Genomic analysis of 220 CTCLs identifies a novel recurrent gain-of-function alteration in RLTPR (p.Q575E)

Abstract

Cutaneous T-cell lymphoma (CTCL) is an incurable non-Hodgkin lymphoma of the skin-homing T cell. In early-stage disease, lesions are limited to the skin, but in later-stage disease, the tumor cells can escape into the blood, the lymph nodes, and at times the visceral organs. To clarify the genomic basis of CTCL, we performed genomic analysis of 220 CTCLs. Our analyses identify 55 putative driver genes, including 17 genes not previously implicated in CTCL. These novel mutations are predicted to affect chromatin (, ,, ), immune surveillance (, ), MAPK signaling (, ), NF-κB signaling (, ), PI-3-kinase signaling (, ), RHOA/cytoskeleton remodeling (), RNA splicing (), T-cell receptor signaling (, ), and T-cell differentiation (). Our analyses identify recurrent mutations in 4 genes not previously identified in cancer. These include CK1α (encoded by ) (p.S27F; p.S27C), PTPRN2 (p.G526E), RARA (p.G303S), and RLTPR (p.Q575E). Last, we functionally validate and as putative oncogenes. encodes a recently described scaffolding protein in the T-cell receptor signaling pathway. We show that RLTPR (p.Q575E) increases binding of RLTPR to downstream components of the NF-κB signaling pathway, selectively upregulates the NF-κB pathway in activated T cells, and ultimately augments T-cell-receptor-dependent production of interleukin 2 by 34-fold. Collectively, our analysis provides novel insights into CTCL pathogenesis and elucidates the landscape of potentially targetable gene mutations.

Genomic analysis reveals recurrent deletion of JAK‐STAT signaling inhibitors HNRNPK and SOCS1 in mycosis fungoides

“…SNVs present in the dbSNP database were filtered out. We searched for pathogenic SNVs in 1461 genes involved in signaling pathways and cellular processes previously reported as affected in CTCL . Gene lists were retrieved from the PathCards database (http://pathcards.genecards.org/).…”

“…We searched for pathogenic SNVs in 1461 genes involved in signaling pathways and cellular processes previously reported as affected in CTCL. [7][8][9][16][17][18][19][20][21][22] Gene lists were retrieved from the PathCards database (http://pathcards.genecards.org/). Only SNVs predicted to produce highly deleterious amino acid substitutions by both SIFT and PolyPhen-2 were further investigated on ClinVar, COSMIC, and literature.…”

Molecular pathogenesis of cutaneous lymphomas

“…These proteins increase binding to downstream complements of the NFκB signalling pathway, thereby selectively upregulating the NFκB pathway‐activated T cells and ultimately augmenting T‐cell‐receptor‐dependent production of IL‐2 by 34‐fold. In these extensive genomic analyses performed by Park et al, 55 genes in lymphoma genesis, including 17 genes not previously implicated in CTCL, were identified (Figure ) . These include 17 novel putative driver genes in CTCL.…”

“…Affected pathways with driver genes in CTCL and 17 newly identified mutated genes by genomic analysis of 220 patients . The size of each pie represents the number of mutations found in the corresponding pathway.…”

Expanding and expounding the genomic map of CTCL

“…In this issue of Blood, Park et al expand the boundaries and improve the resolution of the known mutational map of CTCL. 1 T he term CTCL describes a heterogeneous family of incurable primary extranodal lymphomas of mature T cells that uniformly present in the skin, with a variable risk of systemic dissemination. The most common type of CTCL (;60%) is mycosis fungoides (MF), a low-grade lymphoma of skin-homing CD4 1 memory T cells.…”