Víctor Martínez-Glez. - Instituto de Genética Médica y Molecular (INGEMM). IdiPAZ, Hospital Universitario La Paz, Madrid, España.
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El jueves y viernes 10 y 11 de mayo del 2018 realizamos en la Fundación Ramón Areces un Simposio Internacional, en el cual se trató el tema del mosaicismo somático en malformaciones vasculares.
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Víctor Martínez-Glez. - Instituto de Genética Médica y Molecular (INGEMM). IdiPAZ, Hospital Universitario La Paz, Madrid, España.
- 1. Overview of somatic mosaicism in vascular malformations Victor Martinez-Glez Vascular Malformations Section Institute of Medical and Molecular Genetics (INGEMM) La Paz Hospital - Madrid International Symposium Somatic Mosaicism in Vascular Malformations
- 2. CLASSIFICATION OF VASCULAR ANOMALIES
- 3. ISSVA PROLIFERATING ENDOTHELIUM STRUCTURAL ANOMALIES Simple vascular malformations Combined vascular malformations Benign Capillary malformations (CM) CVM, CVM, CAVM, LVM, CLVM, Infantile hemangioma / Hemangioma of infancy Cutaneous and/or mucosal CM (aka “port-wine” stain ) CLAVM, CVAVM, CLVAVM Congenital hemangioma Telangiectasia Anomalies of major named vessels Tufted angioma Cutis marmorata telangiectatica congenita (CMTC) Spindle-cell hemangioma Nevus simplex / Salmon patch / “angel kiss” Vascular malformations associated with other anomalies Epithelioid hemangioma Others Klippel-Trenaunay syndrome Pyogenic granuloma Lymphatic malformations (LM) Parkes Weber syndrome Others Common (cystic) LM Servelle-Martorell syndrome Generalized lymphatic anomaly (GLA) Sturge-Weber syndrome Locally aggressive or borderline vascular tumors LM in Gorham-Stout disease Limb CM + congenital non-progressive limb hypertrophy Kaposiform hemangioendothelioma Channel type LM Maffucci syndrome Retiform hemangioendothelioma Primary lymphedema Macrocephaly - CM (M-CM / MCAP) Papillary intralymphatic angioendothelioma Others Microcephaly - CM (MICCAP) Composite hemangioendothelioma Venous malformations (VM) CLOVES syndrome Kaposi sarcoma Common VM Proteus syndrome Others Familial VM cutaneo-mucosal (VMCM) Bannayan-Riley-Ruvalcaba sd Blue rubber bleb nevus (Bean) syndrome VM Malignant Glomuvenous malformation (GVM) Provisionally unclassified vascular anomalies Angiosarcoma Cerebral cavernous malformation (CCM) Verrucous hemangioma Epithelioid hemangioendothelioma Others Angiokeratoma Others Arteriovenous malformations (AVM) MLT/CAT Arteriovenous fistula (AVF) (congenital) Kaposiform lymphangiomatosis (KLA) PTEN (type) hamartoma of soft tissue Vascular MalformationsVascular TumoursVASCULAR TUMOURS VASCULAR MALFORMATIONS
- 4. Intramuscular hemangioma Familial intraosseous vascular malformation (VMOS) Verrucous VM Hobnail hemangioma Acquired progressive lymphatic anomaly Fibro adipose vascular anomaly (FAVA) Papillary hemangioma ISSVA 2018??? ISSVA Simple vascular malformations Combined vascular malformations Benign Capillary malformations (CM) CVM, CVM, CAVM, LVM, CLVM, Infantile hemangioma / Hemangioma of infancy Cutaneous and/or mucosal CM (aka “port-wine” stain ) CLAVM, CVAVM, CLVAVM Congenital hemangioma Telangiectasia Anomalies of major named vessels Tufted angioma Cutis marmorata telangiectatica congenita (CMTC) Spindle-cell hemangioma Nevus simplex / Salmon patch / “angel kiss” Vascular malformations associated with other anomalies Epithelioid hemangioma Others Klippel-Trenaunay syndrome Pyogenic granuloma Lymphatic malformations (LM) Parkes Weber syndrome Others Common (cystic) LM Servelle-Martorell syndrome Generalized lymphatic anomaly (GLA) Sturge-Weber syndrome Locally aggressive or borderline vascular tumors