A targeted mutational landscape of angioimmunoblastic T-cell lymphoma.

The genetics of angioimmunoblastic T-cell lymphoma (AITL) are very poorly understood. We defined the mutational landscape of AITL across 219 genes in 85 cases from the United States and Europe. We identified ≥2 mutations in 34 genes, nearly all of which were not previously implicated in AITL. These included loss-of-function mutations in TP53 (n = 4), ETV6 (n = 3), CCND3 (n = 2), and EP300 (n = 5), as well as gain-of-function mutations in JAK2 (n = 2) and STAT3 (n = 4). TET2 was mutated in 65 (76%) AITLs, including 43 that harbored 2 or 3 TET2 mutations. DNMT3A mutations occurred in 28 (33%) AITLs; 100% of these also harbored TET2 mutations (P < .0001). Seventeen AITLs harbored IDH2 R172 substitutions, including 15 with TET2 mutations. In summary, AITL is characterized by high frequencies of overlapping mutations in epigenetic modifiers and targetable mutations in a subset of cases.

[1]  J. Vose,et al.  Molecular profiling improves classification and prognostication of nodal peripheral T-cell lymphomas: results of a phase III diagnostic accuracy study. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  G. Abel,et al.  Low frequency clonal mutations recoverable by deep sequencing in patients with aplastic anemia , 2013, Leukemia.

[3]  G. Wahl,et al.  MDM2, MDMX and p53 in oncogenesis and cancer therapy , 2013, Nature Reviews Cancer.

[4]  B. Nathwani,et al.  Clinicopathologic characteristics of angioimmunoblastic T-cell lymphoma: analysis of the international peripheral T-cell lymphoma project. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  S. Mustjoki,et al.  STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia. , 2012, Blood.

[6]  P. Gaulard,et al.  Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. , 2012, Blood.

[7]  S. Mustjoki,et al.  Somatic STAT3 mutations in large granular lymphocytic leukemia. , 2012, The New England journal of medicine.

[8]  W. Chan,et al.  IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. , 2012, Blood.

[9]  Y. Pekarsky,et al.  NOTCH1 mutations in CLL associated with trisomy 12. , 2012, Blood.

[10]  Christian Bastard,et al.  TET2 and DNMT3A mutations in human T-cell lymphoma. , 2012, The New England journal of medicine.

[11]  Nikhil Wagle,et al.  High-throughput detection of actionable genomic alterations in clinical tumor samples by targeted, massively parallel sequencing. , 2012, Cancer discovery.

[12]  Ryan D. Morin,et al.  Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. , 2012, Blood.

[13]  Steven J. M. Jones,et al.  Frequent mutation of histone modifying genes in non-Hodgkin lymphoma , 2011, Nature.

[14]  P. Opolon,et al.  TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. , 2011, Cancer cell.

[15]  Juliane C. Dohm,et al.  Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia , 2011, Nature.

[16]  Steven J. M. Jones,et al.  MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers , 2011, Nature.

[17]  Raul Rabadan,et al.  Inactivating mutations of acetyltransferase genes in B-cell lymphoma , 2010, Nature.

[18]  R. Gascoyne,et al.  Acquired TNFRSF14 mutations in follicular lymphoma are associated with worse prognosis. , 2010, Cancer research.

[19]  E. Reddy,et al.  Jak/STAT pathways in cytokine signaling and myeloproliferative disorders: approaches for targeted therapies. , 2010, Genes & cancer.

[20]  D. Weisenburger,et al.  International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  Jan Delabie,et al.  Oncogenic CARD11 Mutations in Human Diffuse Large B Cell Lymphoma , 2008, Science.

[22]  T. Molina,et al.  Angioimmunoblastic-like T-cell non Hodgkin's lymphoma: outcome after chemotherapy in 33 patients and review of the literature. , 1999, Leukemia & lymphoma.

[23]  M. Engelhard,et al.  Angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma: prognostic impact of clinical observations and laboratory findings at presentation. The Kiel Lymphoma Study Group. , 1995, Annals of oncology : official journal of the European Society for Medical Oncology.