Status of microsatellite stability in angiosarcoma: Angiosarcoma is a microsatellite stable tumor

2021 ◽  
Author(s):  
Saki Maeda‐Otsuka ◽  
Tselmeg Mijiddorj Myangat ◽  
Ikko Kajihara ◽  
Ryoko Sakamoto ◽  
Saori Yamada‐Kanazawa ◽  
...  
Keyword(s):  
Microsatellite Stability

scholarly journals Emerging Trends for Radio-Immunotherapy in Rectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1374
Author(s):  
Claudia Corrò ◽  
Valérie Dutoit ◽  
Thibaud Koessler
Keyword(s):  
Rectal Cancer ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
T Cell Infiltration ◽  
Emerging Trends ◽  
Tumor Mutational Burden ◽  
Microsatellite Stability

Rectal cancer is a heterogeneous disease at the genetic and molecular levels, both aspects having major repercussions on the tumor immune contexture. Whilst microsatellite status and tumor mutational load have been associated with response to immunotherapy, presence of tumor-infiltrating lymphocytes is one of the most powerful prognostic and predictive biomarkers. Yet, the majority of rectal cancers are characterized by microsatellite stability, low tumor mutational burden and poor T cell infiltration. Consequently, these tumors do not respond to immunotherapy and treatment largely relies on radiotherapy alone or in combination with chemotherapy followed by radical surgery. Importantly, pre-clinical and clinical studies suggest that radiotherapy can induce a complete reprograming of the tumor microenvironment, potentially sensitizing it for immune checkpoint inhibition. Nonetheless, growing evidence suggest that this synergistic effect strongly depends on radiotherapy dosing, fractionation and timing. Despite ongoing work, information about the radiotherapy regimen required to yield optimal clinical outcome when combined to checkpoint blockade remains largely unavailable. In this review, we describe the molecular and immune heterogeneity of rectal cancer and outline its prognostic value. In addition, we discuss the effect of radiotherapy on the tumor microenvironment, focusing on the mechanisms and benefits of its combination with immune checkpoint inhibitors.

Genetic Heterogeneity of Variable Number Tandem Repeats in Thymidylate Synthase Gene in Colorectal Cancer Patients

2004 ◽  
Vol 19 (4) ◽  
pp. 332-336 ◽  
Author(s):  
M. Agostini ◽  
S. Pucciarelli ◽  
P. Calandra ◽  
F. Villani ◽  
M. Lise ◽  
...  
Keyword(s):  
Thymidylate Synthase ◽  
Tandem Repeats ◽  
Colorectal Adenocarcinoma ◽  
Variable Number ◽  
Mismatch Repair Genes ◽  
Pcr Product ◽  
Group A ◽  
Microsatellite Stability ◽  
Group B ◽  
Repair Genes

Purpose To analyze the genetic variability in a variable number of tandem repeats (VNTR) in the thymidylate synthase (TS) enhancer promoter region and assess the influence of functional alterations in mismatch repair genes by analyzing constitutional and tumoral DNA from patients with colorectal adenocarcinoma with a high microsatellite instability (MSI-H) or microsatellite stability (MSS) status. Patients and methods Patients who underwent surgery for colorectal adenocarcinoma were selected from the colorectal database of our institute and, on the basis of MSI status, assigned to a study group and a control group: group A, MSI-H; group B, MSS. Microsatellite status was investigated using the Bethesda recommended panel (BAT-26, BAT-25, D2S123, D5S346, D17S250). In MSI-H patients an additional analysis was made of the microsatellite loci D18S61 and D18S58, both mapping in the region containing the TS gene (18p11.2–11.32). Based on the number of altered microsatellites (≥2, 1, or 0), tumors were considered as having high (MSI-H) or low (MSI-L) instability or microsatellite stability (MSS), respectively. Genotyping for thymidylate synthase promoter polymorphism was carried out on constitutional and tumor DNA of each patient by PCR amplification of the polymorphic region. Results MSI-H was found in 55 patients (group A) and MSS in 50 patients (group B). In none of the MSI-H patients was microsatellite instability found in the additional D18S61 and D18S58 loci. In five group A and ten group B cases the analysis was not performed because constitutional DNA and/or tumoral DNA were not amplifiable. Homozygotes for the triple repeat variant (3R/3R) displayed only the large PCR product, homozygotes for the double repeat variant (2R/2R) displayed only the smaller PCR product, while heterozygotes (2R/3R) displayed both the larger and smaller PCR products. In 3/50 (6%) group A patients and 5/40 (12%) group B patients repeat variations were found in tumoral DNA. Conclusion Our findings demonstrate that there is genetic homogeneity between constitutional and tumoral DNA but do not support the hypothesis that mismatch repair genes are involved in VNTR recombinant events in TS gene variability.

