Phospholipase C gamma 1 (PLCG1) R707Q mutation is counterselected under targeted therapy in a patient with hepatic angiosarcoma

Oncotarget. 2015 Nov 3;6(34):36418-25. doi: 10.18632/oncotarget.5503.

Abstract

Hepatic angiosarcoma is a rare and aggressive vascular neoplasm. Pathogenic driver mutations are largely unknown. We present the case of a patient with recurrent hepatic angiosarcoma, who initially showed good response to sunitinib, followed by progression. Using comprehensive molecular techniques, we explored the potential mechanisms of resistance. By low-read-depth whole-genome sequencing, the comparison of copy number aberrations (CNAs) of the primary tumor to the skin metastatic lesion that developed after progression on sunitinib, revealed high-level amplification of the 4q11-q13.1 region (containing KIT, PDGFRA and VEGFR2 genes) that was sustained in both lesions. Whole exome sequencing on the germline, primary and metastatic tumor DNAs, resulted in 27 confirmed mutations, 19 of which (including TP53 mutation) presented in both primary and metastatic lesions. One mutation, ZNF331 frameshift deletion, was detected only in the primary tumor. In contrast, seven other mutations, including phospholipase C-gamma1 (PLCG1) R707Q mutation, were found only in the metastatic tumor, indicating selection of cells with the resistant genotype under sunitinib pressure. Our study supports the notion that PLCG1-R707Q mutation may confer VEGFR2-independent signaling and may thus cause resistance against VEGF(R)-directed therapies. This case illustrates also the advantages of using next-generation technologies in identifying individualized targeted therapy.

Keywords: PLCG1 mutation; angiosarcoma; resistance; sunitinib; targeted therapy.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use
  • Cytogenetics
  • Female
  • Hemangiosarcoma / drug therapy*
  • Hemangiosarcoma / enzymology
  • Hemangiosarcoma / genetics*
  • Hemangiosarcoma / pathology
  • Humans
  • Indoles / therapeutic use
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Middle Aged
  • Mutation
  • Phospholipase C gamma / genetics*
  • Pyrroles / therapeutic use
  • Signal Transduction
  • Sunitinib

Substances

  • Antineoplastic Agents
  • Indoles
  • Pyrroles
  • PLCG1 protein, human
  • Phospholipase C gamma
  • Sunitinib