancers)

24 pages, 1860 KiB

Open AccessReview

Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability

by Madhura Deshpande, Phillip A. Romanski, Zev Rosenwaks and Jeannine Gerhardt

Cancers 2020, 12(11), 3319; https://doi.org/10.3390/cancers12113319 - 10 Nov 2020

Cited by 58 | Viewed by 9180

Abstract

Mutations in mismatch repair genes leading to mismatch repair (MMR) deficiency (dMMR) and microsatellite instability (MSI) have been implicated in multiple types of gynecologic malignancies. Endometrial carcinoma represents the largest group, with approximately 30% of these cancers caused by dMMR/MSI. Thus, testing for [...] Read more.

Mutations in mismatch repair genes leading to mismatch repair (MMR) deficiency (dMMR) and microsatellite instability (MSI) have been implicated in multiple types of gynecologic malignancies. Endometrial carcinoma represents the largest group, with approximately 30% of these cancers caused by dMMR/MSI. Thus, testing for dMMR is now routine for endometrial cancer. Somatic mutations leading to dMMR account for approximately 90% of these cancers. However, in 5–10% of cases, MMR protein deficiency is due to a germline mutation in the mismatch repair genes MLH1, MSH2, MSH6, PMS2, or EPCAM. These germline mutations, known as Lynch syndrome, are associated with an increased risk of both endometrial and ovarian cancer, in addition to colorectal, gastric, urinary tract, and brain malignancies. So far, gynecological cancers with dMMR/MSI are not well characterized and markers for detection of MSI in gynecological cancers are not well defined. In addition, currently advanced endometrial cancers have a poor prognosis and are treated without regard to MSI status. Elucidation of the mechanism causing dMMR/MSI gynecological cancers would aid in diagnosis and therapeutic intervention. Recently, a new immunotherapy was approved for the treatment of solid tumors with MSI that have recurred or progressed after failing traditional treatment strategies. In this review, we summarize the MMR defects and MSI observed in gynecological cancers, their prognostic value, and advances in therapeutic strategies to treat these cancers. Full article

(This article belongs to the Special Issue Microsatellite Instability and Cancers)

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