Intrinsic Molecular Characteristics of the Immune Subtypes of Salivary Mucoepidermoid Carcinoma

2021 ◽  
Author(s):  
Hyundeok Kang ◽  
Mi-Kyoung Seo ◽  
BeumJin Park ◽  
Yoon Woo Koh ◽  
Dahee Kim ◽  
...  
Keyword(s):  
Mucoepidermoid Carcinoma ◽  
Treatment Options ◽  
Inverse Correlation ◽  
Molecular Characteristics ◽  
Rna Seq ◽  
Molecular Features ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
First Time ◽  
Metabolic Regulators

Abstract Background: Characterising the tumor microenvironment (TME) and immune landscape of cancer has been a promising step towards discovering new therapeutic biomarkers and guiding precision medicine; however, its application in salivary mucoepidermoid carcinoma (MEC) has been sparse. Here, we conducted a comprehensive transcriptomic study to understand the properties of the TME and immune profiles of MEC.Methods: Molecular features in heterogeneous immunophenotypic subgroups of MEC and their intrinsic characteristics were determined by applying bioinformatic and immunoinformatic analyses on 20 matched primary MEC RNA-seq data.Results: In this study, distinct two immunophenotypic subgroups, hot and cold MECs, were uncovered with their distinct molecular features, and potential immune-oncologic therapeutic options for each subgroup were suggested. In search for immunophenotype defining molecular features, tumor mutational burden, CRTC1-MAML2 fusion status, and its fusion neoantigen were not discriminable factors. However, we demonstrate that a significant inverse correlation between lipid metabolism activity and immunogenic state, and lipid metabolic regulators, such as MLXIPL and FASN, which are associated suppression of immune activity, were under-expressed in the immune-hot subgroup, contributing significant role in high immunity of immune active subgroup.Conclusions: Our study has shown heterogeneous immunophenotypic MEC subgroups with their distinctive molecular characteristics and provided potential treatment options tailored to the immune context, which yields, for the first time, new insights into TME of MEC and may help the next step to studying this uncharted cancer.

scholarly journals NCMP-17. MISMATCH REPAIR MUTATIONS AND THE CENTRAL NERVOUS SYSTEM: A CASE SERIES OF GERMLINE MUTATIONS AND CNS MALIGNANCY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii126-ii126
Author(s):  
Amber Ruiz ◽  
Jerome Graber
Keyword(s):  
Treatment Response ◽  
Mismatch Repair ◽  
Case Series ◽  
Germline Mutations ◽  
Molecular Characteristics ◽  
Loss Of Function ◽  
Dna Mismatch ◽  
Mutational Burden ◽  
Increased Risk ◽  
Tumor Mutational Burden

Abstract Our understanding of genetic predispositions for malignancy is continually evolving. One family of germline mutations well described in the literature is that of the DNA mismatch repair mechanism (MMR). Lynch syndrome (LS) is due to a loss of function mutation of several MMR genes- MSH2, MLH1, MSH6, and PMS2. Germline MMR mutations lead to microsatellite instability and loss of genomic integrity resulting in an increased risk for various cancers (colorectal, genitourinary, etc). LS may be as common as 1 in 400 people and some MMR mutations have been associated with gliomas. There is a paucity of information regarding frequency of glioma subtypes as well as tumor genetic and molecular characteristics which have important clinical implications. We describe a case series of 6 individuals with germline MMR mutations and brain tumors. Those with MSH2 and PMS2 mutations (n=3) developed glioblastomas at a mean age at diagnosis of 48 years. These tumors expressed MGMT hyper-methylation and high tumor mutational burden. Only one had IDH-1 mutation. Those with MLH1 mutations (n=3), did not develop gliomas. This raises the question of differential glioma subtype development based on MMR gene. It also highlights the possibility of Lynch-associated gliomas having more favorable treatment response due to MGMT methylation and potential response to immunotherapy based on high tumor mutational burden. Though the sample size is small, there appears to be a preponderance of women compared to men (5:1 respectively). Larger studies are needed to verify CNS involvement in germline MMR mutations. In doing so, we hope to identify factors that may influence clinical management and lead to a better understanding of treatment response and disease prognosis.

