PUBLICATION
Circulating biomarkers in familial cerebral cavernous malformation
- Authors
- Lazzaroni, F., Meessen, J.M.T.A., Sun, Y., Lanfranconi, S., Scola, E., D'Alessandris, Q.G., Tassi, L., Carriero, M.R., Castori, M., Marino, S., Blanda, A., Nicolis, E.B., Novelli, D., Calabrese, R., Agnelli, N.M., Bottazzi, B., Leone, R., Mazzola, S., Besana, S., Catozzi, C., Nezi, L., Lampugnani, M.G., Malinverno, M., Grdseloff, N., Rödel, C.J., Rezai Jahromi, B., Bolli, N., Passamonti, F., Magnusson, P.U., Abdelilah-Seyfried, S., Dejana, E., Latini, R.
- ID
- ZDB-PUB-231220-8
- Date
- 2023
- Source
- EBioMedicine 99: 104914104914 (Journal)
- Registered Authors
- Keywords
- Biomarkers, Familial cerebral cavernous malformation, Proteomics, Vascular biology
- MeSH Terms
-
- Animals
- Antigens, Neoplasm
- Biomarkers
- Cell Adhesion Molecules
- Female
- Hemangioma, Cavernous, Central Nervous System*/etiology
- Hemangioma, Cavernous, Central Nervous System*/genetics
- Humans
- Male
- Microtubule-Associated Proteins/genetics
- Proto-Oncogene Proteins/genetics
- Seizures
- Zebrafish/metabolism
- PubMed
- 38113759 Full text @ EBioMedicine
Citation
Lazzaroni, F., Meessen, J.M.T.A., Sun, Y., Lanfranconi, S., Scola, E., D'Alessandris, Q.G., Tassi, L., Carriero, M.R., Castori, M., Marino, S., Blanda, A., Nicolis, E.B., Novelli, D., Calabrese, R., Agnelli, N.M., Bottazzi, B., Leone, R., Mazzola, S., Besana, S., Catozzi, C., Nezi, L., Lampugnani, M.G., Malinverno, M., Grdseloff, N., Rödel, C.J., Rezai Jahromi, B., Bolli, N., Passamonti, F., Magnusson, P.U., Abdelilah-Seyfried, S., Dejana, E., Latini, R. (2023) Circulating biomarkers in familial cerebral cavernous malformation. EBioMedicine. 99:104914104914.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping