PMID- 35449078
OWN - NLM
STAT- MEDLINE
DCOM- 20220425
LR  - 20231024
IS  - 1756-9966 (Electronic)
IS  - 0392-9078 (Print)
IS  - 0392-9078 (Linking)
VI  - 41
IP  - 1
DP  - 2022 Apr 21
TI  - Circulating cell free DNA and citrullinated histone H3 as useful biomarkers of 
      NETosis in endometrial cancer.
PG  - 151
LID - 10.1186/s13046-022-02359-5 [doi]
LID - 151
AB  - BACKGROUND: Cancer mortality is mainly caused by organ failure and thrombotic 
      events. It has been demonstrated that NETosis, a chromatin release mechanism 
      implemented by neutrophils, may contribute to these lethal systemic effects. Our 
      aim was to investigate NETosis biomarkers in endometrial cancer (EC). METHODS: 
      The experiments were conducted on 21 healthy subjects (HS) with no gynecological 
      conditions, and on 63 EC patients. To assess the presence of NETosis features, 
      IHC and IF was performed using antibodies against citrullinated histone H3 
      (citH3), neutrophil elastase (NE) and histone 2B. Serum levels of cell free DNA 
      (cfDNA), cell free mitochondrial DNA (cfmtDNA) and citH3 were measured by qPCR 
      using one microliter of deactivated serum, and by ELISA assay respectively. 
      Fragmentation pattern of serum cfDNA was analyzed using the Agilent 2100 
      Bioanalyzer and High Sensitivity DNA Chips. Receiver operating characteristic 
      (ROC) analysis was used to identify a cut off for cfDNA and cfmtDNA values able 
      to discriminate between ECs and HSs. Correlation analysis and multiple 
      correspondence analysis (MCA) between cfDNA, mtcfDNA, citH3 and blood parameters 
      were used to identify the potential association among serum parameters in EC 
      grades. RESULTS: We demonstrated the presence of NETosis features in tissues from 
      all EC grades. Serum cfDNA and cfmtDNA levels discriminate ECs from HSs and a 
      direct correlation between citH3 and cfDNA content and an inverse correlation 
      between cfmtDNA and citH3 in EC sera was observed, not detectable in HSs. MCA 
      indicates cfDNA, cfmtDNA and citH3 as features associated to G1 and G2 grades. A 
      correlation between increased levels of cfDNA, citH3 and inflammation features 
      was found. Finally, serum nucleosomal cfDNA fragmentation pattern varies in EC 
      sera and correlates with increased levels of cfDNA, citH3, lymphocytes and 
      fibrinogen. CONCLUSION: Our data highlight the occurrence of NETosis in EC and 
      indicate serum cfDNA and citH3 as noninvasive biomarkers of tumor-induced 
      systemic effects in endometrial cancer.
CI  - (c) 2022. The Author(s).
FAU - Ronchetti, Livia
AU  - Ronchetti L
AD  - SAFU Unit, IRCCS - Regina Elena National Cancer Institute, via Elio Chianesi 53, 
      00144, Rome, Italy.
FAU - Terrenato, Irene
AU  - Terrenato I
AD  - Clinical Trial Center - Biostatistics & Bioinformatics, IRCCS - Regina Elena 
      National Cancer Institute, Rome, Italy.
FAU - Ferretti, Margherita
AU  - Ferretti M
AD  - SAFU Unit, IRCCS - Regina Elena National Cancer Institute, via Elio Chianesi 53, 
      00144, Rome, Italy.
FAU - Corrado, Giacomo
AU  - Corrado G
AD  - Department of Women and Children Health, Gynecologic Oncology Unit, Fondazione 
      Policlinico Universitario A. Gemelli, IRCCS - Universita Cattolica del Sacro 
      Cuore, Roma, Italy.
FAU - Goeman, Frauke
AU  - Goeman F
AD  - SAFU Unit, IRCCS - Regina Elena National Cancer Institute, via Elio Chianesi 53, 
      00144, Rome, Italy.
FAU - Donzelli, Sara
AU  - Donzelli S
AD  - Oncogenomics and Epigenetics Unit, IRCCS - Regina Elena National Cancer 
      Institute, Rome, Italy.