The prognostic role of microsatellite status, tumor mutational burden, and protein expression in CRC.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 572-572 ◽  
Author(s):  
Sarit Schwartz ◽  
Yuan Tian ◽  
Fabiola Cecchi ◽  
Andrew Nguyen ◽  
Yeoun Jin Kim ◽  
...  
Keyword(s):  
Protein Expression ◽  
Treatment Options ◽  
Molecular Profiling ◽  
Clinical Samples ◽  
Rank Test ◽  
P16 Protein ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Patient Subgroups ◽  
P16 Expression

572 Background: Comprehensive molecular profiling of CRC can inform treatment decisions by identifying patient subgroups at varying risks of death. Microsatellite instability (MSI) is prognostic in CRC and is used to select patients for immunotherapy. High tumor mutational burden (TMB) is associated with genomic instability and is prognostic in melanoma. Expression of p16 protein is prognostic in many tumor types. We used proteomic and genomic profiling to measure MSI, TMB and p16 in CRC tumors and to assess associations with patient survival. Methods: In archived clinical samples of CRC, 76 proteins were quantitated with mass spectrometry-based proteomics. MSI was measured by WGS and RNA-seq; unstable loci were quantified in tumor and normal samples. Cutoffs were derived via ROC analysis: high TMB was defined as > 4.5 somatic mutations per megabase; p16 as > 108 amol/ug. Patients were grouped by microsatellite status (MSI vs. microsatellite stable [MSS]), TMB (high vs. low), and p16 protein expression level. Survival curves were compared with the Mantel-Cox log-rank test. Results: Of 145 samples, 39 (27%) had high TMB and 29 (20%) had MSI. Patients with MSI tumors had longer OS than patients with MSS tumors (HR: 0.096; p = 0.003). Similarly, patients with high TMB had longer OS than those with low TMB (HR: 0.076; p < 0.001). High p16 expression was prognostic of poor survival (HR: 2.874; p = 0.019). Among patients with MSS tumors or low TMB, those with low p16 levels had longer OS than patients with high p16 (HR: 0.257; p = 0.002 and HR: 0.249; p = 0.002, for MSS and low TMB, respectively). A combination of MSS, low TMB, and low p16 also differentiated between long and short survivors (HR: 0.249; p = 0.002). These associations remained after adjustment for tumor sidedness. Further analyses of clinical correlates will be presented. Conclusions: A combination of MSS, low TMB and low p16 expression characterized a subset of patients with longer survival. This is important because patients with MSS tumors have limited treatment options but may respond to CDK4/6 inhibitors due to low p16 expression. Molecular profiling of CRC may identify patient subgroups with a relatively poor prognosis who could benefit from personalized therapy.

Characterizing the T cell repertoire in lung squamous cell premalignancy and its association with lesion outcome.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 102-102
Author(s):  
Asaf Maoz ◽  
Carter Merenstein ◽  
Sarah Mazzilli ◽  
Joshua Campbell ◽  
Gang Liu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Squamous Cell ◽  
Lung Squamous Cell Carcinoma ◽  
Premalignant Lesions ◽  
Rna Seq ◽  
Molecular Features ◽  
Mutational Burden ◽  
Tcr Repertoire ◽  
Tcr Diversity

102 Background: The immune response to frank malignancy has been the focus of published work, but little is known about the adaptive immune response to bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma. This study was designed to characterize the T cell receptor (TCR) repertoire in PMLs and its association with clinical, pathological and molecular features. Methods: Endobronchial biopsies (n=294) and brushings (n=137) from high-risk subjects (n=50), undergoing lung cancer screening at approximately 1-year intervals via auto fluorescence bronchoscopy and CT, were profiled by RNA-Seq as part of the Pre-Cancer Genome Atlas (PCGA). We applied the TCR Repertoire Utilities for Solid Tissue/Tumor (TRUST) tool to identify TCR CDR3 sequences in the RNA-Seq data. We quantified the ratio of private (i.e., found in one patient only) and public (i.e. found in two or more patients) TCRs that are found in curated databases with known antigen specificities. We measured the correlation of TCR diversity with previously derived PML transcriptional signatures and molecular subtypes; and with mutational burden among a subset of biopsies (n=115) also profiled with whole exome sequencing. Results: We detected 40,421 unique TCR sequences, of which 3,396 (8.4%) were found in more than one sample and 1,057 (2.6%) were found in two or more patients (i.e. Public). TCRs with known antigen specificities were enriched among public TCRs (p < 0.001). In PMLs with a proliferative molecular subtype reflective of dysplasia (n=80), TCR diversity was decreased in PMLs that regressed versus PMLs that progressed (p=0.045). TCR diversity was negatively associated with a transcriptional signature of T-cell mediated immune activation (Spearman’s rho -0.26, p < 0.001) but was not associated with mutational burden. Conclusions: To our knowledge, this is the first characterization of the TCR repertoire associated with bronchial premalignant lesions. TCR diversity may help predict the efficacy of the host immune response to PMLs but it is not associated with mutational burden. Further studies are needed to leverage these findings and explore the potential for immunoprevention of PMLs.