scholarly journals Potential Mechanism of Immune Evasion Associated with the Master Regulator ASCL2 in Microsatellite Stability in Colorectal Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Qian Yang ◽  
Guowei Huang ◽  
Liyan Li ◽  
Enmin Li ◽  
Liyan Xu
Keyword(s):  
Colorectal Cancer ◽  
Immune Evasion ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Novel Treatments ◽  
T Cell Infiltration ◽  
Immune Resistance ◽  
Unbiased Gene ◽  
Ifn Γ ◽  
Microsatellite Stability

Colorectal cancer (CRC) has two major subtypes, microsatellite instability (MSI) and microsatellite stability (MSS) based on the genomic instability. In this study, using computational programs, we identified 9 master transcription factors (TFs) based on epigenomic profiling in MSS CRC samples. Notably, unbiased gene set enrichment analysis (GSEA) showed that several master TFs were strongly associated with immune-related functions in TCGA MSS CRC tissues, such as interferon gamma (IFN-γ) and interferon alpha (IFN-α) responses. Focusing to the top candidate, ASCL2, we found that CD8+ T cell infiltration was low in ASCL2 overexpressed MSS CRC samples. Compared with other gastrointestinal (GI) cancers (gastric cancer, MSI CRC, and esophageal cancer), ASCL2 is specifically upregulated in MSS CRC. Moreover, we identified 28 candidate genes in IFN-γ and IFN-α response pathways which were negatively correlated with ASCL2. Together, these results link transcriptional dysregulation with the immune evasion in MSS CRC, which may advance the understanding of immune resistance and contribute to developing novel treatments of MSS CRC.

scholarly journals PL2.2 Pembrolizumab (PEM) in recurrent high-grade glioma (HGG)patients with mismatch repair deficiency (dMMR): an observational study

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii2-iii2
Author(s):  
M Caccese ◽  
M Simonelli ◽  
M Fassan ◽  
M Padovan ◽  
P Persico ◽  
...  
Keyword(s):  
Immune Checkpoint Inhibitor ◽  
Brain Mri ◽  
High Grade Glioma ◽  
Median Number ◽  
Anaplastic Gliomas ◽  
Repair Deficiency ◽  
Grade 3 ◽  
Microsatellite Stability ◽  
Ecog Ps

