Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions

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, Mayo Clinic researchers integrated mate-pair DNA and RNA next-generation sequencing to identify chromosomal rearrangements encoding expressed fusion transcripts in PTCL, NOS. Two of eleven cases had novel fusions involving VAV1, encoding a truncated form of the VAV1 guanine nucleotide exchange factor important in T-cell receptor (TCR) 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 (ALCL; 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. The researchers 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.

Distribution of 378 genomic events identified by mate-pair sequencing in 11 cases of PTCL, NOS

rna-seq

A. Number of genomic events per case. B-D. Representative Circos diagrams illustrating heterogeneity in the degree of complexity of genomic events among PTCLs: B, High complexity; C, focally high complexity with multiple rearrangements involving chromosomes 16 and 19 (chromothripsis); and D, low complexity. E. Distribution of intrachromosomal and interchromosomal events. F. Distribution of events based on involvement of genes or non-genic regions, and identification of expression fusion transcripts by RNA sequencing.

Boddicker RL, Razidlo GL, Dasari S, Zeng Y, Hu G, Knudson RA, Greipp PT, Davila JI, Johnson SH, Porcher JC, Smadbeck JB, Eckloff BW, Billadeau DD, Kurtin PJ, McNiven MA, Link BK, Ansell SM, Cerhan JR, Asmann YW, Vasmatzis G, Feldman AL. (2016) Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma. Blood [Epub ahead of print]. [abstract]

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