Biological and Clinical Relevance of Genetic Alterations in Peripheral T-cell Lymphomas.

Abstract

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T-cell neoplasms with different clinical, biological, and molecular features. These include PTCL, not otherwise specified, nodal T follicular helper cell lymphomas (nTFHLs), anaplastic large cell lymphoma (ALCL), extranodal natural killer (NK)/T-cell lymphoma (ENKTL), and adult T-cell leukemia/lymphoma (ATLL). Over the past decade, several genetic studies using targeted, whole-exome, and more recently whole-genome sequencing have identified numerous driver alterations in PTCLs. These alterations include mutations, copy number alterations, and structural variations (SVs) involving T-cell receptor/NF-κB (such as PLCG1, VAV1, and CD28) and JAK/STAT (JAK3 and STAT3) pathway components, epigenetic regulators (TET2, DNMT3A, and ARID1A), immune-associated molecules (HLA-A/B, CD58, and PD-L1), and tumor suppressors (TP53 and CDKN2A), which are shared among various PTCL subtypes. Conversely, subtype-specific alterations, such as RHOA G17V and IDH2 R172 mutations in nTFHLs; ALK fusions in ALCL; DDX3X and MSN mutations in ENKTL; and PRKCB, CIC, and CCR4 mutations in ATLL. Regarding the clinical relevance of genetic alterations, combining genetic information with clinical factors has been reported to improve prognostic stratification in several subtypes of PTCLs, such as ENKTL and ATLL. Additionally, several genetic alterations may have the potential to predict a response to a specific molecularly targeted agent, such as ALK fusions for ALK inhibitors, PD-L1 SVs for immune checkpoint inhibitors (including anti-PD-1 antibodies), and mutations in epigenetic regulators for histone deacetylase inhibitors and hypomethylating agents. In this study, we summarize the current understanding of somatic alterations in various subtypes of PTCLs and highlight their clinical utility.