EGAGenomicsDiether Lambrechtshttps://ega-archive.org/dacs/EGAC00001000042EGAEGA DAC EGAC00001000042EGAdiether.lambrechts@vib-kuleuven.beHepatic 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.DNA replication errors that persist as mismatch mutations make up the molecular fingerprint of mismatch repair (MMR)-deficient tumors and convey them with resistance to standard therapy. Using whole-genome and whole-exome sequencing, we here confirm an MMR-deficient mutation signature that is distinct from other tumor genomes, but surprisingly similar to germ-line DNA, indicating that a substantial fraction of human genetic variation arises through mutations escaping MMR. Moreover, we identify a large set of recurrent indels that may serve to detect microsatellite instability (MSI). Indeed, using endometrial tumors with immunohistochemically proven MMR deficiency, we optimize a novel marker set capable of detecting MSI and show it to have greater specificity and selectivity than standard MSI tests. Additionally, we show that recurrent indels are enriched for the 'DNA double-strand break repair by homologous recombination' pathway. Consequently, DSB repair is reduced in MMR-deficient tumors, triggering a dose-dependent sensitivity of MMR-deficient tumor cultures to DSB inducers.Phospholipase C gamma 1 (PLCG1) R707Q mutation is counterselected under targeted therapy in a patient with hepatic angiosarcoma.Mismatch repair deficiency endows tumors with a unique mutation signature and sensitivity to DNA double-strand breaks.Prenen Hans H, Smeets Dominiek D, Mazzone Massimiliano M, Lambrechts Diether D, Sagaert Xavier X, Sciot Raf R, Debiec-Rychter Maria MZhao Hui H, Thienpont Bernard B, Yesilyurt Betül Tuba BT, Moisse Matthieu M, Reumers Joke J, Coenegrachts Lieve L, Sagaert Xavier X, Schrauwen Stefanie S, Smeets Dominiek D, Matthijs Gert G, Aerts Stein S, Cools Jan J, Metcalf Alex A, Spurdle Amanda A, Amant Frederic F, Lambrechts Diether DPlcg-1, PLC-gamma, treatment, Therapy, malignant angioendothelioma, NCKAP3, Phospholipase C gamma1, Phospholipase C gamma2, Angiosarcoma, malignant, PLC gamma 2, Phospholipase C gamma 1, Phospholipase C gamma 2, Angiosarcomas, Phospholipase C gammaD, angiosarcoma (disease), patient, angiosarcoma, PLC-gamma D, Plc-gamma1, Treatments, Client, hemangiosarcoma, PLC148, Mutations, blood vessel sarcoma, PLC gamma1, hemangiosarcoma., PPLCA, Therapeutic, Patient, Clients, PLC-gamma 2, Phospholipase C gamma D, PLC1, disease management, Therapies, Plc-1, Treatment, vascular sarcoma, malignant hemangioendothelioma, PLC-II, sarcoma of blood vessel, PLCgamma2, PLCgamma1, AI894140, Hemangiosarcomas, Cdedthe integument, NCKAP3, vascular tissue tumor, Materials, insensitive, SU 011248, pelt, Vegf120, Skn-li, selection process, CT24332, Xkl-1, KDR, CG13783, Tp53, CG13780, CG13781, CG13782, Mutations, DmelCG7103, KL receptor activity, Gsfsco1, primary tumour, bbl, SCO5, tumor of vascular system, SCO1, Whole Transcriptome, Transcriptome Sequencing, PLC-II, GD-VEGF, tumor of vascular tissue, Gsfsow3, Gsfsco5, PLCgamma1, vascular system neoplasm, integumentum commune, SOW3, AI115593, CG34378, treatment, me75, vgr1, Genomes, BCC7, APDGFR, Complete Exome Sequencing, Whole Transcriptome Sequencing, sVEGFR-2, dermoid system, entire skin, W, angiosarcoma, D17Mit170, T1, geographical area, Fam91a1, Otf11, EP1624, Therapies, Bs, Phospholipase, Vascular Endothelial Growth Factor-A, Krd-1, Sl, AV220772, skin and subcutaneous tissue, single organism