Proteomic identification of new diagnostic biomarkers of early-stage cutaneous mycosis fungoides.
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SUBMITTER: Leng L
PROVIDER: S-EPMC9198347 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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Proteomic identification of new diagnostic biomarkers of early-stage cutaneous mycosis fungoides.
Leng Ling L Liu Zhaorui Z Ma Jie J Zhang Shiyu S Wang Yukun Y Lv Luye L Zhu Yunping Y Gao Dunqin D Wang Yujie Y Wang Juncheng J Liu Yuehua Y Liu Jie J
Cancer communications (London, England) 20220120 6
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Project description:Primary cutaneous T-cell lymphoma (CTCL) is responsible for two-thirds of cutaneous lymphoma cases. Mycosis fungoides (MF), the most common subtype of CTCL comprises approximately 60% of CTCLs. Due to the similar clinical features of MF and inflammatory diseases such as eczema and psoriasis, early-stage MF can easily be misdiagnosed as chronic inflammatory dermatoses, posing a diagnostic challenge to the dermatologist. Early-stage MF is characterized by a favorable prognosis with long-term survival similar to or slightly lower than that of age-matched healthy people, with a 5-year survival between 88% and 100%. In contrast, advanced-stage MF shows aggressive progression, and the median survival time of patients with lymph node and visceral involvement is only 13 months. Therefore, it is important to achieve early diagnosis to improve prognosis, yet there are few specific biomarkers for the early diagnosis and prognosis of MF. In this study, we described the pathological features of MF during the early and advanced stages through proteomics technology, providing clues for the pathogenesis of MF as well as biomarkers for malignant tumors in the early stage. More importantly, diagnostic biomarkers of early-stage MF were identified by comparing the proteomic characteristics of early-stage MF and inflammatory diseases, with the goal of preventing delayed therapy due to misdiagnosis.
2020-11-28 | PXD022798 |
Project description:Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma. Early-stage disease is characterized by superficial infiltrates of small- to medium-sized atypical epidermotropic T lymphocytes that are clonal related. Nevertheless, the percentage of atypical T cells is low with many admixed reactive immune cells. Despite earlier studies, the composition and spatial characteristics of the cutaneous lymphocytic infiltrate has been incompletely characterized. Here, we applied mass cytometry to profile the immune system in skin biopsies of patients with early-stage MF and in normal skin from healthy individuals. Single-cell suspensions were prepared and labeled with a 43-antibody panel, and data were acquired on a Helios mass cytometer. Unbiased hierarchical clustering of the data identified the major immune lineages and heterogeneity therein. This revealed patient-unique cell clusters in both the CD4+ and myeloid cell compartments but also phenotypically distinct cell clusters that were shared by most patients. To characterize the immune compartment in the tissue context, we developed a 36-antibody panel and performed imaging mass cytometry on MF skin tissue. This visualized the structure of MF skin and the distribution of CD4+ T cells, regulatory T cells, CD8+ T cells, malignant T cells, and various myeloid cell subsets. We observed clusters of CD4+ T cells and multiple types of dendritic cells (DCs) identified through differential expression of CD11c, CD1a, and CD1c in the dermis. These results indicated substantial heterogeneity in the composition of the local immune infiltrate but suggest a prominent role for clustered CD4-DC interactions in disease pathogenesis. Probably, the local inhibition of such interactions may constitute an efficient treatment modality.
| S-EPMC8997708 | biostudies-literature
Project description:Patients with mycosis fungoides (MF) developing tumors or extracutaneous lesions usually have a poor prognosis with no cure has so far been available. To identify potential novel biomarkers for MF at the tumor stage, a genomic mapping of 41 cutaneous lymphoma biopsies was used to explore for significant genes.The gene expression profiling datasets of MF were obtained from Gene Expression Omnibus database (GEO). Gene modules were simulated using Weighted Gene Co-expression Network Analysis (WGCNA) and the top soft-connected genes (hub genes) were filtrated with a threshold (0.5). Subsequently, module eigengenes were calculated and significant biological pathways were enriched based on the KEGG database.Four genetic modules were simulated with 3263 genes collected from the whole genomic profile based on cutoff values. Significant diseases genetic terminologies associated with tumor stage MF were found in black module. Subsequently, 13 hub genes including CFLAR, GCNT2, IFNG, IL17A, IL22, MIP, PLCG1, PTH, PTPN6, REG1A, SNAP25, SUPT7L, and TP63 were shown to be related to cutaneous T-cell lymphoma (CTCL) and adult T-cell lymphoma/leukemia (ATLL).In summary, in addition to the reported genes (IL17F, PLCG1, IFNG, and PTH) in CTCL/ATLL, the other high instable genes may serve as novel biomarkers for the regulation of the biological processes and molecular mechanisms of CTLT (MF/SS).