LM in Gorham-Stout disease Limb CM + congenital non-progressive limb hypertrophy Kaposiform hemangioendothelioma Channel type LM Maffucci syndrome Retiform hemangioendothelioma Primary lymphedema Macrocephaly - CM (M-CM / MCAP) Papillary intralymphatic angioendothelioma Others Microcephaly - CM (MICCAP) Composite hemangioendothelioma Venous malformations (VM) CLOVES syndrome Kaposi sarcoma Common VM Proteus syndrome Others Familial VM cutaneo-mucosal (VMCM) Bannayan-Riley-Ruvalcaba sd Blue rubber bleb nevus (Bean) syndrome VM Malignant Glomuvenous malformation (GVM) Provisionally unclassified vascular anomalies Angiosarcoma Cerebral cavernous malformation (CCM) Verrucous hemangioma Epithelioid hemangioendothelioma Others Angiokeratoma Others Arteriovenous malformations (AVM) MLT/CAT Arteriovenous fistula (AVF) (congenital) Kaposiform lymphangiomatosis (KLA) PTEN (type) hamartoma of soft tissue Vascular MalformationsVascular Tumours PROLIFERATING ENDOTHELIUM STRUCTURAL ANOMALIES VASCULAR TUMOURS VASCULAR MALFORMATIONS
- 5. • Most vascuar malformations are identified by history and physical examination • Imaging and histopathology are useful for atypical cases • Clinical heterogeneous • Variable response to treatment (mainly sirolimus in LM) • Resection, laser, scleroterapy, and/or embolization • Control • Common progression and recurrence • Mosaicism Diagnosis
- 6. TIMELINE 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015
- 7. HHT - FIRST GERMLINE GENE 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015 ATLAS CLÍNICO DE ANOMALÍAS VASCULARES. Eulalia Basega Torres, Juan Carlos López-Gutierrez, Ana Martín Santiago y Pedro Redondo Bellón. Aula Médica. 2016.
- 8. VM - GERMLINE GENE 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015
- 9. LYMPHEDEMA - GERMLINE GENE 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015 ATLAS CLÍNICO DE ANOMALÍAS VASCULARES. Eulalia Basega Torres, Juan Carlos López-Gutierrez, Ana Martín Santiago y Pedro Redondo Bellón. Aula Médica. 2016.
- 10. GVM - GERMLINE GENE 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015
- 11. GVM - GERMLINE GENE 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015
- 12. CM-AVM - GERMLINE GENE 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015
- 13. PTEN - VM + MACROCEPHALY 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015
- 14. AKT1 - FIRST MOSAIC GENE 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015
- 15. 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015 SIROLIMUS - VM TREATMENT
- 16. 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015 PIK3CA - MOSAIC GENE
- 17. 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015 TIE2 - MOSAIC VMs
- 18. LM - PROS 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015
- 19. PROS - CRITERIA 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015
- 20. CM-AVM - PATTERNS 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015
- 21. PIK3CA - TESTING 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015
- 22. GNA11 - CM + OVERGROWTH 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015
- 23. 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015 TIE2 - BRBN
- 24. 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015 TIE2 - BRBN
- 25. PIK3CA - CLAPO 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015
- 26. GVM - FIRST GERMLINE GENE 1982 Classification 1984 ENG HHT 1986 TIE2 VM 1988 FLT4 Lymph 1999 KRIT1 CCM 2000 FOXC2 Lymph-Distiq 2002 GLMN GVM 2003 RASA1 CM-AVM 2007 PTEN VM AKT1 Proteus Sirolimus VA IDH1/2 Ollier/Maffucci 2012 PIK3CA MCAP/CLOVES GNAQ Sturge-Weber TIE2 VM Rev PI3K-AKT-mTOR Rev ISSVA PIK3CA LM PIK3CA VM MAP3K3 VVM PIK3CA PROS 2016 Pattern CM-AVM PIK3CA Dx Yield GNA11 CM-OG BRBN TIE2 MAP2K1 ExtCran AVM PIK3CA CLAPO RAS/MAPK VsM 2017 2018 2014 2011 2013 2015