FAU - Mandoj, Chiara
AU  - Mandoj C
AD  - Clinical Pathology Unit, IRCCS - Regina Elena National Cancer Institute, Rome, 
      Italy.
FAU - Merola, Roberta
AU  - Merola R
AD  - Clinical Pathology Unit, IRCCS - Regina Elena National Cancer Institute, Rome, 
      Italy.
FAU - Zampa, Ashanti
AU  - Zampa A
AD  - Gynecologic Oncology Unit, IRCCS - Regina Elena National Cancer Institute, Rome, 
      Italy.
FAU - Carosi, Mariantonia
AU  - Carosi M
AD  - Anatomy Pathology Unit, IRCCS - Regina Elena National Cancer Institute, Rome, 
      Italy.
FAU - Blandino, Giovanni
AU  - Blandino G
AD  - Oncogenomics and Epigenetics Unit, IRCCS - Regina Elena National Cancer 
      Institute, Rome, Italy.
FAU - Conti, Laura
AU  - Conti L
AD  - Clinical Pathology Unit, IRCCS - Regina Elena National Cancer Institute, Rome, 
      Italy.
FAU - Lobascio, Anna Maria
AU  - Lobascio AM
AD  - Gynecologic Oncology Unit, IRCCS - Regina Elena National Cancer Institute, Rome, 
      Italy.
FAU - Iacobelli, Marcello
AU  - Iacobelli M
AD  - Gynecologic Oncology Unit, IRCCS - Regina Elena National Cancer Institute, Rome, 
      Italy.
FAU - Vizza, Enrico
AU  - Vizza E
AD  - Gynecologic Oncology Unit, IRCCS - Regina Elena National Cancer Institute, Rome, 
      Italy.
FAU - Piaggio, Giulia
AU  - Piaggio G
AD  - SAFU Unit, IRCCS - Regina Elena National Cancer Institute, via Elio Chianesi 53, 
      00144, Rome, Italy.
FAU - Gurtner, Aymone
AU  - Gurtner A
AUID- ORCID: 0000-0002-7661-9059
AD  - SAFU Unit, IRCCS - Regina Elena National Cancer Institute, via Elio Chianesi 53, 
      00144, Rome, Italy. aymone.gurtner@ifo.it.
AD  - Institute of Translational Pharmacology (IFT), National Research Council (CNR), 
      Rome, Italy. aymone.gurtner@ifo.it.
LA  - eng
PT  - Journal Article
DEP - 20220421
PL  - England
TA  - J Exp Clin Cancer Res
JT  - Journal of experimental & clinical cancer research : CR
JID - 8308647
RN  - 0 (Biomarkers)
RN  - 0 (Cell-Free Nucleic Acids)
RN  - 0 (Histones)
SB  - IM
EIN - J Exp Clin Cancer Res. 2023 Oct 24;42(1):278. PMID: 37875975
MH  - Biomarkers
MH  - *Cell-Free Nucleic Acids/pharmacology
MH  - *Endometrial Neoplasms/genetics
MH  - *Extracellular Traps/genetics
MH  - Female
MH  - Histones
MH  - Humans
MH  - Neutrophils
PMC - PMC9027343
OTO - NOTNLM
OT  - Circulating cell-free DNA
OT  - Citrullinated Histone H3
OT  - DNA cfDNA fragmentation pattern
OT  - DNA size distribution
OT  - Liquid biopsy
OT  - NETosis
OT  - NETs
OT  - Neutrophil Elastase
OT  - Tumor induced systemic effects
COIS- The authors declare that they have no competing interests.
EDAT- 2022/04/23 06:00
MHDA- 2022/04/26 06:00
PMCR- 2022/04/21
CRDT- 2022/04/22 05:11
PHST- 2021/10/20 00:00 [received]
PHST- 2022/04/06 00:00 [accepted]
PHST- 2022/04/22 05:11 [entrez]
PHST- 2022/04/23 06:00 [pubmed]
PHST- 2022/04/26 06:00 [medline]
PHST- 2022/04/21 00:00 [pmc-release]
AID - 10.1186/s13046-022-02359-5 [pii]
AID - 2359 [pii]
AID - 10.1186/s13046-022-02359-5 [doi]
PST - epublish
SO  - J Exp Clin Cancer Res. 2022 Apr 21;41(1):151. doi: 10.1186/s13046-022-02359-5.