Correction to: A gene expression assay for simultaneous measurement of microsatellite instability and anti-tumor immune activity.
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ABSTRACT:
SUBMITTER: Danaher P
PROVIDER: S-EPMC6419377 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
Publications
Correction to: A gene expression assay for simultaneous measurement of microsatellite instability and anti-tumor immune activity.
Danaher Patrick P Warren Sarah S Ong Su Fey SF Elliott Nathan N Cesano Alessandra A Ferree Sean S
Journal for immunotherapy of cancer 20190315 1
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Project description:BackgroundClinical benefit from checkpoint inhibitors has been associated in a tumor-agnostic manner with two main tumor traits. The first is tumor antigenicity, which is typically measured by tumor mutation burden, microsatellite instability (MSI), or Mismatch Repair Deficiency using gene sequence platforms and/or immunohistochemistry. The second is the presence of a pre-existing adaptive immune response, typically measured by immunohistochemistry (e.g. single analyte PD-L1 expression) and/or gene expression signatures (e.g. tumor "inflamed" phenotype). These two traits have been shown to provide independent predictive information. Here we investigated the potential of using gene expression to predict tumor MSI, thus enabling the measurement of both tumor antigenicity and the level of tumor inflammation in a single assay, possibly reducing sample requirement, turn-around time, and overall cost.MethodsUsing The Cancer Genome Atlas RNA-seq datasets with the greatest MSI-H incidence, i.e. those from colon (n = 208), stomach (n = 269), and endometrial (n = 241) cancers, we trained an algorithm to predict tumor MSI from under-expression of the mismatch repair genes MLH1, PMS2, MSH2, and MSH6 and from 10 additional genes with strong pan-cancer associations with tumor hypermutation. The algorithms were validated on the NanoString nCounter™ platform in independent cohorts of colorectal (n = 52), endometrial (n = 11), and neuroendocrine (n = 4) tumors pre-characterized using the MMR immunohistochemistry assay.ResultsIn the validation cohorts, the algorithm showed high prediction accuracy of tumor MSI status, with sensitivity of at least 88% attained at thresholds chosen to achieve 100% specificity. Furthermore, MSI status was compared to the Tumor Inflammation Signature (TIS), an analytically validated diagnostic assay which measures a suppressed adaptive immune response in the tumor and enriches for response to immune checkpoint blockade. TIS score was largely independent of MSI status, suggesting that measuring both parameters may identify more patients that would respond to immune checkpoint blockade than either assay alone.ConclusionsDevelopment of a gene expression signature of MSI status raises the possibility of a combined diagnostic assay on a single platform which measures both tumor antigenicity and presence of a suppressed adaptive immune response. Such an assay would have significant advantages over multi-platform assays for both ease of use and turnaround time and could lead to a diagnostic test with improved clinical performance.
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Project description: Not available
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Project description:Microsatellite instability (MSI) is a key secondary effect of a defective DNA mismatch repair mechanism resulting in incorrectly replicated microsatellites in many malignant tumors. Historically, MSI detection has been performed by fragment analysis (FA) on a panel of representative genomic markers. More recently, using next-generation sequencing (NGS) to analyze thousands of microsatellites has been shown to improve the robustness and sensitivity of MSI detection. However, NGS-based MSI tests can be prone to population biases if NGS results are aligned to a reference genome instead of patient-matched normal tissue. We observed an increased rate of false positives in patients of African ancestry with an NGS-based diagnostic for MSI status utilizing 7317 microsatellite loci. We then minimized this bias by training a modified calling model that utilized 2011 microsatellite loci. With these adjustments 100% (95% CI: 89.1% to 100%) of African ancestry patients in an independent validation test were called correctly using the updated model. This poses not only a significant technical improvement but also has an important clinical impact on directing immune checkpoint inhibitor therapy.
