Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma.

Autor:	Boddicker RL; Department of Laboratory Medicine and Pathology., Razidlo GL; Center for Basic Research in Digestive Diseases, Division of Gastroenterology & Hepatology, Department of Biochemistry and Molecular Biology, and., Dasari S; Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN;, Zeng Y; Department of Laboratory Medicine and Pathology, Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China;, Hu G; Department of Laboratory Medicine and Pathology., Knudson RA; Medical Genome Facility., Greipp PT; Department of Laboratory Medicine and Pathology, Medical Genome Facility., Davila JI; Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN;, Johnson SH; Center for Individualized Medicine, and Department of Molecular Medicine, Mayo Clinic, Rochester, MN;, Porcher JC; Department of Laboratory Medicine and Pathology., Smadbeck JB; Department of Laboratory Medicine and Pathology., Eckloff BW; Medical Genome Facility., Billadeau DD; Department of Biochemistry and Molecular Biology, and., Kurtin PJ; Department of Laboratory Medicine and Pathology., McNiven MA; Center for Basic Research in Digestive Diseases, Division of Gastroenterology & Hepatology, Department of Biochemistry and Molecular Biology, and., Link BK; Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA;, Ansell SM; Division of Hematology and., Cerhan JR; Department of Health Sciences Research, Mayo Clinic, Rochester, MN; and., Asmann YW; Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL., Vasmatzis G; Center for Individualized Medicine, and Department of Molecular Medicine, Mayo Clinic, Rochester, MN;, Feldman AL; Department of Laboratory Medicine and Pathology.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2016 Sep 01; Vol. 128 (9), pp. 1234-45. Date of Electronic Publication: 2016 Jun 13.
DOI:	10.1182/blood-2016-03-707141
Abstrakt:	Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of T-cell malignancies that generally demonstrate aggressive clinical behavior, often are refractory to standard therapy, and remain significantly understudied. The most common World Health Organization subtype is PTCL, not otherwise specified (NOS), essentially a "wastebasket" category because of inadequate understanding to assign cases to a more specific diagnostic entity. Identification of novel fusion genes has contributed significantly to improving the classification, biologic understanding, and therapeutic targeting of PTCLs. Here, we integrated mate-pair DNA and RNA next-generation sequencing to identify chromosomal rearrangements encoding expressed fusion transcripts in PTCL, NOS. Two of 11 cases had novel fusions involving VAV1, encoding a truncated form of the VAV1 guanine nucleotide exchange factor important in T-cell receptor signaling. Fluorescence in situ hybridization studies identified VAV1 rearrangements in 10 of 148 PTCLs (7%). These were observed exclusively in PTCL, NOS (11%) and anaplastic large cell lymphoma (11%). In vitro, ectopic expression of a VAV1 fusion promoted cell growth and migration in a RAC1-dependent manner. This growth was inhibited by azathioprine, a clinically available RAC1 inhibitor. We also identified novel kinase gene fusions, ITK-FER and IKZF2-ERBB4, as candidate therapeutic targets that show similarities to known recurrent oncogenic ITK-SYK fusions and ERBB4 transcript variants in PTCLs, respectively. Additional novel and potentially clinically relevant fusions also were discovered. Together, these findings identify VAV1 fusions as recurrent and targetable events in PTCLs and highlight the potential for clinical sequencing to guide individualized therapy approaches for this group of aggressive malignancies. (© 2016 by The American Society of Hematology.)
Databáze:	MEDLINE
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