scholarly journals Response to anti-PD1 immunotherapy in patients with metastatic cutaneous sarcoma: case reports and literature review

2020 ◽  
Vol 2020 (1) ◽  
Author(s):  
Aline Cristini Vieira ◽  
Thais Baccili Cury Megid ◽  
Raissa Melo ◽  
David Muniz ◽  
Alessandra Corte Real Salgues ◽  
...  
Keyword(s):  
Case Reports ◽  
Treatment Options ◽  
Surgical Excision ◽  
Predictive Biomarker ◽  
Immune Checkpoint Blockade ◽  
Targeted Agents ◽  
Mutational Burden ◽  
Metastatic Setting ◽  
Tumor Mutational Burden

Abstract Dermal sarcomas represent a group or rare malignancies of mesenchymal origin. Although surgical excision with wide margins can be curative, in the advanced/metastatic setting, treatment options are limited and the benefit from anthracycline-based chemotherapy or targeted agents is usually short-lived. Tumor mutational burden and PD-L1 expression scores can be used as predictive biomarker for response to immunotherapy in some metastatic cancers. The role of immune-checkpoint blockade for sarcoma patients remains investigational. Here we present three cases of dermal sarcomas with high TMB and PD-L1 expression and responses to anti-PD1 agents in two of them.

scholarly journals Multiomics Analysis of Transcriptome, Epigenome, and Genome Uncovers Putative Mechanisms for Dilated Cardiomyopathy

2021 ◽  
Vol 2021 ◽  
pp. 1-29
Author(s):  
Li Liu ◽  
Jianjun Huang ◽  
Yan Liu ◽  
Xingshou Pan ◽  
Zhile Li ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Differentially Expressed ◽  
Molecular Characteristics ◽  
Rna Seq ◽  
Frequent Mutation ◽  
Protein Protein Interaction ◽  
Molecular Features ◽  
Differentially Methylated Genes ◽  
And Control ◽  
Control Samples

Objective. Multiple genes have been identified to cause dilated cardiomyopathy (DCM). Nevertheless, there is still a lack of comprehensive elucidation of the molecular characteristics for DCM. Herein, we aimed to uncover putative molecular features for DCM by multiomics analysis. Methods. Differentially expressed genes (DEGs) were obtained from different RNA sequencing (RNA-seq) datasets of left ventricle samples from healthy donors and DCM patients. Furthermore, protein-protein interaction (PPI) analysis was then presented. Differentially methylated genes (DMGs) were identified between DCM and control samples. Following integration of DEGs and DMGs, differentially expressed and methylated genes were acquired and their biological functions were analyzed by the clusterProfiler package. Whole exome sequencing of blood samples from 69 DCM patients was constructed in our cohort, which was analyzed the maftools package. The expression of key mutated genes was verified by three independent datasets. Results. 1407 common DEGs were identified for DCM after integration of the two RNA-seq datasets. A PPI network was constructed, composed of 171 up- and 136 downregulated genes. Four hub genes were identified for DCM, including C3 ( degree = 24 ), GNB3 ( degree = 23 ), QSOX1 ( degree = 21 ), and APOB ( degree = 17 ). Moreover, 285 hyper- and 321 hypomethylated genes were screened for DCM. After integration, 20 differentially expressed and methylated genes were identified, which were associated with cell differentiation and protein digestion and absorption. Among single-nucleotide variant (SNV), C>T was the most frequent mutation classification for DCM. MUC4 was the most frequent mutation gene which occupied 71% across 69 samples, followed by PHLDA1, AHNAK2, and MAML3. These mutated genes were confirmed to be differentially expressed between DCM and control samples. Conclusion. Our findings comprehensively analyzed molecular characteristics from the transcriptome, epigenome, and genome perspectives for DCM, which could provide practical implications for DCM.

scholarly journals A Combined Two-mRNA Signature Associated With PD-L1 and Tumor Mutational Burden for Prognosis of Lung Adenocarcinoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Congkuan Song ◽  
Zhiquan Wu ◽  
Qingwen Wang ◽  
Yujin Wang ◽  
Zixin Guo ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Data Sets ◽  
Multiple Gene ◽  
Molecular Features ◽  
Mutational Burden ◽  
Wide Range ◽  
Tumor Mutational Burden ◽  
Risk Patients ◽  
New Perspective ◽  
Complementary Value