| S-EPMC7476819 | biostudies-literature
Project description:Gastric cancer (GC) remains a leading cause of cancer mortality worldwide. Genetic factors are implicated, including DNA mismatch repair (MMR) deficiency manifested as tumor microsatellite instability (MSI). However, a standardized panel of markers and a definition of low-versus-high level MSI in GC are lacking. We examined a population-based cohort of early onset (<or=50 yrs) gastric cancer. We identified 211 cases of early onset gastric cancer in Central-East Ontario from 1989 to 1993, with archival material available for 139 cases. Testing included a six-mononucleotide marker panel and a three-MMR immunohistochemical panel. Overall, 30% (41 of 139) of GC were MSI+, with allelic shifts at one to eight markers. An unexpected discordance between the BAT-25, BAT-26, and BAT-40 markers was observed in the MSI+ cases. Six cases showing multiple loci instability (>or=3 markers MSI+/MSI-high) demonstrated MMR protein deficiency. Three novel hMLH1 mutations (two germline frameshift and one somatic nonsense) were also found. The only significant clinicopathological associations were increased tumor size in MSI+ cases (P=0.04) and Lauren histotype (P=0.006) and tumor grade (P=0.007) in MSI-high cases. Tumor size, location, depth, nodal status, and Ming subtype were significant prognostic variables. Therefore, we propose a new definition of high-level MSI based on unifying characteristics of instability of more than or equal to three of six mononucleotide markers and loss of MMR protein expression.
| S-EPMC1888489 | biostudies-literature
Project description:JAK1 frameshift mutations may promote cancer cell immune evasion by impeding upregulation of the antigen presentation pathway in microsatellite unstable endometrial cancers (ECs). This study investigated the JAK1 mutation frequency, its functional implication in immune evasion and its prognostic significance in microsatellite unstable EC. Microsatellite instability and three microsatellite repeats within JAK1 were analyzed in 181 ECs. Sixty-two (34%) ECs showed microsatellite instability, of which 22 (35%) had a JAK1 mutation. LMP7, TAP1 and HLA class I protein expression and the presence of CD8-positive T-cells were analyzed in the microsatellite unstable ECs. JAK1 mutant microsatellite unstable ECs showed impaired upregulation of LMP7 (P=0.074) and HLA class I (P<0.001), validated using RNAseq data of the TCGA. TAP1 expression and presence of CD8-positive T-cells were not related to JAK1 mutations. In 198 additional microsatellite unstable ECs, the JAK1 mutation frequency was confirmed but no prognostic significance was found. For, JAK1 wildtype (n=135, 72%) and mutant (n=52, 28%) ECs, 10-year recurrence free rates were 84% and 77% (P=0.301). These observations show that JAK1 mutations are highly frequent in microsatellite unstable EC, not associated with survival, but are associated with impaired upregulation of LMP7 and HLA class I and may therefore facilitate immune escape.
| S-EPMC5129978 | biostudies-literature
Project description:The presence of Fusobacterium nucleatum (F. nucleatum) in colorectal carcinoma tissue has been associated with microsatellite instability (MSI), lower-level T-cell infiltrates, and poor clinical outcomes. Considering differences in the tumor-immune microenvironment between MSI-high and non-MSI-high carcinomas, we hypothesized that the association of F. nucleatum with immune response might differ by tumor MSI status. Using samples from 1,041 rectal and colon cancer patients within the Nurses' Health Study and Health Professionals Follow-up Study, we measured F. nucleatum DNA in tumor tissue by a quantitative polymerase chain reaction assay. Multivariable logistic regression models were used to examine the association between F. nucleatum status and histopathologic lymphocytic reactions or density of CD3+ cells, CD8+ cells, CD45RO (PTPRC)+ cells, or FOXP3+ cells in strata of tumor MSI status. We adjusted for potential confounders, including CpG island methylator phenotype; LINE-1 methylation; and KRAS, BRAF, and PIK3CA mutations. The association of F. nucleatum with tumor-infiltrating lymphocytes (TIL) and intratumoral periglandular reaction differed by tumor MSI status (P interaction = 0.002). The presence of F. nucleatum was negatively associated with TIL in MSI-high tumors [multivariable odds ratio (OR), 0.45; 95% confidence interval (CI), 0.22-0.92], but positively associated with TIL in non-MSI-high tumors (multivariable OR 1.91; 95% CI, 1.12-3.25). No significant differential association was observed for peritumoral lymphocytic reaction, Crohn-like lymphoid reaction, or T-cell densities. In conclusion, the association of F. nucleatum with immune response to colorectal carcinoma differs by tumor MSI status, suggesting that F. nucleatum and MSI status interact to affect antitumor immune reactions. Cancer Immunol Res; 6(11); 1327-36. ©2018 AACR See related Spotlight on p. 1290.
