title: Phospholipase C gamma 1 (PLCG1) R707Q mutation is counterselected under targeted therapy in a patient with hepatic angiosarcoma.
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.
authors.affiliation: Digestive Oncology, University Hospitals Leuven and Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: Prenen
authors.affiliation: Laboratory for Translational Genetics, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium.|Laboratory for Translational Genetics, Vesalius Research Center, VIB, Leuven, Belgium.
authors.forename: Dominiek
authors.initials: D
authors.lastname: Smeets
authors.affiliation: Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium.|Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.affiliation: Laboratory for Translational Genetics, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium.|Laboratory for Translational Genetics, Vesalius Research Center, VIB, Leuven, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Department of Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Sagaert
authors.affiliation: Department of Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.affiliation: Department of Human Genetics, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D003582:Cytogenetics; D005260:Female; D006394:Hemangiosarcoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D051966:Phospholipase C gamma / Q000235:genetics*; D011758:Pyrroles / Q000627:therapeutic use; D015398:Signal Transduction; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; C522157:PLCG1 protein, human; D051966:Phospholipase C gamma; D000077210:Sunitinib
keywords: PLCG1 mutation; angiosarcoma; resistance; sunitinib; targeted therapy