A Recurrent Activating PLCG1 Mutation in Cardiac Angiosarcomas Increases Apoptosis Resistance and Invasiveness of Endothelial Cells

K Kunze, T Spieker, U Gamerdinger, K Nau, J Berger… - Cancer research, 2014 - AACR
K Kunze, T Spieker, U Gamerdinger, K Nau, J Berger, T Dreyer, JR Sindermann, A Hoffmeier…
Cancer research, 2014AACR
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 …
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. PLCγ1 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 PLCγ1-R707Q mutant in endothelial cells revealed reduced PLCγ1-Y783 phosphorylation with concomitant increased c-RAF/MEK/ERK1/2 phosphorylation, increased IP3 amounts, and increased Ca2+-dependent calcineurin activation compared with ectopic expressed PLCγ1-wild-type. Furthermore, cofilin, whose activation is associated with actin skeleton reorganization, showed decreased phosphorylation, and thus activation after expression of PLCγ1-R707Q compared with PLCγ1-wild-type. At the cellular level, expression of PLCγ1-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 PLCγ1-R707Q mutation causes constitutive activation of PLCγ1 and may represent an alternative way of activation of KDR/PLCγ1 signaling besides KDR activation in angiosarcomas, with implications for VEGF/KDR targeted therapies. Cancer Res; 74(21); 6173–83. ©2014 AACR.
AACR