Details

Autor(en) / Beteiligte

• Xiao, M.Z.X.
• Hennessey, D.
• Iyer, A.
• O’Keefe, S.
• Zhang, F.
• Sivanand, A.
• Gniadecki, R.

Titel

Transcriptomic changes during stage progression of mycosis fungoides

Ist Teil von

• British journal of dermatology (1951), 2022-03, Vol.186 (3), p.520-531

Ort / Verlag

England: Oxford University Press

Erscheinungsjahr

2022

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• Summary Background Mycosis fungoides (MF) is the most common cutaneous T‐cell lymphoma, which in the early patch/plaque stages runs an indolent course. However, ~25% of patients with MF develop skin tumours, a hallmark of progression to the advanced stage, which is associated with high mortality. The mechanisms involved in stage progression are poorly elucidated. Objectives We sought to address the hypothesis of MF cell trafficking between skin lesions by comparing transcriptomic profiles of skin samples in different clinical stages of MF. Methods We 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) as well as plaques and tumours from patients in late‐stage disease [late‐stage plaques (LSP, n = 10) and tumours (TMR, n = 15)]. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to determine pathway changes specific for different lesions which were linked to the recurrent somatic mutations overrepresented in MF tumours. Results The key upregulated pathways during stage progression were those related to cell proliferation and survival (MEK/ERK, Akt‐mTOR), T helper cell (Th)2/Th9 signalling [interleukin (IL)4, STAT3, STAT5, STAT6], meiomitosis (CT45A1, CT45A3, STAG3, GTSF1, 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 haematogenous self‐seeding. Conclusions Stage 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 may be caused by haematogenous cell percolation between discrete skin lesions. What is already known about this topic? Mycosis fungoides (MF) is the most common cutaneous T‐cell lymphoma characterized by a favourable prognosis in the early patch/plaque stage. Development of tumours heralds progression to the advanced stage and a significant increase in mortality. What does this study add? Tumour progression is associated with recurrent mutations which can be linked to the upregulation of signalling pathways controlling cell proliferation, survival, mitosis and DNA repair. We speculate that the percolation of malignant cells between lesions and tumour self‐seeding may mediate stage progression in MF. What is the translational message? The development of cutaneous tumours in MF heralds stage progression and increased mortality. MF tumours show upregulation in several targetable signalling pathways involved in cell proliferation and survival. Ectopic expression of cancer/testis genes may explain mitotic aberrations in MF tumours. Transcriptomic analysis supports the scenario in which high‐grade malignant cells can spread haematogenously and seed other skin lesions (tumour self‐seeding). Early, aggressive treatment of tumours may prevent tumour self‐seeding and improve patient prognosis. Linked Comment: G. Dobos and C. Assaf. Br J Dermatol 2022; 186:387–388.