<i>CDKN2A</i> deletion is a frequent event associated with poor outcome in patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS).

Nodal peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) remains a diagnosis encompassing a heterogenous group of PTCL cases not fitting criteria for more homogeneous subtypes. They are characterized by a poor clinical outcome when treated with anthracycline-containing regimens. A better understanding of their biology could improve prognostic stratification and foster the development of novel therapeutic approaches. Recent targeted and whole exome sequencing studies have shown recurrent copy number abnormalities (CNAs) with prognostic significance. Here, investigating 5 formalin-fixed, paraffin embedded cases of PTCL-NOS by whole genome sequencing (WGS), we found a high prevalence of structural variants and complex events, such as chromothripsis likely responsible for the observed CNAs. Among them, CDKN2A and PTEN deletions emerged as the most frequent aberration, as confirmed in a final cohort of 143 patients with nodal PTCL. The incidence of CDKN2A and PTEN deletions among PTCL-NOS was 46% and 26%, respectively. Furthermore, we found that co-occurrence of CDKN2A and PTEN deletions is an event associated with PTCL-NOS with absolute specificity. In contrast, these deletions were rare and never co-occurred in angioimmunoblastic and anaplastic lymphomas. CDKN2A deletion was associated with shorter overall survival in multivariate analysis corrected by age, IPI, transplant eligibility and GATA3 expression (adjusted HR =2.53; 95% CI 1.006-6.3; p=0.048). These data suggest that CDKN2A deletions may be relevant for refining the prognosis of PTCL-NOS and their significance should be evaluated in prospective trials.