Circulating biomarkers in familial cerebral cavernous malformationResearch in context
Francesca Lazzaroni,
Jennifer M.T.A. Meessen,
Ying Sun,
Silvia Lanfranconi,
Elisa Scola,
Quintino Giorgio D'Alessandris,
Laura Tassi,
Maria Rita Carriero,
Marco Castori,
Silvia Marino,
Adriana Blanda,
Enrico B. Nicolis,
Deborah Novelli,
Roberta Calabrese,
Nicolò M. Agnelli,
Barbara Bottazzi,
Roberto Leone,
Selene Mazzola,
Silvia Besana,
Carlotta Catozzi,
Luigi Nezi,
Maria G. Lampugnani,
Matteo Malinverno,
Nastasja Grdseloff,
Claudia J. Rödel,
Behnam Rezai Jahromi,
Niccolò Bolli,
Francesco Passamonti,
Peetra U. Magnusson,
Salim Abdelilah-Seyfried,
Elisabetta Dejana,
Roberto Latini
Affiliations
Francesca Lazzaroni
Vascular Biology Unit, IFOM ETS-The AIRC Institute of Molecular Oncology, Milan, Italy; Hematology Department, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy; Corresponding author. Hematology Department, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.
Jennifer M.T.A. Meessen
Department of Acute Brain and Cardiovascular Injury, Institute for Pharmacological Research Mario Negri IRCCS, Milan, Italy
Ying Sun
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
Silvia Lanfranconi
Department of Neurology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
Elisa Scola
Department of Neurology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
Quintino Giorgio D'Alessandris
Department of Neurosurgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Department of Neuroscience, Università Cattolica del Sacro Cuore, Roma, Italy
Laura Tassi
Claudio Munari Epilepsy Surgery Centre, ASST Niguarda Hospital, Milan, Italy
Maria Rita Carriero
Cerebrovascular Disease Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Marco Castori
Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
Silvia Marino
IRCCS Centro Neurolesi “Bonino Pulejo”, Messina, Italy
Adriana Blanda
Department of Acute Brain and Cardiovascular Injury, Institute for Pharmacological Research Mario Negri IRCCS, Milan, Italy
Enrico B. Nicolis
Department of Acute Brain and Cardiovascular Injury, Institute for Pharmacological Research Mario Negri IRCCS, Milan, Italy
Deborah Novelli
Department of Acute Brain and Cardiovascular Injury, Institute for Pharmacological Research Mario Negri IRCCS, Milan, Italy
Roberta Calabrese
Department of Acute Brain and Cardiovascular Injury, Institute for Pharmacological Research Mario Negri IRCCS, Milan, Italy
Nicolò M. Agnelli
Department of Acute Brain and Cardiovascular Injury, Institute for Pharmacological Research Mario Negri IRCCS, Milan, Italy
Barbara Bottazzi
IRCCS Humanitas Research Hospital, Rozzano, Italy
Roberto Leone
IRCCS Humanitas Research Hospital, Rozzano, Italy
Selene Mazzola
Laboratory Medicine, Desio Hospital, Università Milano Bicocca, Milan, Italy
Silvia Besana
Laboratory Medicine, Desio Hospital, Università Milano Bicocca, Milan, Italy
Carlotta Catozzi
Department of Experimental Oncology, Istituto Europeo di Oncologia IRCCS, Milano, Italy
Luigi Nezi
Department of Experimental Oncology, Istituto Europeo di Oncologia IRCCS, Milano, Italy
Maria G. Lampugnani
Vascular Biology Unit, IFOM ETS-The AIRC Institute of Molecular Oncology, Milan, Italy; Department of Acute Brain and Cardiovascular Injury, Institute for Pharmacological Research Mario Negri IRCCS, Milan, Italy
Matteo Malinverno
Vascular Biology Unit, IFOM ETS-The AIRC Institute of Molecular Oncology, Milan, Italy
Nastasja Grdseloff
Department of Zoophysiology, Institute of Biochemistry and Biology, University of Potsdam, Germany
Claudia J. Rödel
Department of Zoophysiology, Institute of Biochemistry and Biology, University of Potsdam, Germany
Behnam Rezai Jahromi
Department of Neurosurgery, Helsinki University Hospital, Helsinki, Finland
Niccolò Bolli
Hematology Department, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, 20122, Milan, Italy
Francesco Passamonti
Hematology Department, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, 20122, Milan, Italy
Peetra U. Magnusson
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
Salim Abdelilah-Seyfried
Department of Zoophysiology, Institute of Biochemistry and Biology, University of Potsdam, Germany
Elisabetta Dejana
Vascular Biology Unit, IFOM ETS-The AIRC Institute of Molecular Oncology, Milan, Italy; Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
Roberto Latini
Department of Acute Brain and Cardiovascular Injury, Institute for Pharmacological Research Mario Negri IRCCS, Milan, Italy
Summary: Background: Cerebral Cavernous Malformation (CCM) is a rare cerebrovascular disease, characterized by the presence of multiple vascular malformations that may result in intracerebral hemorrhages (ICHs), seizure(s), or focal neurological deficits (FND). Familial CCM (fCCM) is due to loss of function mutations in one of the three independent genes KRIT1 (CCM1), Malcavernin (CCM2), or Programmed Cell death 10 (PDCD10/CCM3). The aim of this study was to identify plasma protein biomarkers of fCCM to assess the severity of the disease and predict its progression. Methods: Here, we have investigated plasma samples derived from n = 71 symptomatic fCCM patients (40 female/31 male) and n = 17 healthy donors (HD) (9 female/8 male) of the Phase 1/2 Treat_CCM trial, using multiplexed protein profiling approaches. Findings: Biomarkers as sCD14 (p = 0.00409), LBP (p = 0.02911), CXCL4 (p = 0.038), ICAM-1 (p = 0.02013), ANG2 (p = 0.026), CCL5 (p = 0.00403), THBS1 (p = 0.0043), CRP (p = 0.0092), and HDL (p = 0.027), were significantly different in fCCM compared to HDs. Of note, sENG (p = 0.011), THBS1 (p = 0.011) and CXCL4 (p = 0.011), were correlated to CCM genotype. sROBO4 (p = 0.014), TM (p = 0.026) and CRP (p = 0.040) were able to predict incident adverse clinical events, such as ICH, FND or seizure. GDF-15, FLT3L, CXCL9, FGF-21 and CDCP1, were identified as predictors of the formation of new MRI-detectable lesions over 2-year follow-up. Furthermore, the functional relevance of ang2, thbs1, robo4 and cdcp1 markers was validated by zebrafish pre-clinical model of fCCM. Interpretation: Overall, our study identifies a set of biochemical parameters to predict CCM progression, suggesting biological interpretations and potential therapeutic approaches to CCM disease. Funding: Italian Medicines Agency, Associazione Italiana per la Ricerca sul Cancro (AIRC), ERC, Leducq Transatlantic Network of Excellence, Swedish Research Council.