Due to biological heterogeneity, lung adenocarcinoma (LUAD) patients with the same stage may exhibit variable responses to immunotherapy and a wide range of outcomes. It is urgent to seek a biomarker that can predict the prognosis and response to immunotherapy in these patients. In this study, we identified two genes (ANLN and ARNTL2) from multiple gene expression data sets, and developed a two-mRNA-based signature that can effectively distinguish high- and low-risk patients and predict patients’ response to immunotherapy. Furthermore, taking full advantage of the complementary value of clinical and molecular features, we combined the immune prognostic signature with clinical features to construct and validate a nomogram that can predict the probability of high tumor mutational burden (&gt;10 mutations per megabyte). This may improve the estimation of immunotherapy response in LUAD patients, and provide a new perspective for clinical screening of immunotherapy beneficiaries.

scholarly journals Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Pancreatic Cancer: Systematic Review and Still-Open Questions

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3119
Author(s):  
Rita T. Lawlor ◽  
Paola Mattiolo ◽  
Andrea Mafficini ◽  
Seung-Mo Hong ◽  
Maria L. Piredda ◽  
...  
Keyword(s):  
Systematic Review ◽  
Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Molecular Feature ◽  
Molecular Features ◽  
Mutational Burden ◽  
Open Questions ◽  
Potential Biomarker ◽  
Starting Point ◽  
Tumor Mutational Burden

Tumor mutational burden (TMB) is a numeric index that expresses the number of mutations per megabase (muts/Mb) harbored by tumor cells in a neoplasm. TMB can be determined using different approaches based on next-generation sequencing. In the case of high values, it indicates a potential response to immunotherapy. In this systematic review, we assessed the potential predictive role of high-TMB in pancreatic ductal adenocarcinoma (PDAC), as well as the histo-molecular features of high-TMB PDAC. High-TMB appeared as a rare but not-negligible molecular feature in PDAC, being present in about 1.1% of cases. This genetic condition was closely associated with mucinous/colloid and medullary histology (p < 0.01). PDAC with high-TMB frequently harbored other actionable alterations, with microsatellite instability/defective mismatch repair as the most common. Immunotherapy has shown promising results in high-TMB PDAC, but the sample size of high-TMB PDAC treated so far is quite small. This study highlights interesting peculiarities of PDAC harboring high-TMB and may represent a reliable starting point for the assessment of TMB in the clinical management of patients affected by pancreatic cancer.

scholarly journals Characterization of genomic alterations in Chinese colorectal cancer patients

2020 ◽  
Vol 51 (1) ◽  
pp. 120-129
Author(s):  
Wei Huang ◽  
Hui Li ◽  
Xiaoliang Shi ◽  
Minglin Lin ◽  
Cun Liao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Genomic Alteration ◽  
Molecular Characteristics ◽  
Tumor Differentiation ◽  
Cancer Genes ◽  
Exact Test ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Colorectal Cancer Patients

Abstract Objective Colorectal cancer is one of the most prevalent types of cancer worldwide. Right-sided and left-sided colorectal cancer (RCC and LCC) patients respond differently to treatment. We aimed to identify the different mutational profile between RCC and LCC and provided evidence for future precision therapy. Methods A total of 630 Chinese colorectal cancer patients, including 467 (74.1%) LCC and 163 (25.9%) RCC, were enrolled in this cohort. Both formalin-fixed paraffin-embedded tumor tissues and matching blood samples were collected and deep sequenced targeting 450 cancer genes for genomic alteration analysis. Tumor mutational burden was measured by an algorithm developed in-house. Correlation analysis was performed by Fisher’s exact test. Results The most common mutated genes were TP53 (77.0%), APC (71.7%), KRAS (50.0%), SMAD4 (19.8%), PIK3CA (18.3%), FBXW7 (17.5%), TCF7L2 (12.5%), SOX9 (11.3%), LRP1B (10.8%), ARID1A (10.3%) and FAT4 (10.3%). The mutation frequencies of TP53 and APC in LCC were significantly higher than that of RCC, while the mutation frequency of PIK3CA was lower than that of RCC. Six gene fusions were specifically detected in RCC patients. Colorectal cancer sites were associated with gender (P = 4.15 × 10−5) and tumor differentiation (P = 0.059). In LCC, the gender-associated genes were FAT4, EP300, FAT1, LRP1, ARID1B, AR, FYN and TAF1, while in RCC, they were ARID1A, SMARCA4, LRP1 and GRIN2A. The mutations of 18 genes were associated with tumor differentiation (8 for LCC and 10 for RCC). High tumor mutational burden was more common in RCC. Our results implied more potential targeted drug therapy opportunities for RCC. Conclusion We describe the different molecular characteristics of LCC and RCC. Our result supported a better prognosis of RCC than LCC in Chinese colorectal cancer patients.

