Correlation of Mismatch Repair Deficiency with Clinicopathological Features and Programmed Death-Ligand 1 Expression in Thyroid Carcinoma

Abstract Background Mutations in DNA mismatch repair (MMR) genes associated with thyroid carcinoma (TC) have rarely been reported, especially in East Asian populations. Methods We examined tumor tissue from a cohort of 241 patients diagnosed with TC between 2008 and 2020. MMR proteins were detected using tissue microarray-based immunohistochemistry in order to identify MMR-protein-deficient (MMR-D) and MMR-protein-intact (MMR-I) tumors. We retrospectively summarized the clinicopathologic characteristics of patients with MMR-D TC, measured the expression of PD-L1, and recorded overall survival (OS) and other clinical outcomes. Results In our cohort, there were 18 (7.5%) MMR-D (MLH1, MSH2, MSH6, and PMS2) patients, including 12 with papillary TC (PTC) (6.7%), 2 with poorly differentiated TC (PDTC) (4.7%), and 4 with anaplastic TC (ATC) (22.2%). Half of them (9/18) showed a specific deletion in MSH6, and 6 of them also carried variants in the MSH6 and PMS2 gene. Survival was significantly better in patients with MMR-D ATC than in those with MMR-I tumors (p=0.033). Four of the 18 MMR-D patients (22%) were found to be PD-L1 positive. Their OS was much shorter than that of PD-L1-negative patients. Conclusions MMR-D and PD-L1 positivity appear to be associated with clinicopathological characteristics and prognosis in TC. The results indicate that MMR status may have important prognostic significance in TC. Therefore, immune checkpoint inhibitors that target the PD-1/PD-L1 pathway may be a treatment option for TCs.

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Heterogeneous constitutional mismatch repair deficiency with MSH6 missense mutation clinically benefits from pembrolizumab and regorafenib combination therapy: a case report and literature review

Hereditary Cancer in Clinical Practice ◽

10.1186/s13053-021-00165-2 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Tong Xie ◽

Qin Feng ◽

Zhongwu Li ◽

Ming Lu ◽

Jian Li ◽

...

Keyword(s):

Mismatch Repair ◽

Kinase Inhibitor ◽

Checkpoint Inhibitors ◽

Combined Therapy ◽

Dual Therapy ◽

Circulating Tumor Dna ◽

Targeted Sequencing ◽

Dna Mismatch ◽

Repair Deficiency ◽

Mutation Burden

Abstract Background Germline DNA mismatch repair (MMR) gene aberrations are associated with colorectal cancer (CRC) predisposition and high tumor mutation burden (TMB-H), with increased likelihood of favorable response to immune checkpoint inhibitors (ICIs). Case presentation We present a 32-year old male patient diagnosed with constitutional MMR deficiency (CMMRD) CRC whose MMR immunohistochemistry (IHC) revealed inconsistent results from two tumor blocks. Targeted sequencing of two tumor specimens used in MMR-IHC and plasma-derived circulating tumor DNA consistently revealed the detection of bi-allelic germline MSH6 c.3226C > T (p.R1076C) mutation, TMB-H as well as the genetic heterogeneity of the tumor samples. Unexpectedly, both blocks were microsatellite stable (MSS) after PCR confirmation. Interestingly, the patient failed to show response to ICI monotherapy or dual therapy, but clinically benefitted from combined therapy of ICI pembrolizumab plus multi-kinase inhibitor regorafenib. Conclusion Our case reported a CMMRD patient with heterogeneous MMR results who showed complicated response to ICIs, highlighting the importance of accurate diagnosis using targeted sequencing with multiple specimens to reveal the possible mechanism of response to ICI in patients with CMMRD.

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DNA Mismatch Repair Deficiency and Immune Checkpoint Inhibitors in Gastrointestinal Cancers

Gastroenterology ◽

10.1053/j.gastro.2018.11.071 ◽

2019 ◽

Vol 156 (4) ◽

pp. 890-903 ◽

Cited By ~ 13

Author(s):

Juan Ruiz-Bañobre ◽

Ajay Goel

Keyword(s):

Mismatch Repair ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Dna Mismatch Repair ◽

Checkpoint Inhibitors ◽

Gastrointestinal Cancers ◽

Mismatch Repair Deficiency ◽

Dna Mismatch ◽

Repair Deficiency ◽

Dna Mismatch Repair Deficiency

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Mutation and Microsatellite Burden Predict Response to PD-1 Inhibition in Children with Germline DNA Replication Repair Deficiency

10.21203/rs.3.rs-155292/v1 ◽

2021 ◽

Author(s):

Uri Tabori ◽

Daniel Morgenstern ◽

Sumedha Sudhaman ◽

Anirban Das ◽

Ailish Coblentz ◽

...