- 27. LESSONS: Pathways / Location and timing / Distribution / Expression / Lethal genes / 2º Hit / Function VEGF-C CCBE1 VEGFR-3 PTPN14 KIF11 PIK3CA PTEN C-MET HGF SHP2 SOS1 AKT AKT1 AKT2 AKT3 RASA 1 RAS HRAS KRAS NRAS RAF BRAF MAP3K3 MEK MAP2K1 ERK IKBKG mTOR GATA2 FOXC2 SOX18 NF-KB GJA1 GJC2 ITG9 TIE2 G- protein coupled receptor GNA11 GNAQ CCM KRIT1 CCM2 PDCD10 VEGFR-2 ENG ACVRL1 GDF2 SMAD4 GLMN IDH1 IDH2 STAMB P G-prot/MEK RAF RAS TKR/TGF-β PI3K/AKT/mTOR VEGF/R
- 28. LESSONS: Pathways / Location and timing / Distribution / Expression / Lethal genes / 2º Hit / Function
- 29. LESSONS: Pathways / Location and timing / Distribution / Expression / Lethal genes / 2º Hit / Function
- 30. GNAQ • 87% of sporadic or syndromic (SWS) CM (MAF 1-22%). • Endothelial cells (3-43%), pericytes (0%), stromal cells (0,4-11%), blood (0,3%) Tissue/organ Cell type LESSONS: Pathways / Location and timing / Distribution / Expression / Lethal genes / 2º Hit / Function
- 31. LESSONS: Pathways / Location and timing / Distribution / Expression / Lethal genes / 2º Hit / Function
- 32. • Cells bearing the mutation can survive only in a mosaic state • Schimmelpenning-Feuerstein-Mims syndrome • McCune-Albright syndrome • Klippel-Trenaunay syndrome • Sturge-Weber syndrome • Neurocutaneous melanosis • Proteus syndrome • Delleman-Oorthuys syndrome LESSONS: Pathways / Location and timing / Distribution / Expression / Lethal genes / 2º Hit / Function
- 33. • Cells bearing the mutation can survive only in a mosaic state • Schimmelpenning-Feuerstein-Mims syndrome • McCune-Albright syndrome • Klippel-Trenaunay syndrome • Sturge-Weber syndrome • Neurocutaneous melanosis • Proteus syndrome • Delleman-Oorthuys syndrome LESSONS: Pathways / Location and timing / Distribution / Expression / Lethal genes / 2º Hit / Function
- 34. LESSONS: Pathways / Location and timing / Distribution / Expression / Lethal genes / 2º Hit / Function
- 35. VEGF-C CCBE1 VEGFR-3 PTPN14 KIF11 PIK3CA PTEN C-MET HGF SHP2 SOS1 AKT AKT1 AKT2 AKT3 RASA1 RAS HRAS KRAS NRAS RAF BRAF MAP3K3 MEK MAP2K1 ERK IKBKG mTOR GATA2 FOXC2 SOX18 NF-KB GJA1 GJC2 ITG9 TIE2 G-protein coupled receptor GNA11 GNAQ CCM KRIT1 CCM2 PDCD10 VEGFR-2 ENG ACVRL1 GDF2 SMAD4 GLMN IDH1 IDH2 STAMBP GOF and somatic LOF and germline + somatic 2nd hit LESSONS: Pathways / Location and timing / Distribution / Expression / Lethal genes / 2º Hit / Function
- 36. VEGF-C CCBE1 VEGFR-3 PTPN14 KIF11 PIK3CA PTEN C-MET HGF SHP2 SOS1 AKT AKT1 AKT2 AKT3 RASA1 RAS HRAS KRAS NRAS RAF BRAF MAP3K3 MEK MAP2K1 ERK IKBKG mTOR GATA2 FOXC2 SOX18 NF-KB GJA1 GJC2 ITG9 TIE2 G-protein coupled receptor GNA11 GNAQ CCM KRIT1 CCM2 PDCD10 VEGFR-2 ENG ACVRL1 GDF2 SMAD4 GLMN IDH1 IDH2 STAMBP GERMLINE MOSAIC 2nd HIT Mix / Unkwn GOF G-prot/MEK RAF RAS TKR/TGF-β PI3K/AKT/mTOR VEGF/R LESSONS
- 37. Mosaic NC 2nd Hit GL GNAQ GNA11 MAP2K1 ENG ACVRL1 SMAD4 GDF2 TEK GLMN KRIT1 CCM2 PDCD10 MAP3K3 PIK3CA KIF11 AKT1 PTEN FLT4 VEGFC GJC2 FOXC2 SOX18 GATA2 CCBE1 PTPN14 IDH1 IDH2 STAMBP OA EPHB4 NCRAS RASA1 Microcephaly - CM (MICCAP) VM CM Lym LM Proteus syndrome Bannayan-Riley-Ruvalcaba syndrome PTEN - overgrowth and lipomas CLOVES MCAP CLAPO Familial VM cutaneo-mucosal (VMCM) Blue rubber bleb nevus (Bean) syndrome VM Glomuvenous malformation Cerebral cavernous malformation Verrucous VM Maffucci syndrome Hypotrichosis-lymphedema-telangiectasia Primary lymphedema with myelodysplasia Hennekam lymphangiectasia-lymphedema Microcephaly w/wo chorioret, lymph, or ID Lymphedema-choanal atresia Common VM HHT Common (cystic) LM Generalized lymphatic anomaly (GLA) Nonne-Milroy syndrome Primary hereditary lymphedema Lymphedema-distichiasis Cutaneous and/or mucosal CM Sturge-Weber syndrome CM with bone and/or soft tissue hyperplasia Sporadic AVM / AVF CM-AVM Parkes Weber syndrome PI3KG-prot/MEK VEGFTKR/TGF-β RAF AKT LESSONS: Pathways / Location and timing / Distribution / Expression / Lethal genes / 2º Hit / Function