Abstract BACKGROUND Pem, an immune checkpoint inhibitor, demonstrated to be activein various neoplasms with MMRd. No data exists about its efficacy in MMRdglioma patients. MATERIAL AND METHODS MMRd HGG relapsed after receiving RT and CT weretreated with Pem. MMR status was analyzed by immunohistochemistry,including the MLH1, MSH2, MSH6, and PMS2 markers. MMR deficiency wasdefined as presence of a weak (wMMRd) or absent (aMMRd) signal atimmunohistochemistry for at least one MMR protein. Other inclusion criteriawere: ECOG PS 0–2, histologically confirmed gliomas, dexamethasone ≤4 mg.Pem was administrated at 200 mg every 3 weeks until progression disease orunacceptable toxicity. Tumor response was evaluated by brain MRI every 10 weeksaccording to the RANO criteria. OS and PFS were evaluated by Kaplan-Meiercurves. CTCAE v4.0 was used for toxicity. RESULTS among 167 glioma patients, we found 22 MMRd gliomas. 12 PTS were treated with Pem: 8 wMMRd and 4 aMMRd. According to Bethesda criteria, allPTS had microsatellite stability. Tumor histologies included 5 anaplasticastrocytoma, 1 anaplastic oligodendroglioma, 6 glioblastoma (GBM). MSH2deficiency was found in 6 cases, MSH6 deficiency in 9 cases, PMS2 and MLH1deficiency in 2 cases. Median number of prior line of chemotherapy was 1 (range 1–5). Stable disease (SD) was reported in 4 PTS (33%); 8 PTS showedprogressive disease (PD). PTS with anaplastic gliomas showed a statisticallysignificant association with SD (p=0.03, OR=3); all GBM PTS reported PD; status of MMRd (weak/absent), IDH (mutated/wild-type), MSH2 and MLH6(deficient/proficient) were not associated with SD. Median follow up was 14.7 ms. OS was 5.6 ms (95% CI 0.1–13.8), PFS 2.4 ms (95% CI 1.8–2.9). OS was 2.8 ms and 5.6 ms (p=0.9), PFS was 1.8 ms and 3.1 ms (p=0.5) in PTS with wMMRd and aMMRd. PTS reporting SD and PD had PFS of 7.4 ms (95% CI 4.6–10.2) and 1.8 ms (95% CI 0.2–3.4), p=0.002; OS was “not reached” and 2.8 ms in PTS having SD vs PD (p=0.04). Grade ≥3 adverse eventswere reported in 8% of PTS. CONCLUSION a subgroup of recurrent MMRd HGG might benefit from Pem,especially anaplastic gliomas. There was a trend for a longer PFS and OS in PTS with aMMRd. Analyses for identifying additional molecular predictive factors is ongoing.

scholarly journals The combination of Tislelizumab and apatinib obtained complete remission for alpha-fetoprotein-producing gastric cancer with microsatellite stability: case report

2021 ◽  
Author(s):  
Jinyu Xiang ◽  
CongCong Wang ◽  
Wenjing Gong ◽  
Aina Liu ◽  
Ping Sun
Keyword(s):  
Gastric Cancer ◽  
Complete Remission ◽  
Combined Treatment ◽  
Progression Free Survival ◽  
Rare Type ◽  
Continuous Application ◽  
Substantial Progress ◽  
Microsatellite Stability ◽  
One Year

Abstract BackgroundAlpha‑fetoprotein (AFP)‑producing gastric cancer (AFPGC) is a rare type of gastric cancer with high metastasis rate and poor prognosis. Despite substantial progress in the treatment of many solid tumors, there are no reports of the safety and effectiveness of immune checkpoint inhibitor (ICI) in combination with anti-angiogenesis in AFPGC patients with microsatellite stability (MSS).Case presentationThis is a case of a 69-year-old man who was diagnosed with metastatic AFPGC. After the progression of resistance to chemotherapy, Tislelizumab combined with apatinib was attempted, although the patient was microsatellite stable. With 3 cycles of combination therapy, a partial remission (PR, shrunk by 56%) was obtained, and the quality of life improved significantly. Surprisingly, after more than one year of continuous application of the above treatment regimen, both the primary and metastatic tumors in this patient eventually disappeared, which achieved complete remission (CR) without surgery. Following the combined treatment, the patient had a progression-free survival of more than 16 months and now is still in continue to benefit. ConclusionsThis is the first report that we are aware of on the effective treatment of AFPGC with Tislelizumab in combination with Apatinib. This provides a highly effective and tolerable therapeutic strategy for microsatellite-stabilized AFPGC.

scholarly journals Mismatch Repair Proteins and Microsatellite Instability in Colorectal Carcinoma (MLH1, MSH2, MSH6 and PMS2): Histopathological and Immunohistochemical Study

2017 ◽  
Vol 5 (1) ◽  
pp. 9-13 ◽  
Author(s):  
Nour El Hoda S. Ismael ◽  
Samar A. El Sheikh ◽  
Suzan M. Talaat ◽  
Eman M. Salem
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Immunohistochemical Study ◽  
Survival Rates ◽  
Immunohistochemical Expression ◽  
Egyptian Patients ◽  
Mismatch Repair Proteins ◽  
Microsatellite Stability ◽  
Colorectal Cancer Patients