| S-EPMC6215508 | biostudies-literature
Project description:Colorectal cancer (CRC), also known as colon cancer, is the third most common cancer and the fourth most cause of cancer-related death in the world. CRC can be classified into two major subtypes, including microsatellite instability (MSI) and microsatellite stability (MSS), which showed different characteristics in immunotherapy. Low sensitivity of diagnostic biomarkers and metastasis are still the principal cause of mortality, especially in MSI. Here, applying computational programs, we identified recurring expression programs based on single cell RNA sequencing (scRNA-Seq) data of CRC cell lines. Notably, three MSI specific recurring modules were identified by non-negative matrix factorization (NMF). High NMF score genes enriched in the function of metabolism and inflammatory response. Focusing on top specific active transcription factor (TF), RUNX3 (Runt-related transcription factor 3), our results suggest that T cell infiltration was increased in RUNX3 high MSI CRC samples. Unbiased Gene Set Enrichment Analysis (GSEA) showed that RUNX3 was strongly associated with immune and metastasis related functions, such as Interferon Gamma (IFN-γ) and EPITHELIAL MESENCHYMAL TRANSITION (EMT). In addition, RUNX3 shows specific highly activated at epigenetic level in MSI compared with other gastrointestinal carcinomas. Positive correlation between RUNX3 and most immune checkpoints further confirmed RUNX3 might have crucial roles in MSI cancer progression and immunotherapy. Taken together, these results indicate significant tumor heterogeneity of two CRC subtypes at single-cell level and epigenetic modification level. These results also linked transcriptional dysregulation with immune infiltration at single-cell level in MSI, which may advance the application of scRNA-Seq technology in immunotherapy and contribute to developing novel biomarkers of this malignancy.
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Project description:MotivationMicrosatellite instability (MSI) is an important indicator of larger genome instability and has been linked to many genetic diseases, including Lynch syndrome. MSI status is also an independent prognostic factor for favorable survival in multiple cancer types, such as colorectal and endometrial. It also informs the choice of chemotherapeutic agents. However, the current PCR-electrophoresis-based detection procedure is laborious and time-consuming, often requiring visual inspection to categorize samples. We developed MSIsensor, a C++ program for automatically detecting somatic microsatellite changes. It computes length distributions of microsatellites per site in paired tumor and normal sequence data, subsequently using these to statistically compare observed distributions in both samples. Comprehensive testing indicates MSIsensor is an efficient and effective tool for deriving MSI status from standard tumor-normal paired sequence data.Availability and implementationhttps://github.com/ding-lab/msisensor
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Project description:Deficiency in DNA MMR activity results in tumors with a hypermutator phenotype, termed microsatellite instability (MSI). Beyond its utility in Lynch syndrome screening algorithms, today MSI has gained importance as predictive biomarker for various anti-PD-1 therapies across many different tumor types. Over the past years, many computational methods have emerged to infer MSI using either DNA- or RNA-based approaches. Considering this together with the fact that MSI-high tumors frequently exhibit a hypermethylated phenotype, herein we developed and validated MSIMEP, a computational tool for predicting MSI status from microarray DNA methylation tumor profiles of colorectal cancer samples. We demonstrated that MSIMEP optimized and reduced models have high performance in predicting MSI in different colorectal cancer cohorts. Moreover, we tested its consistency in other tumor types with high prevalence of MSI such as gastric and endometrial cancers. Finally, we demonstrated better performance of both MSIMEP models vis-à-vis a MLH1 promoter methylation-based one in colorectal cancer.
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Project description: Not available
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