- 38. MOSAICISM & THE PATIENT
- 40. MOSAICISM & NGS Study of variants in somatic mosaicism Validation of candidate variants Sanger (>20%) Pyrosequencing (>5%) ddPCR (>0,1%)
- 41. EVALUATION OF MOSAIC VASCULAR ANOMALIES • Classification • Mosaicism • Embryology / Timing • Gene / Pathway / Expression / Lethality • Location / distribution • Second Hit • Samples, testing, analysis
- 42. • Mosaicism classification • Vascular malformations - Clinical classification – Controversies / recent advances – Are all capillary malformations the same? – Histopathology • Vascular malformations associated with other anomalies – Combined vascular and non-vascular mosaic anomalies – Classification, taxonomy • Genotyping and phenotyping – Samples, detection, and bioinformatic challenges • Research – Functional Studies – Animal models – Editing tools • Genetic counselling CHALLENGES
- 43. Acknowledgements Vascular Malformations Section (MALVA) Lara Rodríguez-Laguna, BSc. MSc. Gema Gordo, BSc. MSc. Dr. Pablo Lapunzina INGEMM Coordinator Dr. Juan Carlos Lopez-Gutierrez Vascular Anomalies Unit Coordinator Bioinformatics Section (INGEMM) Genomics Section (INGEMM) Noelia Agra, BSc. PhD. Dr. Marta Feito Dermatology Dept. Victor Martinez-Glez, MD. PhD.
Notas do Editor
- Hi again. In the previous presentation we have seen how today we know that individuals are indeed complex mosaics with multiple genotypes acquired from embryonic development to adulthood. In the field of vascular anomalies, the increasing detection of low mosaic mutations in new or known genes demands a change in the model of approaching patients and research. I am going to make a small overview of somatic mosaicism in vascular malformations, reviewing some concepts that may be useful for the rest of the symposium.
- Let’s start by defining vascular anomalies, which comprise a heterogeneous group of disorders characterized by abnormal growth or development of blood or lymphatic vessels. Since the diagnosis of vascular anomalies is often challenging due to the large variety of conditions with a wide range of clinical manifestations and severity, a classification of all these anomalies was necessary. The first classification of vascular anomalies is from 1982, and divided benign vascular anomalies into hemangiomas and vascular malformations.
- This classification was later adopted by the International Society for the Study of Vascular Anomalies (ISSVA) in 1996 and modified to categorize vascular anomalies as vascular tumors or vascular malformations. Vascular tumors are characterized by the abnormal proliferation of endothelial cells and aberrant blood vessels. In contrast, vascular malformations are networks of abnormal vessels that form during fetal development and have normal endothelial cell turn over. The most recent version of this classification is from 2014, where new knowledge was incorporated. Thus, focusing on the vascular malformations, which are the subject of this symposium, these are basically classified by the type of structure involved (arterial, capillary, venous or lymphatic) and the malformation hemodynamics (high-flow or low-flow), each one with different specific presentations. On the other hand, we have the combined malformations, those of major named vessels, those associated with other non-vascular anomalies, and a section for those not classified in any of these sections.