| S-EPMC6392713 | biostudies-literature
Project description:BackgroundThe PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study is a prospective analysis of an international database. Here we examine front-line treatments and quality of life (QoL) in patients with newly diagnosed mycosis fungoides (MF).ObjectivesTo identify (i) differences in first-line approaches according to tumour-nodes-metastasis-blood (TNMB) staging; (ii) parameters related to a first-line systemic approach and (iii) response rates and QoL measures.MethodsIn total, 395 newly diagnosed patients with early-stage MF (stage IA-IIA) were recruited from 41 centres in 17 countries between 1 January 2015 and 31 December 2018 following central clinicopathological review.ResultsThe most common first-line therapy was skin-directed therapy (SDT) (322 cases, 81·5%), while a smaller percentage (44 cases, 11·1%) received systemic therapy. Expectant observation was used in 7·3%. In univariate analysis, the use of systemic therapy was significantly associated with higher clinical stage (IA, 6%; IB, 14%; IIA, 20%; IA-IB vs. IIA, P < 0·001), presence of plaques (T1a/T2a, 5%; T1b/T2b, 17%; P < 0·001), higher modified Severity Weighted Assessment Tool (> 10, 15%; ≤ 10, 7%; P = 0·01) and folliculotropic MF (FMF) (24% vs. 12%, P = 0·001). Multivariate analysis demonstrated significant associations with the presence of plaques (T1b/T2b vs. T1a/T2a, odds ratio 3·07) and FMF (odds ratio 2·83). The overall response rate (ORR) to first-line SDT was 73%, while the ORR to first-line systemic treatments was lower (57%) (P = 0·027). Health-related QoL improved significantly both in patients with responsive disease and in those with stable disease.ConclusionsDisease characteristics such as presence of plaques and FMF influence physician treatment choices, and SDT was superior to systemic therapy even in patients with such disease characteristics. Consequently, future treatment guidelines for early-stage MF need to address these issues.
| S-EPMC7704558 | biostudies-literature
Project description: Not available
| S-EPMC5501930 | biostudies-literature
Project description:IntroductionThe majority of patients with mycosis fungoides (MF) have an indolent disease course, but a substantial fraction (20-30%) of patients progress to advanced stages - usually with a grave prognosis. Early differentiation between indolent and aggressive types of MF is important for the choice of treatment regimen and monitoring of the individual patient. Good biomarkers are therefore desired.MethodsHere, we used spatial transcriptomics on skin samples at time-of-diagnosis to enable prediction of patients who later progressed to advanced stages of MF. Formalin-fixed, paraffin-embedded skin biopsies at time of diagnosis from six patients with MF who progressed to advanced stages of disease within 4 months to 12 years after diagnosis, and nine patients who remained in early-stage disease over 9 to 27 years were analyzed using the GeoMx Digital Spatial Profiler to capture spatially resolved high-plex RNA gene expression data. Five different regions of interest (the epidermis, the basal layer of epidermis, CD4+ T-cells and neighboring cells, and Pautrier's microabscesses) were profiled for further assessment.Results and discussionInterestingly, RUNX2, SHMT2, and MCM7 were upregulated in the enriched population of malignant T-cells in Pautrier's microabscesses in patients who later developed advanced stages of disease. Expression of RUNX2, SHMT2 and MCM7 in malignant T-cells was confirmed in a subset of patients in MF skin using scRNA-seq datasets across multiple studies and correlating with stage of disease. Taken together, we provide first evidence that RUNX2 has potential as a biomarker to identify MF patients progressing to advanced stage disease. As RUNX2 has not previously been linked to MF, our data also shows the analytical strength of combining spatial transcriptomics with scRNA-seq analysis.
