Abstract
Cutaneous T-cell lymphoma is a group of incurable extranodal non-Hodgkin lymphomas that develop from the skin-homing CD4+ T cell. Mycosis fungoides and Sézary syndrome are the most common histological subtypes. Although next-generation sequencing data provided significant advances in the comprehension of the genetic basis of this lymphoma, there is not uniform consensus on the identity and prevalence of putative driver genes for this heterogeneous group of tumors. Additional studies may increase the knowledge about the complex genetic etiology characterizing this lymphoma. We used SNP6 arrays and GISTIC algorithm to prioritize a list of focal somatic copy-number alterations in a dataset of multiple sequential samples from 21 Sézary syndrome patients. Our results confirmed a prevalence of significant focal deletions over amplifications: single well-known tumor suppressors, such as TP53, PTEN, and RB1, are targeted by these aberrations. In our cohort, ZEB1 (TCF8, ZFHX1A) spans a deletion having the highest level of significance. In a larger group of 43 patients, we found that ZEB1 is affected by deletions and somatic inactivating mutations in 46.5% of cases; also, we found potentially relevant ZEB1 germline variants. The survival analysis shows a worse clinical course for patients with ZEB1 biallelic inactivation. Multiple abnormal expression signatures were found associated with ZEB1 depletion in Sézary patients we verified that ZEB1 exerts a role in oxidative response of Sézary cells. Our data confirm the importance of deletions in the pathogenesis of cutaneous T-cell lymphoma. The characterization of ZEB1 abnormalities in Sézary syndrome fulfils the criteria of a canonical tumor suppressor gene. Although additional confirmations are needed, our findings suggest, for the first time, that ZEB1 germline variants might contribute to the risk of developing this disease. Also, we provide evidence that ZEB1 activity in Sézary cells, influencing the reactive oxygen species production, affects cell viability and apoptosis.
Highlights
Sézary syndrome (SS) is characterized by erythroderma, lymphadenopathy, and leukemic involvement of the peripheral blood
We used SNP 6 arrays and GISTIC2.0 algorithm to identify genes targeted by focal somatic copy-number alterations (SCNAs), likely representing candidate “drivers” for cancer growth[26,29], in a dataset composed of 33 samples, collected at different time points, from 21 SS patients and 3 cutaneous T-cell lymphoma (CTCL) cell lines (Hut[78], H9, HH)
If the chromosomes most frequently affected by copy-number gains were considered, the following GISTIC segments may assume importance: 10p15.1 with 19% of SS tumors affected (4/21) spanning PRKCQ gene, 8q24.13, altering 62% of cases (13/21 and 3/3 cell lines) encompassing two genes, one of which is MYC, already cited as candidate gene in SS2, and 17q12, involving 52% of tumors (11/21 and 2/3 cell lines), where the GISTIC peak falls in close proximity of an uncharacterized openreading frame (C17orf102) (Fig. 1)
Summary
Sézary syndrome (SS) is characterized by erythroderma, lymphadenopathy, and leukemic involvement of the peripheral blood. The prevalence of SS is around 0.3 cases per 100,000 people and it accounts for less than 5% of all cutaneous T-cell lymphoma (CTCL). Despite numerous efforts to characterize the events of its pathogenesis, SS remains an incurable and fatal disease. Multiple genomic array-based studies have delineated a complex profile of chromosome aberrations characterizing SS genome with multiple sporadic genetic events of gains/losses in addition to recurrent abnormalities affecting mainly chromosome 8, 9, 10, and 172–5. The mutational landscape of CTCL, compiled with recent reports of next-generation sequencing (NGS) data, identified a broad range of genes variously affected by somatic copy-number alterations (SCNAs) and somatic singlenucleotide variants, involved, predominantly, in the T-cell activation and apoptosis, activation of NF-kB, JAK/STAT signaling, chromatin remodeling, and DNA damage
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