- Simplified terminology and classification have improved consistency in the diagnosis of vascular anomalies. Of course, is not exempt from failures and shortcomings, some of which will probably be solved at the next ISSVA congress within 3 weeks. And this is an important problem because issues such as natural history, including age at onset and progression, and genetic counseling may vary considerably depending on the phenotype, the genetic cause and the inheritance pattern.
- In clinical practice, there are vascular malformations with a typical clinical course, easy to diagnose on physical exam, while others are atypical, maybe deep lesions involving vital structures for which clinical diagnosis is unclear or insufficient. Imaging studies and Histopathology are then essential for an accurate diagnosis. There is also a variable response to treatment (mainly sirolimus in LM) and the surgical approach is usually by resection, laser, scleroterapy, and embolization, but in many cases a follow-up attitude is simply maintained without intervention, either due to the mild compromise, or precisely because of the contrary. What is clear today is that somatic mosaicism is an essential part of the pathogenesis and phenotype of vascular malformations, explaining both the clinical variability and the difficulty in discovering the genes that cause each pathology.
- So let's see a bit of the history of how mosaicism in vascular malformations was discovered. I will not mention all of them, but I will mention some of the works that have brought us here today. I already mentioned that the first classification is from 1982.
- And two years later, the first gene associated to a VascM was discovered. Germline mutations in Endoglin gene causes Hereditary hemorrhagic telangiectasia (HHT), characterized by multiple arteriovenous malformations that lack capillaries, resulting in direct connections between arteries and veins. This causes epistaxis and Telangiectases most evident on the lips, tongue, buccal mucosa, face, chest, and fingers. Mutations in ENG are found constitutively, and today, other 3 genes has been associated with HHT, all within the transforming growth factor signaling pathway.
- In 1986 this paper described that germline mutations in the TEK gene were present in patients with familial venous malformations. These mutations in TEK, which codes for the tyrosine kinase receptor TIE2, cause gain of function on this protein, that is critical for communication of endothelial and smooth muscle cell in venous morphogenesis. As we will see later, this gene is very interesting and will serve as an example to show the etiopathogenic and phenotypic complexity generated by somatic mosaicism.
- In 1988, the first gene causing lymphedema, the FLT4 gene, was discovered. Lymphedema, more than a malformation by itself, is the consequence of alterations in the lymphatic system. Leaving aside the lymphedema generated as a result of cancer treatment or due to trauma or infections, the number of pathologies with a genetic cause that are mainly characterized by lymphedema, or in which the lymphedema is part of a syndromic pathology, is extensive and several causing genes are known. However, many patients remain without molecular diagnosis in these pathologies. The genetic causes of lymphedema so far are germline mutations, either inherited or de novo.
- An important part of vascular malformations are due to alterations in the endothelial cells. However, in Glomuvenous malformations (GVM), caused by germline mutations in glomulin, the affected cell type is the vascular smooth muscle cells.
- That as we see here, they are part of the structure of the capillary vessels. Thus, GVM represents one clear example demonstrating the link between different cell types involved in the development of vascular malformations.
- In 2003 this work described that the CM and associated arteriovenous malformations, can be caused by germline heterozygous and inactivating mutations in RASA1 gene. This gene facilitates the inactivation of Ras pathway. Thus, loss of RASA1 function amplifies RAS downstream signalling, with numerous consequences, including aberrant proliferation and angiogenesis
- This work does not address a discovery itself, but helped to delineate the spectrum of VascM associated with the PTEN gene. This oncogene was already known for its involvement in cancer and for causing the Bannayan-Riley-Ruvalcaba and Cowden syndromes. Although VascM are not a main characteristic, these patients do present vascular malformations. This work described that those vascular anomalies in patients with a germline PTEN mutation are typically multifocal and intramuscular combinations of fast-flow channels and ectopic fat. But, beyond that, this work helped us to understand the molecular mechanisms of VascMs when associated with other genetic syndromes. For example, this might be used to understand how different genes from the same molecular pathway associates common alterations in fatty tissue, overgrowth and VascMs.