Keyword(s):

Mismatch Repair ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Tumour Microenvironment ◽

Dual Roles ◽

Dna Mismatch ◽

Repair Deficiency ◽

Mutation Burden ◽

Synchronous Cancers ◽

Sustained Responses

Abstract Cancers arising from germline DNA mismatch-repair or polymerase-proofreading deficiencies (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion/deletion (MS-indel) burden in humans and are lethal due to inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICI) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI in these patients. ICI treatment of 45 progressive/recurrent tumours from 38 patients revealed durable objective responses in the majority, culminating in 3-year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations/Mb) enriched for combined MMRD+PPD, while MS-indels predicted response in MMRD tumours with lower mutation burden (10-100 mutations/Mb). Further, both mechanisms were associated with increased immune infiltration even in “immunologically-cold” tumours such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and associated with immune activation in both the tumour microenvironment and systemically. Further, patients with flare continuing ICI treatment achieved durable responses. Our study demonstrates improved survival for patients with tumours not previously known to respond to ICI, including CNS and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained responses to immunotherapy.

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Tumor Mutational Burden and Mismatch Repair Deficiency Discordance as a Mechanism of Immunotherapy Resistance

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2020.7680 ◽

2021 ◽

Vol 19 (2) ◽

pp. 130-133

Author(s):

Agata A. Bielska ◽

Walid K. Chatila ◽

Henry Walch ◽

Nikolaus Schultz ◽

Zsofia K. Stadler ◽

...

Keyword(s):

Lynch Syndrome ◽

Mismatch Repair ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Cancer Syndrome ◽

Dna Mismatch ◽

Mutational Burden ◽

Repair Deficiency ◽

Tumor Mutational Burden

Lynch syndrome is a heritable cancer syndrome caused by a heterozygous germline mutation in DNA mismatch repair (MMR) genes. MMR-deficient (dMMR) tumors are particularly sensitive to immune checkpoint inhibitors, an effect attributed to the higher mutation rate in these cancers. However, approximately 15% to 30% of patients with dMMR cancers do not respond to immunotherapy. This report describes 3 patients with Lynch syndrome who each had 2 primary malignancies: 1 with dMMR and a high tumor mutational burden (TMB), and 1 with dMMR but, unexpectedly, a low TMB. Two of these patients received immunotherapy for their TMB-low tumors but experienced no response. We have found that not all Lynch-associated dMMR tumors have a high TMB and propose that tumors with dMMR and TMB discordance may be resistant to immunotherapy. The possibility of dMMR/TMB discordance should be considered, particularly in less-typical Lynch cancers, in which TMB evaluation could guide the use of immune checkpoint inhibitors.

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RARE-55. CHALLENGES AND SPECIFIC STRATEGIES FOR CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY SYNDROME IN LOW RESOURCE SETTINGS. ON BEHALF OF THE INTERNATIONAL RRD CONSORTIUM IN LOW RESOURCE SETTINGS PANEL

Neuro-Oncology ◽

10.1093/neuonc/noaa222.765 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii454-iii454

Author(s):

Rejin Kebudi ◽

Nisreen Amayiri N ◽

Malak Abedalthagafi ◽

Asim Noor Rana ◽

Slman Kirmani ◽

...

Keyword(s):

Mismatch Repair ◽

Checkpoint Inhibitors ◽

Immune Therapy ◽

Malignant Gliomas ◽

Mismatch Repair Deficiency ◽

Term Survival ◽

Low Resource Settings ◽

Low Resource ◽

Repair Deficiency ◽

Constitutional Mismatch Repair Deficiency

Abstract Germline biallelic mutations in one of the mismatch repair genes (MSH2/MSH6/MLH1/PMS2 results in constitutional mismatch repair deficiency (CMMRD), a condition associated with multiple tumors arising from multiple organs during childhood, and these individuals rarely reach adulthood. The paucity of information with respect to these conditions leads to mismanagement and may be a factor in the high mortality of patients with CMMRD. Two international consortia, the European CARE4CMMRD, and the international replication repair deficiency (RRD) consortium, are addressing the many challenges associated with this condition. To address specific issues surrounding the management of CMMRD in low and middle income countries (LMIC), a multidisciplinary taskforce of 11 specialists from nine countries was formed. Preliminary conclusions are: 1) Immunohistochemistry for CMMRD should be considered for all patients with suggestive clinical features. In countries where CMMRD is common, malignant gliomas, colon cancers and T cell lymphomas should be stained routinely as the prevalence of CMMRD in these tumors can exceed 40%. 2) Temozolomide should not be used in the management of malignant glioma. By contrast, preclinical studies have suggested increased sensitivity to nitrosoureas. For the management of CMMRD related lymphoma and leukemia, mercaptopurines should not be avoided or discontinued as a part of the standard of care before more data are collected. 3) Management with checkpoint inhibitors should be limited to centers with intensive care units and expertise in complex supportive care to manage side effects of immune therapy. 4) Surveillance protocols have demonstrated long term survival benefits and should be implemented in LMIC.

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