Journal article

Publication year: 2014

Pages: 6173-6183

Journal: Cancer Research

Volume number: 74

Issue number: 21

ISSN: 0008-5472

eISSN: 1538-7445

Open access status: Green

DOI Link: https://doi.org/10.1158/0008-5472.CAN-14-1162

Publisher: American Association for Cancer Research

Abstract: 
Primary cardiac angiosarcomas are rare tumors with unfavorable prognosis. Pathogenic driver mutations are largely unknown. We therefore analyzed a collection of cases for genomic aberrations using SNP arrays and targeted next-generation sequencing (tNGS) of oncogenes and tumor-suppressor genes. Recurrent gains of chromosome 1q and a small region of chromosome 4 encompassing KDR and KIT were identified by SNP array analysis. Repeatedly mutated genes identified by tNGS were KDR with different nonsynonymous mutations, MLL2 with different nonsense mutations, and PLCG1 with a recurrent nonsynonymous mutation (R707Q) in the highly conserved autoinhibitory SH2 domain in three of 10 cases. PLC gamma 1 is usually activated by Y783 phosphorylation and activates protein kinase C and Ca2+-dependent second messengers, with effects on cellular proliferation, migration, and invasiveness. Ectopic expression of the PLC gamma 1-R707Q mutant in endothelial cells revealed reduced PLC gamma 1-Y783 phosphorylation with concomitant increased c-RAF/MEK/ERK1/2 phosphorylation, increased IP3 amounts, and increased Ca2+-dependent calcineurin activation compared with ectopic expressed PLC gamma 1-wild-type. Furthermore, cofilin, whose activation is associated with actin skeleton reorganization, showed decreased phosphorylation, and thus activation after expression of PLC gamma 1-R707Q compared with PLC gamma 1-wild-type. At the cellular level, expression of PLC gamma 1-R707Q in endothelial cells had no influence on proliferation rate, but increased apoptosis resistance and migration and invasiveness in in vitro assays. Together, these findings indicate that the PLC gamma 1-R707Q mutation causes constitutive activation of PLC gamma 1 and may represent an alternative way of activation of KDR/PLC gamma 1 signaling besides KDR activation in angiosarcomas, with implications for VEGF/KDR targeted therapies. (C)2014 AACR.

Harvard Citation style: Kunze, K., Spieker, T., Gamerdinger, U., Nau, K., Berger, J., Dreyer, T., et al. (2014) A Recurrent Activating PLCG1 Mutation in Cardiac Angiosarcomas Increases Apoptosis Resistance and Invasiveness of Endothelial Cells, Cancer Research, 74(21), pp. 6173-6183. https://doi.org/10.1158/0008-5472.CAN-14-1162

APA Citation style: Kunze, K., Spieker, T., Gamerdinger, U., Nau, K., Berger, J., Dreyer, T., Sindermann, J., Hoffmeier, A., Gattenloehner, S., & Braeuninger, A. (2014). A Recurrent Activating PLCG1 Mutation in Cardiac Angiosarcomas Increases Apoptosis Resistance and Invasiveness of Endothelial Cells. Cancer Research. 74(21), 6173-6183. https://doi.org/10.1158/0008-5472.CAN-14-1162