scholarly journals Intra-patient stability of tumor mutational burden from tissue biopsies at different time points in advanced cancers

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Timothy V. Pham ◽  
Aaron M. Goodman ◽  
Smruthy Sivakumar ◽  
Garrett Frampton ◽  
Razelle Kurzrock
Keyword(s):  
Solid Tumor ◽  
Landscape Heterogeneity ◽  
Pearson Correlation ◽  
Predictive Biomarker ◽  
Molecular Characteristics ◽  
Mutational Burden ◽  
Before And After ◽  
Tumor Mutational Burden ◽  
The University ◽  
Tumor Biopsies

Abstract Background Tumor mutational burden (TMB) may be a predictive biomarker of immune checkpoint inhibitor (ICI) responsiveness. Genomic landscape heterogeneity is a well-established cancer feature. Molecular characteristics may differ even within the same tumor specimen and undoubtedly evolve with time. However, the degree to which TMB differs between tumor biopsies within the same patient has not been established. Methods We curated data on 202 patients enrolled in the PREDICT study (NCT02478931), seen at the University of California San Diego (UCSD), who had 404 tissue biopsies for TMB (two per patient, mean of 722 days between biopsies) to assess difference in TMB before and after treatment in a pan-cancer cohort. We also performed an orthogonal analysis of 2872 paired pan-solid tumor biopsies in the Foundation Medicine database to examine difference in TMB between first and last biopsies. Results The mean (95% CI) TMB difference between samples was 0.583 [− 0.900–2.064] (p = 0.15). Pearson correlation showed a flat line for time elapsed between biopsies versus TMB change indicating no correlation (R2 = 0.0001; p = 0.8778). However, in 55 patients who received ICIs, there was an increase in TMB (before versus after mean mutations/megabase [range] 12.50 [range, 0.00–98.31] versus 14.14 [range, 0.00–100.0], p = 0.025). Analysis of 2872 paired pan-solid tumor biopsies in the Foundation Medicine database also indicated largely stable TMB patterns; TMB increases were only observed in specific tumors (e.g., breast, colorectal, glioma) within certain time intervals. Conclusions Overall, our results suggest that tissue TMB remains stable with time, though specific therapies such as immunotherapy may correlate with an increase in TMB. Trial registration NCT02478931, registered June 23, 2015.

scholarly journals What is the burden of proof for tumor mutational burden in gliomas?

2020 ◽  
Author(s):  
Mustafa Khasraw ◽  
Kyle M Walsh ◽  
Amy B Heimberger ◽  
David M Ashley
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Solid Tumors ◽  
Treatment Options ◽  
Burden Of Proof ◽  
Predictive Biomarkers ◽  
Cns Tumors ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Pan Cancer

Abstract The treatment of patients with a variety of solid tumors has benefitted from immune checkpoint inhibition targeting the anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis. The US Food and Drug Administration (FDA) granted accelerated approval of PD-1 inhibitor, pembrolizumab, for the treatment of adult and pediatric patients with high tumor mutational burden (TMB-H), solid tumors that have progressed following prior treatment, and who have no other treatment options, including the extension to tumors of the central nervous system (CNS). In general, pan-cancer approvals are viewed positively to empower patients and clinicians. There are subsets (eg, BRAF, NTRK) for which this pathway for approval is appropriate. However, the pan-cancer FDA approval of pembrolizumab raises several concerns regarding the generalizability of the evidence to other tumor types, including managing patients with gliomas and other CNS tumors. The cutoff for TMB-H is not well defined. There are intrinsic immunological differences between gliomas and other cancers types, including the immunosuppressive glioma microenvironment, the tumor’s effects on systemic immune function, and the transformation of the T-cell populations to an exhausted phenotype in glioma. Here, we address the caveats with pan-cancer approvals concerning gliomas and complexities of the unique CNS immune environment, discuss potential predictive biomarkers, including TMB, and explain why the recent approval should be applied with caution in CNS tumors.

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