Genetics Abnormalities with Clinical Impact in Primary Cutaneous Lymphomas

Abstract

Primary cutaneous lymphomas comprise a heterogeneous group of extranodal non-Hodgkin lymphomas (NHL) that arise from skin resident lymphoid cells and are manifested by specific lymphomatous cutaneous lesions with no evidence of extracutaneous disease at the time of diagnosis. They may originate from mature T-lymphocytes (70% of all cases), mature B-lymphocytes (25–30%) or, rarely, NK cells. Cutaneous T-cell lymphomas (CTCL) comprise a heterogeneous group of T-cell malignancies including Mycosis Fungoides (MF) the most frequent subtype, accounting for approximately half of CTCL, and Sézary syndrome (SS), which is an erythrodermic and leukemic subtype characterized by significant blood involvement. The mutational landscape of MF and SS by NGS include recurrent genomic alterations in the TCR signaling effectors (i.e., PLCG1), the NF-κB elements (i.e., CARD11), DNA damage/repair elements (TP53 or ATM), JAK/STAT pathway elements or epigenetic modifiers (DNMT3). Genomic copy number variations appeared to be more prevalent than somatic mutations. Other CTCL subtypes such as primary cutaneous anaplastic large cell lymphoma also harbor genetic alterations of the JAK/STAT pathway in up to 50% of cases. Recently, primary cutaneous aggressive epidermotropic T-cell lymphoma, a rare fatal subtype, was found to contain a specific profile of JAK2 rearrangements. Other aggressive cytotoxic CTCL (primary cutaneous γδ T-cell lymphomas) also show genetic alterations in the JAK/STAT pathway in a large proportion of patients. Thus, CTCL patients have a heterogeneous genetic/transcriptional and epigenetic background, and there is no uniform treatment for these patients. In this scenario, a pathway-based personalized management is required. Cutaneous B-cell lymphoma (CBCL) subtypes present a variable genetic profile. The genetic heterogeneity parallels the multiple types of specialized B-cells and their specific tissue distribution. Particularly, many recurrent hotspot and damaging mutations in primary cutaneous diffuse large B-cell lymphoma of the leg type, involving MYD88 gene, or BCL6 and MYC translocations and BLIMP1 or CDKN2A deletions are useful for diagnostic and prognostic purposes for this aggressive subtype from other indolent CBCL forms.

A comparison of the International Consensus and 5th WHO classifications of T‐cell lymphomas and histiocytic/dendritic cell tumours

“…Other genetic and epigenetic abnormalities in primary cutaneous ALCL are reviewed elsewhere. 131,135 The rare cases of ALK+ primary cutaneous ALCL show a favourable outcome. 133 These cases should be staged accurately because skin lesions triggered by insect bites can be the first manifestation of systemic ALK+ ALCL.…”

“…Classification and diagnostic criteria of these entities remain the same in the ICC and the WHO‐HAEM5. Primary cutaneous ALCL characteristically lacks the genetic alterations found in systemic CD30+ ALCL but carries rearrangements of the IRF4/DUSP22 locus in about 20% of cases, mutations involving the IL6‐JAK1‐STAT3 pathway in 15%–30% of cases, 131 and very rarely TP63 132 or ALK rearrangements 133 . Primary cutaneous ALCL with TP63 rearrangements exhibit an aggressive clinical behaviour similar to that of systemic ALCL with TP63 rearrangements 132 .…”

“…Moreover, whole‐transcriptome sequencing has revealed the NPM1‐TYK2 gene fusion in about 5% of primary cutaneous ALCL 134,135 ; these cases usually show nuclear STAT5 expression. Other genetic and epigenetic abnormalities in primary cutaneous ALCL are reviewed elsewhere 131,135 …”

Role of cytokine in malignant T-cell metabolism and subsequent alternation in T-cell tumor microenvironment

“…The C>T transition in the P53 gene is a UV signature mutation ( 128 ) that is very crucial for tumor progression and is the most frequent gene mutation associated with CTCL, but this mutation is more frequent in the later stage of cancer than the early tumor stage in MF ( 125 , 126 ). Mutations in important cell-cycle regulators like RB1 and CDKN1B/CDKN2A are also common in CTCL ( 69 , 129 ). A sufficient supply of oxygen and nutrient is of utmost importance to sustain the growing mass of the tumor ( 11 , 15 , 19 , 20 ).…”

JAK Inhibitors in Cutaneous T-Cell Lymphoma: Friend or Foe? A Systematic Review of the Published Literature

“…The JAK/STAT signaling pathway, central to the pathophysiology of CTCL, is frequently dysregulated through JAK1, JAK3, STAT3, and STAT5B point mutations and copy number gains in JAK2, STAT3, and STAT5B [ 14 , 15 , 16 , 17 ]. These genetic aberrations lead to overactive signaling, driving uncontrolled cell proliferation and survival, characteristic of the disease [ 18 , 19 ]. Of note, the specific JAK/STAT pathway proteins that might be affected by different mutations vary in different subtypes of CTCL [ 20 , 21 , 22 ], as shown in Figure 1 .…”