| S-EPMC11491341 | biostudies-literature
Project description:BackgroundSkin diseases have been shown to worsen psychological distress, which, in turn, may be detrimental to treatment outcomes. Both the impact of psychological distress on response to treatment in mycosis fungoides (MF) and the effect of treatments on psychological well-being are unclear.ObjectivesTo evaluate (1) the association between pretreatment psychological morbidity and treatment outcome in early-stage MF and (2) the impact of response to treatment on psychological well-being.MethodsThis was a prospective cohort study of patients with early-stage MF who started a new stage-directed treatment for their disease. The response was determined using the modified severity-weighted assessment tool, and psychological distress was assessed using the 12-item General Health Questionnaire (GHQ-12) and Penn State Worry Questionnaire (PSWQ). Participants were followed for 1 year.ResultsIn all, 24 consecutive patients were recruited. Objective response rate was 71% (17/24), consistent with existing literature. Prior to treatment, 9 patients (38%) had clinically significant psychological distress on the GHQ-12, while 8 (33%) demonstrated high-level worry on the PSWQ. Of these patients, 6 had pathologic scores on both instruments. Patients with significantly less baseline anxiety/depression on the GHQ-12 responded better to treatment than patients with higher levels (P = .004). In addition, responders' mean GHQ-12 scores decreased by 39% and their PSWQ scores by 17%, whereas nonresponders' GHQ-12 scores increased by 93% (P = .042) and their PSWQ scores by 11% (P = .019).ConclusionsThese findings suggest that (1) baseline psychological distress is associated with worse outcomes in patients with early-stage MF and that (2) effective treatment improves psychological morbidity.
| S-EPMC10908191 | biostudies-literature
Project description:IntroductionMycosis fungoides (MF), Sézary syndrome (SS) and other cutaneous T-cell lymphomas (CTCLs) can have a severe impact on quality of life (QoL) and itch, but early MF is insufficiently investigated despite representing most patients. This single center study investigated associations between QoL/itch/depressive symptoms and clinical phenotypes in patients with CTCL with particular focus on early MF-stages.MethodsPatients were included during routine dermatological care. The primary outcomes included Dermatology Life Quality Index (DLQI), EuroQoL 5D (EQ-5D) index, Montgomery-Åsberg Depression Rating Scale - Self report (MADRS-S), and itch measured with a visual analogue scale (VAS-itch).ResultsIn the total CTCL cohort (n=76), median EQ-5D index was impaired in female vs male patients (0.73 vs 0.85, p = 0.040). Among early MF patients (n=58), increased disease activity correlated with impaired DLQI (r = 0.413, p = 0.0014) and EQ-5D index (r = -0.317, p = 0.0161). Early MF patients with plaques vs only patches reported impaired EQ-5D index (median 0.725 vs 0.848, p = 0.0032) and increased itch (median VAS 3.27 vs 0.43, p = 0.0006). MF patients with stage IB vs IA reported impaired DLQI (median 5.00 vs 1.00, p = 0.0006), impaired EQ-5D index (median 0.725 vs 0.848, p = 0.0040) and increased itch (median VAS 3.37 vs 0.54, p = 0.0487).DiscussionAlthough early MF patients reported generally a mild impact on QoL, this study highlights the need for disease management optimization for subgroups of early MF patients, including those with plaques, stage IB and higher disease activity.
| S-EPMC11906425 | biostudies-literature
Project description:Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma; in advanced stages, it can involve multiple organs and has a poor prognosis. Early detection of the disease is still urgent, but there is no optimal therapy for advanced MF. In the present study, quantitative proteomic analyses (label-free quantitation, LFQ) were applied to tissue samples of different stages of MF and tissue samples from controls (eczema patients and healthy donors) to conduct preliminary molecular analysis to clarify the pathogenesis of the disease. Differential protein expression analysis demonstrated that 113 and 305 proteins were associated with the early and advanced stages of MF, respectively. Gene ontology (GO) enrichment analysis was conducted to determine the potential functions of the proteins, which could be classified into three categories: biological process, cellular component, and molecular function. The results revealed that a series of biological processes, including "initiation of DNA replication" and "nucleosome assembly," were involved in the disease. Moreover, cellular components, including the "desmosome" and "integrin complex," may affect the invasion and metastasis of MF via molecular functions, including "integrin binding" and "cadherin binding". Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis demonstrated that "focal adhesion DNA replication," "Toll-like receptor signalling pathway" and other pathways were also involved. A parallel reaction monitoring (PRM) assay was applied to validate the identified differentially expressed proteins. In conclusion, the above proteomic findings may have great diagnostic and prognostic value in diverse malignancies, especially MF. Nevertheless, further studies are still needed to explore the precise mechanisms of MF.
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Project description: Not available
| S-EPMC10582838 | biostudies-literature