Genetics Abnormalities with Clinical Impact in Primary Cutaneous Lymphomas.

Abstract

Simple SummaryThe genetic landscape of cutaneous T-cell lymphomas analyzed by sequencing high throughput techniques shows a heterogeneous somatic mutational profile and genomic copy number variations in the TCR signaling effectors, the NF-κB elements, DNA damage/repair elements, JAK/STAT pathway elements and epigenetic modifiers. A mutational and genomic stratification of these patients provides new opportunities for the development or repurposing of (personalized) therapeutic strategies. The genetic heterogeneity in cutaneous B-cell lymphoma parallels with the specific subtype. Damaging mutations in primary cutaneous diffuse large B-cell lymphoma of the leg type, involving MYD88 gene, or BCL6 and MYC translocations or CDKN2A deletions are useful for diagnostic purposes. The more indolent forms, as the primary cutaneous lymphoma of follicle center cell (somatic mutations in TNFRSF14 and 1p36 deletions) and the cutaneous lymphoproliferative disorder of the marginal zone cells (FAS gene), present with a more restricted pattern of genetic alterations.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.