Correlation of mismatch repair deficiency with clinicopathological features and programmed death-ligand 1 expression in thyroid carcinoma

Qiao, Peipei; Tian, Kai-Sai; Han, Lei; Ma, Ben; Shen, Chunying; Zhao, Runyu; Zhang, Yi; Wei, Wenjun; Chen, Xiaoping

doi:10.1007/s12020-022-03031-w

Cited by 7 publications

(6 citation statements)

References 57 publications

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“…For instance, a retrospective study published in 2022 on 241 individuals with TC examined the MMR protein status (either deficient or intact): 7.5% of TCs (N = 18 cases, as follows: N1 = 12 papillary TCs, N2 = 2 poorly differentiated TC, N3 = 4 anaplastic TCs) were MMR-deficient for all four MMR proteins, which correlated with the fact that 50% of them had an MSH6 deletion, while 50% of them underlined variants of MSH6 and PMS2. Interestingly, 22% of N was PD-L1-positive, which is associated with a shorter recorded overall survival versus MMRdeficient-PD-L1 negative subjects [57]. This study emphasizes the importance of the MMR status in TC in terms of prognosis and options for therapy, which is otherwise not routinely necessary since most differentiated TCs have an excellent prognosis.…”

Section: Tc and Mmr/msi Involvementmentioning

confidence: 70%

Pathogenic Insights into DNA Mismatch Repair (MMR) Genes–Proteins and Microsatellite Instability: Focus on Adrenocortical Carcinoma and Beyond

Cârșote

Turturea

Turturea³

et al. 2023

Diagnostics

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DNA damage repair pathways, including mismatch repair (MMR) genes, are prone to carcinoma development in certain patients. The assessment of the MMR system is widely recognized as part of strategies concerning solid tumors (defective MMR cancers), especially MMR proteins (through immunohistochemistry), and molecular assays for microsatellite instability (MSI). We aim to highlight the status of MMR genes–proteins (including MSI) in the relationship with ACC (adrenocortical carcinoma) according to current knowledge. This is a narrative review. We included PubMed-accessed, full-length English papers published between January 2012 and March 2023. We searched studies on ACC patients for whom MMR status was assessed, respectively subjects harboring MMR germline mutations, namely Lynch syndrome (LS), who were diagnosed with ACC. MMR system assessments in ACCs involve a low level of statistical evidence. Generally, there are two main types of endocrine insights: 1. the role of MMR status as a prognostic marker in different endocrine malignancies (including ACC)—which is the topic of the present work, and 2. establishing the indication of immune checkpoint inhibitors (ICPIs) in selective, mostly highly aggressive, non-responsive to standard care forms upon MMR evaluation (which belongs to the larger chapter of immunotherapy in ACCs). Our one-decade, sample-case study (which, to our knowledge, it is the most comprehensive of its kind) identified 11 original articles (from 1 patient to 634 subjects per study diagnosed with either ACC or LS). We identified four studies published in 2013 and 2020 and two in 2021, three cohorts and two retrospective studies (the publication from 2013 includes a retrospective and a cohort distinct section). Among these four studies, patients already confirmed to have LS (N = 643, respective 135) were found to be associated with ACC (N = 3, respective 2), resulting in a prevalence of 0.0046%, with a respective of 1.4% being confirmed (despite not having a large amount of similar data outside these two studies). Studies on ACC patients (N = 364, respective 36 pediatric individuals, and 94 subjects with ACC) showed that 13.7% had different MMR gene anomalies, with a respective of 8.57% (non-germline mutations), while 3.2% had MMR germline mutations (N = 3/94 cases). Two case series included one family, with a respective four persons with LS, and each article introduced one case with LS-ACC. Another five case reports (between 2018 and 2021) revealed an additional five subjects (one case per paper) diagnosed with LS and ACC (female to male ratio of 4 to 1; aged between 44 and 68). Interesting genetic testing involved children with TP53-positive ACC and further MMR anomalies or an MSH2 gene-positive subject with LS with a concurrent germline RET mutation. The first report of LS-ACC referred for PD-1 blockade was published in 2018. Nevertheless, the use of ICPI in ACCs (as similarly seen in metastatic pheochromocytoma) is still limited. Pan-cancer and multi-omics analysis in adults with ACC, in order to classify the candidates for immunotherapy, had heterogeneous results, and integrating an MMR system in this larger and challenging picture is still an open issue. Whether individuals diagnosed with LS should undergo surveillance for ACC has not yet been proven. An assessment of tumor-related MMR/MSI status in ACC might be helpful. Further algorithms for diagnostics and therapy, also taking into consideration innovative biomarkers as MMR-MSI, are necessary.