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide. Microsatellite instability (MSI) is detected in about 15% of all colorectal cancers. CRC with MSI has particular characteristics such as improved survival rates and better prognosis. They also have a distinct sensitivity to the action of chemotherapy.AIM: The aim of the study was to detect microsatellite instability in a cohort of colorectal cancer Egyptian patients using the immunohistochemical expression of mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2).MATERIAL AND METHODS: Cases were divided into Microsatellite stable (MSS), Microsatellite unstable low (MSI-L) and Microsatellite unstable high (MSI-H). This Microsatellite stability status was correlated with different clinicopathological parameters.RESULTS: There was a statistically significant correlation between the age of cases, tumor site & grade and the microsatellite stability status. There was no statistically significant correlation between the gender of patients, tumor subtype, stage, mucoid change, necrosis, tumor borders, lymphocytic response, lymphovascular emboli and the microsatellite stability status.CONCLUSION: Testing for MSI should be done for all colorectal cancer patients, especially those younger than 50 years old, right sided and high-grade CRCs.

scholarly journals Superpixel image segmentation of VISTA expression in colorectal cancer and its relationship to the tumoral microenvironment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dongling Wu ◽  
Sean Hacking ◽  
Taisia Vitkovski ◽  
Mansoor Nasim
Keyword(s):  
Colorectal Cancer ◽  
Image Segmentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Disease Free Survival ◽  
Tumor Stage ◽  
The United States ◽  
Mutational Status ◽  
Microsatellite Stability

AbstractColorectal cancer (CRC) is the third most common cause of cancer related death in the United States (Jasperson et al. in Gastroenterology 138:2044–2058, 10.1053/j.gastro.2010.01.054, 2010). Many studies have explored prognostic factors in CRC. Today, much focus has been placed on the tumor microenvironment, including different immune cells and the extracellular matrix (ECM). The present study aims to evaluate the role of V-domain immunoglobulin suppressor of T cell activation (VISTA). We utilized QuPath for whole slides image analysis, performing superpixel image segmentation (SIS) on a 226 patient-cohort. High VISTA expression correlated with better disease-free survival (DFS), high tumor infiltrative lymphocyte, microsatellite instability, BRAF mutational status as well as lower tumor stage. High VISTA expression was also associated with mature stromal differentiation (SD). When cohorts were separated based on SD and MMR, only patients with immature SD and microsatellite stability were found to correlate VISTA expression with DFS. Considering raised VISTA expression is associated with improved survival, TILs, mature SD, and MMR in CRC; careful, well-designed clinical trials should be pursued which incorporate the underlying tumoral microenvironment.

Microsatellite instability diagnosis using the fully automated Idylla platform: feasibility study of an in-house rapid molecular testing ancillary to immunohistochemistry in pathology laboratories

2019 ◽  
Vol 72 (12) ◽  
pp. 830-835 ◽  
Author(s):  
Laura Samaison ◽  
Mélanie Grall ◽  
Frédéric Staroz ◽  
Arnaud Uguen
Keyword(s):  
Microsatellite Instability ◽  
Feasibility Study ◽  
Molecular Analysis ◽  
Diagnostic Tool ◽  
Microsatellite Analysis ◽  
Molecular Testing ◽  
Molecular Analyses ◽  
Microsatellite Stability ◽  
Rapid Treatment

AimTo study the performances of the Idylla MSI Assay in the diagnosis of microsatellite instability (MSI) or microsatellite stability (MSS).MethodsWe selected 12 tumour samples previously tested for MSI focusing on cases with discrepant results between MLH1, PMS2, MSH2 and MSH6 immunohistochemistry and microsatellite molecular analyses (five cases) or doubtful immunohistochemistry (two cases). Idylla MSI Assay was compared with retrospective immunohistochemistry and molecular results.ResultsIdylla MSI Assay showed an almost perfect concordance with microsatellite analysis results previously obtained (only one case with not fully conclusive analysis due to sample exhaustion). The full molecular analysis took less than 150 min per sample and revealed no mutation in any of the seven microsatellite sequences in five MSS samples and four to six mutated ones in seven MSI-High samples.ConclusionAt the era when the determination of MSI/MSS status is becoming important for rapid treatment choices, the Idylla MSI Assay consists of a valuable easy-to-perform diagnostic tool that allows, complementary to MLH1, PMS2, MSH2 and MSH6 immunohistochemistry, the diagnosis of MSI/MSS status in a single day.

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