Biology subjects

Sivanand, A.

Publications and source records attributed to Sivanand, A..

2 recordsLinked to original sources

bioRxiv2021

Transcriptomic Changes During Stage Progression of Mycosis Fungoides

BackgroundMycosis fungoides (MF) is the most common cutaneous T cell lymphoma, which in the early patch/plaque stages runs an indolent course. However, ~25% of MF patients develop skin tumors, a hallmark of progression to the advanced stage and associated with high mortality. The mechanisms involved in stage progression are poorly elucidated. MethodsWe performed whole-transcriptome and whole-exome sequencing of malignant MF cells from skin biopsies obtained by laser-capture microdissection. We compared three types of MF lesions: early-stage plaques (ESP, n=12), and plaques and tumors from patients in late-stage disease (late-stage plaques, LSP, n=10, and tumors, TMR, n=15). Gene Ontology (GO) and KEGG analysis were used to determine pathway changes specific for different lesions which we linked to the recurrent somatic mutations overrepresented in MF tumors. ResultsThe key upregulated pathways during stage progression were those related to cell proliferation and survival (MEK/ERK, Akt-mTOR), Th2/Th9 signaling (IL4, STAT3, STAT5, STAT6), meiomitosis (CT45A1, CT45A3, STAG3, GTSF1, and REC8) and DNA repair (PARP1, MYCN, OGG1). Principal coordinate clustering of the transcriptome revealed extensive gene expression differences between early (ESP) and advanced-stage lesions (LSP and TMR). LSP and TMR showed remarkable similarities at the level of the transcriptome, which we interpreted as evidence of cell percolation between lesions via hematogenous self-seeding. ConclusionStage progression in MF is associated with Th2/Th9 polarization of malignant cells, activation of proliferation, survival, as well as increased genomic instability. Global transcriptomic changes in multiple lesions are probably caused by hematogenous cell percolation between discrete skin lesions.

bioinformatics↗

bioRxiv2020

The neoantigen landscape of mycosis fungoides

BackgroundMycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, has a dismal prognosis in advanced stages. Treatments for advanced disease are mostly palliative and MF remains incurable. Although MF is a known immunogenic neoplasm, immunotherapies such as interferons and the immune checkpoint inhibitors yield inconsistent results. Since the number, HLA-binding strength and subclonality of neoantigens are correlated with the therapeutic responses, we aimed here to characterize the landscape of neoantigens in MF. MethodsWe conducted whole exome and whole transcriptome sequencing of 24 MF samples (16 plaque, 8 tumour) from 13 patients. Bioinformatic pipelines (Mutect2, OptiType, MuPeXi) were used for in silico mutation calling, HLA typing, and neoantigen prediction. Phylogenetic analysis was used to subdivide the malignant cell population into stem and clades (subclones). Clonality of neaontigens was determined by matching neoantigens to the stem and clades of the phylogenetic tree of each MF sample. ResultsMF has a high mutational load (median 3217 non synonymous mutations), resulting in a significant number of total neoantigens (median 1309 per sample) and high-affinity neoantigens (median 328). In stage I disease most neoantigens were clonal but with progression to stage II, subclonal neoantigens comprised >50% of the total. There was very little overlap in neoantigens across patients or between different lesions on the same patient, indicating a high degree of genetic heterogeneity. ConclusionsAnalysis of the neoantigen landscape of MF revealed a very high neoantigen load and thus a significant immunogenic potential of this lymphoma. However, neoantigenic heterogeneity and significant subclonality might limit the efficacy of immunotherapy. We hypothesize that neoantigen number and subclonality might be useful biomarkers determining sensitivity to immunotherapeutic strategies.

cancer biology↗