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Section: Tc and Mmr/msi Involvementmentioning

confidence: 70%

Pathogenic Insights into DNA Mismatch Repair (MMR) Genes–Proteins and Microsatellite Instability: Focus on Adrenocortical Carcinoma and Beyond

Cârșote

Turturea

Turturea³

et al. 2023

Diagnostics

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“…However, its possible combination with the checkpoint PD-L1 inhibitor atezolizumab for the treatment of ATC has not been highlighted yet. Such a combination could further improve the patient survival and further inhibit the metastasis by targeting several pathways at once and, in particular, those tumors which highlighted an over-expression of PD-L1 and a deficient mismatch repair machinery [ 28 , 29 ]. The current study evidenced an effective reduction in cell viability of primary ATC cells after irradiation and administration of atezolizumab.…”

Section: Discussionmentioning

confidence: 99%

Anti-Proliferative Effect of Radiotherapy and Implication of Immunotherapy in Anaplastic Thyroid Cancer Cells

Wächter

Roth

Gercke

et al. 2023

Life

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Radiotherapy and immunotherapy have shown promising efficacy for the treatment of solid malignancies. Here, we aim to clarify the potential of a combined application of radiotherapy and programmed cell death-ligand 1 (PD-L1) monoclonal antibody atezolizumab in primary anaplastic thyroid cancer (ATC) cells. The radiation caused a significant reduction in cell proliferation, measured by luminescence, and of the number of colonies. The addition of atezolizumab caused a further reduction in cell proliferation of the irradiated ATC cells. However, the combined treatment did not cause either the exposure of the phosphatidylserine or the necrosis, assessed by luminescence/fluorescence. Additionally, a reduction in both uncleaved and cleaved forms of caspases 8 and 3 proteins was detectable in radiated cells. The DNA damage evidenced the over-expression of TP53, CDKN1A and CDKN1B transcripts detected by RT-qPCR and the increase in the protein level of P-γH2AX and the DNA repair deputed kinases. PD-L1 protein level increased in ATC cells after radiation. Radiotherapy caused the reduction in cell viability and an increase of PD-L1-expression, but not apoptotic cell death in ATC cells. The further combination with the immunotherapeutic atezolizumab could increase the efficacy of radiotherapy in terms of reduction in cell proliferation. Further analysis of the involvement of alternative cell death mechanisms is necessary to clarify their cell demise mechanism of action. Their efficacy represents a promising therapy for patients affected by ATC.

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“…These preliminary results suggested that anti-PD-L1 antibody treatment could be effective in patients with MSI PDAC. MSI was reported in approximately 10–15% of thyroid carcinomas (TC) [ 175 , 176 , 177 ]; moreover, a correlation between MSI and clinical-pathological features was observed. Particularly, MSI TCs were generally papillary or anaplastic and poorly differentiated histotypes.…”

Section: Msi In Other Malignanciesmentioning

confidence: 99%

“…Particularly, MSI TCs were generally papillary or anaplastic and poorly differentiated histotypes. A recent study showed that MSI TC patients have a good prognosis compared to MSS TC [ 177 ]. Although several clinical trials are being evaluated for the efficacy of pembrolizumab, nivolumab and atezolizumab in MSI TC, until now no immunological therapy has been approved for MSI TC [ 178 , 179 ].…”

Section: Msi In Other Malignanciesmentioning

confidence: 99%

“…Although several clinical trials are being evaluated for the efficacy of pembrolizumab, nivolumab and atezolizumab in MSI TC, until now no immunological therapy has been approved for MSI TC [ 178 , 179 ]. The ICI targeting the PD-1/PD-L1 pathway may be a treatment option for MSI TC; however, further studies are needed [ 177 ]. The frequency of MSI brain tumors is very low, ranging from 2% to 3% of cases [ 27 , 116 ].…”

Section: Msi In Other Malignanciesmentioning

confidence: 99%

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Microsatellite Instability: From the Implementation of the Detection to a Prognostic and Predictive Role in Cancers

Amato

Franco

Facchini

et al. 2022

IJMS

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Microsatellite instability (MSI) has been identified in several tumors arising from either germline or somatic aberration. The presence of MSI in cancer predicts the sensitivity to immune checkpoint inhibitors (ICIs), particularly PD1/PD-L1 inhibitors. To date, the predictive role of MSI is currently used in the selection of colorectal cancer patients for immunotherapy; moreover, the expansion of clinical trials into other cancer types may elucidate the predictive value of MSI for non-colorectal tumors. In clinical practice, several assays are used for MSI testing, including immunohistochemistry (IHC), polymerase chain reaction (PCR) and next-generation sequencing (NGS). In this review, we provide an overview of MSI in various cancer types, highlighting its potential predictive/prognostic role and the clinical trials performed. Finally, we focus on the comparison data between the different assays used to detect MSI in clinical practice.

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Correlation of mismatch repair deficiency with clinicopathological features and programmed death-ligand 1 expression in thyroid carcinoma

Cited by 7 publications

References 57 publications

Pathogenic Insights into DNA Mismatch Repair (MMR) Genes–Proteins and Microsatellite Instability: Focus on Adrenocortical Carcinoma and Beyond

Pathogenic Insights into DNA Mismatch Repair (MMR) Genes–Proteins and Microsatellite Instability: Focus on Adrenocortical Carcinoma and Beyond

Anti-Proliferative Effect of Radiotherapy and Implication of Immunotherapy in Anaplastic Thyroid Cancer Cells

Microsatellite Instability: From the Implementation of the Detection to a Prognostic and Predictive Role in Cancers

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