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Mod Pathol. 2019 Apr 25. doi: 10.1038/s41379-019-0279-8. [Epub ahead of print]

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

Author information

1
Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy. antolaginestra3@gmail.com.
2
Università della Svizzera Italiana, Institute of Oncology Research, Bellinzona, Switzerland.
3
Division of Haematopathology, IEO European Institute of Oncology IRCCS, Milan, Italy.
4
Department of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
5
Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy.
6
Division of Cancer Research Center "Giorgio Prodi" University of Bologna, Bologna, Italy.
7
Division of Pathological Anatomy, Quality and Safety of Diagnosis and Treatment, Città della Salute e della Scienza, Turin, Italy.
8
Division of Pathology Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia, Brescia, Italy.
9
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
10
Division of Haematopathology, IEO European Institute of Oncology IRCCS, Milan, Italy. stefano.pileri@ieo.it.

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.

PMID:
31028364
DOI:
10.1038/s41379-019-0279-8

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