- Something that is also evident in the Proteus syndrome. And here we come to 2011, the awakening of the discovery of genetic causes in somatic alterations associated with VascM, thanks to the use of high-throughput technologies able to detect small fractions of mutated alleles within a tissue sample. This paper shows how activating mutations in the AKT1 gene are detected in different tissues and cell lines in mosaics ranging from 1 to almost 50%. Remember that 50% would be an heterecigote state and therefore the mutation would be present in all cells. Here we must highlight something important, mutations in Proteus are not only seen in a somatic mosaic, that is, in the affected tissues, but also those mutations are not found in germinal state. This will serve to talk later about the concept of lethality.
- That same year, the use of drugs aimed at specific molecular targets, specifically rapamycin, an inhibitor of mTOR, which as we see here acts downstream AKT, was already being tested for Vascular Anomalies. Unfortunately, the experience with this promising drug is still scarce and it is not known why there are patients with a good response and others not. Some new drugs on these same molecular pathways are currently being tested.
- And here we have the pop star in the world of vascular mosaics, the PIK3CA gene. Detected in affected tissues from patients with complex syndromes mainly associated with overgrowth, either megalencephaly or lipomatous overgrowth. Syndromes in which the VascM are also characteristic. I will talk more about this gene later.
- Before I mentioned that germline TEK mutations were described in 1986 as a cause of familial venous malformations. In this work in 2013, somatic mutations of this same gene were detected in sporadic venous malformations. But this will become more interesting a few years later as I will comment soon.
- By 2015, the number of apparently unrelated pathologies, caused by PIK3CA, was already large. Here we see that somatic and activating mutations in PIK3CA are also related to both isolated LM and to syndromes in which LM are a major component.
- So it was necessary to put some order. This work proposed to include all alterations caused by PIK3CA under the term PROS. Diagnostic criteria and guidelines for molecular diagnosis were also established. This figure shows very well, for each pathology, the relationship between phenotypic severity and distribution, as a consequence of the specific time and place during the embryonic development in which the mutation arose. One of the main concepts of somatic mosaicism.
- Fortunately, not all publications are based on molecular discoveries. There are still some, and necessary works, in which important clinical patterns are provided, something that far from being closed, still has much to explore and is important in terms of classification and diagnosis.
- Of course, there are also works oriented to give recommendations for genetic testing, like this one for the PROS spectrum.
- Last year somatic mutations were described in this gene, GNA11, important in the diagnosis of another clinical entity called DCMO. As its name suggests, it is a somewhat diffuse clinical classification, and will also be discussed in this symposium.
- Now, here comes the most interesting part of the TEK gene. In this work Authors identified mosaic double (cis) mutations (that is, two somatic mutations on the same allele) in the TEK gene as the principal cause of BRBN.
- But the interesting thing about this work is on this figure, where authors show different types of mutations according to the different possible phenotypes of the venous malformations associated with this gene. Familial venous malformations are caused by a somatic mutation in a patient who already had a germline mutation. Unifocal VMs are caused by unique somatic mutations, but with more severe effects on the protein function than those found in germinal cases. The multifocal venous malformations show two somatic mutations and the BRBN has double mosaic (cis) mutations. With this, the complexity of the second hit concept within the mosaicism is clearly exposed.
- To end with this timeline, two more publications from this year, 2018. This first one, in which mutations in PIK3CA are also described for CLAPO syndrome. This article raised the question of whether we should continue calling each of the syndromes caused By PIK3CA by their original name or whether it would be better to call them all as PROS. In this way, the controversy genotype only or only on phenotype only classifications re-emerged. This topic will also be addressed in this symposium.
- Finally, this most recent publication, in which authors detected multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, a pathway commonly activated in cancer and also known as causing the RAS-opathies, another group of genetic developmental syndromes.
- So what have we learned? On the one hand, we can see how the genes that cause VascMs are grouped in a few molecular pathways that are also quite related to each other. On the other, that the elucidation of the genetic causes of vascular malformations found in inherited syndromes, as well as the identification of specific somatic mutations in both inherited and sporadic forms, has played an invaluable role in understanding normal and pathological blood vessel structure and function. The biochemical connections between these pathways might also suggest that at least in some cases, therapies developed for one type of vascular malformation might show some efficacy for others.
- In addition, returning to the concept of mosaicism, we have learned that the specific characteristics of a VascM depends, among other things, on the number of affected cells, on the moment of the embryonic development in which the mutation arose, and on its specific location.