signaling, stai, malignant angioendothelioma, Therapy, Dmel_CG31629, Angiosarcoma, vegf1, SU11248, Exome, Angiosarcomas, Tr-kit, Vegfr-b, Vegfr-c, integumental organ, CG7103, VEGFR, Tl3, Tl2, VEGF27Ca, VEGF27Cb, Glioma-Derived Vascular Endothelial Cell Growth Factor, sunitinib, 8222, PBT, ZNF361, Flk-1, metastatic disease, FLK1, VEGF-A, Flk1, BC033609, SU-011248, Vegfr, VEGFR binding, kl1-A, Genetic Materials, NOS, vascular sarcoma, CD309, bfy, Pdgfr-2, KIT, VGR1, Vgr1, 4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, neoplasms, Genetic Material, VEGFR2, protein-tyrosine kinase receptor flk-1, tyrosine-protein kinase Kit, PDGFR-2, RITA, pbt, Complete Transcriptome, positional polypeptide feature, resistant, Vpf, VPF, Dmel_CG13783, whole genome, kit, Treatments, hemangiosarcoma, mKIAA0493, ZNF463, metastatic, vertebrate epidermis, Patient, primary tumor, Material, metastatic tumor, Lecithinase, SU-11248, PV2, Whole Exome Sequencing, P53, p44, bhy, Cistron, entire integument, Vascular Endothelial Growth Factor, 2-dihydroindolylidenemethyl)-2, dermal system, Transcriptome Sequencings, Glioma Derived Vascular Endothelial Cell Growth Factor, neoplasm of vascular tissue, Hemangiosarcomas, AI894140, Vasculotropin, vegfa, krk1, Cded, PVF, Pvf, dermis plus epidermis plus hypodermis, region of skin, VEGF receptor binding, neoplasm of vascular system, region or site annotation, Complete Exome, DmelCG34378, Otf-11, PVR, SU 11248, p53, number, SCF receptor activity, Gene, PVF1, PVF3, PVF2, LFS1, presence, epidermis, Vascular Permeability Factor, l(1)G0146, pvf1, vascular neoplasm, PPLCA, pvf2, pvf3, scfr, Vascular, vascular, pvr, resistance, DmelCG13780, Sutent, Plc-1, Low, vegf-a, SCFR, VEGF164, Skn-1a, DmVEGFR, study, Permeability Factor, positional, Fdc, WES, Complete, Exome Sequencings, skin, Genetic, CG8222, PDGFR2, Lecithinases, PVFs, FLK-1, DmVEGF-3, DmVEGF-2, SKIN, CD140a, Sequencing, VEGF-2, Genotypes, DmVEGF-1, RHEPDGFRA, skin organ, Whole Exome, Trp53, Clients, Ly73, Whole, PLC1, vascular endothelial growth factor receptor ligand, malignant hemangioendothelioma, TRP53, sarcoma of blood vessel, Sunitinib Malate, CD140A, kinase NYK, Plcg-1, Vegf27Cb, sunitinibum, proto-oncogene c-Kit, Vegf27Ca, Oct-11a, cou, Complete Exome Sequencings, vascular neoplasms, Vegf164, 5-(5-Fluoro-2-oxo-1, malignant, skin zone, angiosarcoma (disease), 6130401C07, Cistrons, Client, Plc-gamma1, Cell, metastatic neoplasm, Xp53, PLC148, read, count in organism, skin plus hypodermis, Exome Sequencing, disease management., Lr, Oct11, skin region, CG4492, Genogroup, KIT ligand receptor activity, vascular tumors, sequence, Vegf17e-a, CG31629, rare (European definition), PDGFACE, Skin-1a, Vegf17e-b, tegument, Skin, Vegf17E, XKrk1, skin benign neoplasm, MVCD1, c-KIT, Vegf, VEGF2-B, Complete Transcriptome Sequencing, Vegf188, vascular tumor, vascular system neoplasm (disease), primary neoplasia, vascular system tumor, vertebrate integument, vascular tissue neoplasm, patient, CD117, DmelCG8222, primary structure of sequence macromolecule, Epoc-1, blood vessel sarcoma, portion of skin, kinase insert domain receptor, Genogroups, c-kit, VEGF, VEGFR-A, Pressures, signalling process, integument, C-Kit, Therapeutic, DEL, Ssm, SU011248, cardinality, metastatic tumour, Bra, xkl-1, tumors, fetal liver kinase 1, Treatment, VEGFR-2, vascular endothelial growth factor, vegffalseVIB VRC Data Access CommitteeData Access Committee 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