Whole exome sequencing reveals mutations in FAT1 tumor suppressor gene clinically impacting on peripheral T-cell lymphoma not otherwise specified

Abstract

Peripheral T-cell lymphoma not otherwise specified represents a diagnostic category comprising clinically, histologically, and molecularly heterogeneous neoplasms that are poorly understood. The genetic landscape of peripheral T-cell lymphoma not otherwise specified remains largely undefined, only a few sequencing studies having been conducted so far. In order to improve our understanding of the genetics of this neoplasm, we performed whole exome sequencing along with RNA-sequencing in a discovery set of 21 cases. According to whole exome sequencing results and mutations previously reported in other peripheral T-cell lymphomas, 137 genes were sequenced by a targeted deep approach in 71 tumor samples. In addition to epigenetic modifiers implicated in all subtypes of T-cell neoplasm (TET2, DNMT3A, KMT2D, KMT2C, SETD2), recurrent mutations of the FAT1 tumor suppressor gene were for the first time recorded in 39% of cases. Mutations of the tumor suppressor genes LATS1, STK3, ATM, TP53, and TP63 were also observed, although at a lower frequency. Patients with FAT1 mutations showed inferior overall survival compared to those with wild-type FAT1. Although peripheral T-cell lymphoma not otherwise specified remains a broad category also on molecular grounds, the present study highlights that FAT1 mutations occur in a significant proportion of cases, being provided with both pathogenetic and prognostic impact.