- So, as we see in the figure of this paper, an important consideration is that somatic mutations occur in different cell types and tissues as well as in different developmental stages. Mutations in GNAQ causes non-syndromic Port-wine stains, but also the Sturge-Weber syndrome, a severe neurocutaneous disorder. Nevertheless, both conditions likely affect the same cell types (the, endothelial cells). The milder phenotype of the birthmarks could result from a later developmental origin of the mutation. Also, mutations in GNAQ, when occurring in melanocytes later in life, is a frequent driver mutation in uveal melanoma. Other mosaic mutations also differ in their clinical importance based on cell or tissue-specific involvement. McCune-Albright syndrome (OMIM #174800) is caused by somatic activating mutations in GNAS which is expressed biallelically through most of the body, but the maternal allele is imprinted in particular tissues such as the pituitary, and progressive osseous heteroplasia and pseudopseudohypoparathyroidism result from loss of function mutations in the paternal allele. Here, somatic AKT1 mutations are associated with cancer and Proteus syndrome. The AKT2 gene is associated with diabetes. And Somatic mutations in AKT3 cause a specific Megalencephaly syndrome. This genes have specific tissue expression, thus highlight the complex interaction of localized somatic mutation with tissue or cell-specific gene expression and signaling pathways.
- We have also learned that the concept of mosaicism is not always easy to understand. For example, what is affected tissue? Let's look at this example. The somatic mutations of the GNAQ gene cause 87% of the sporadic or syndromic CM, and when studying an affected tissue, the pathogenic variant can be detected in mosaics that vary between 1 and 22%, but if we look a little more closely, in fact that mutation is concentrated in the endothelial cells and not in the rest of the components of the capillary vessels. Actually, within the endothelial cells there are also percentages of mosaicism. Theoretically, a given mutation can be present in all cell types of the body but not in all the cells. Explain this is somewhat more complicated.
- We have also learned about the importance of the specific function of the affected gene. The expression or cellular localization of the PIK3CA gene with another gene such as GATA2 is not comparable ammosng different tissues,
- Another important concept learned is that of lethal genes. As early as 1987, Dr. Happle proposed that mutated genes not compatible with life in germinal form can only be found in the somatic mosaicism, and proposed a series of syndromes in which this mechanism was highly probable.
- 30 years later, Dr. Happle published this work on the classification of cutaneous mosaicism in which he reviewed the works confirming this concept.
- In addition to the TEK gene, the second hit hypothesis has been demonstrated in the genes associated with CCM or RASA1. Also, if we look at the glomovenous malformations, the second hit can also be a uniparental isodisomy, so in genetic terms we have also learned that there are more things besides strictly genic variations.
- We have also seen how gain-of-function mutations are mainly associated with somatic mosaicism, while loss-of-function mutations are more frequent in the germ line or in the cases of second hit.
- Although this figure would not win a graphic design award, while preparing this talk I thought that maybe it could serve to visualize several of these concepts at the same time, just to demonstrate the complexity of this type of malformations. The VEGF pathway is more associated with germline mutations causing lymphatic malformations, the genes with gain of function to mosaicism, and in some cases we can find genes with different patterns. So there are many conditions that must be taken into account in each case.
- The graphic was ugly, yes, but the table version is even worse. But as I did it, I'm showing it to you.
- So what all this means for the patient? First, we must take into account these concepts in order to recognize different alterations and what they mean, such as why the midline capillary malformations in the lower lip and lower lip are embryologically different and therefore have different consequences.
- Or that we should recognize a mosaic pattern to study the right sample in each patient and the parents.
- And that it is important to know which technique will allow us to detect genetic alterations in low mosaics.
- Therefore, all these concepts are important when evaluating a patient.
- But we still have many challenges to solve. In future talks of this symposium we will talk about how mosaicism in general still needs an adequate classification, as well as the classification of vascular malformations, which has important controversies, we will talk specifically about CM. Non-vascular manifestations and conflicts regarding taxonomy will also be discussed. We will also review the associations between phenotype and genotype, as well as the difficulty in diagnosis, including the bioinformatic challenges of the analysis of massive data for the search of low mosaics. Then we will immerse ourselves in the world of functional studies. For example, in vivo models can help to uncover the secrets of the development of vascular malformation. We will also see what can offer us the new techniques of gene editing in the somatic pathologies. Finally, as it can not be otherwise, the challenges of the somatic mosaicism in the genetic counseling will also be discussed.
- I want to thank all the people I work with every day, and all of you for being here today.