TY - JOUR
T1 - Association of PARP1 polymorphisms with response to chemotherapy in patients with high-risk neuroblastoma
AU - Avitabile, Marianna
AU - Lasorsa, Vito Alessandro
AU - Cantalupo, Sueva
AU - Cardinale, Antonella
AU - Cimmino, Flora
AU - Montella, Annalaura
AU - Capasso, Dalila
AU - Haupt, Riccardo
AU - Amoroso, Loredana
AU - Garaventa, Alberto
AU - Quattrone, Alessandro
AU - Corrias, Maria Valeria
AU - Iolascon, Achille
AU - Capasso, Mario
N1 - Funding Information:
This study was supported by grants from Associazione Italiana per la Ricerca sul Cancro (Grant no. 19255 to MC and Grant no 20757 to AI); Ministero della Salute (GR-2011-02348722 to MC), Fondazione Italiana per la Lotta al Neuroblastoma (to MC and VMC); Associazione Oncologia Pediatrica e Neuroblastoma (to MC) and Regione Campania ?SATIN' grant 2018-2020 (to MC). FC was supported by Fondazione Umberto Veronesi post-Doc Fellowship.
Publisher Copyright:
© 2020 Università degli Studi di Napoli Federico II. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - The genetic aetiology and the molecular mechanisms that characterize high-risk neuroblastoma are still little understood. The majority of high-risk neuroblastoma patients do not take advantage of current induction therapy. So far, one of the main reasons liable for cancer therapeutic failure is the acquisition of resistance to cytotoxic anticancer drugs, because of the DNA repair system of tumour cells. PARP1 is one of the main DNA damage sensors involved in the DNA repair system and genomic stability. We observed that high PARP1 mRNA level is associated with unfavourable prognosis in 3 public gene expression NB patients’ datasets and in 20 neuroblastomas analysed by qRT-PCR. Among 4983 SNPs in PARP1, we selected two potential functional SNPs. We investigated the association of rs907187, in PARP1 promoter, and rs2048426 in non-coding region with response chemotherapy in 121 Italian patients with high-risk NB. Results showed that minor G allele of rs907187 associated with induction response of patients (P =.02) and with decrease PARP1 mRNA levels in NB cell line (P =.003). Furthermore, rs907187 was predicted to alter the binding site of E2F1 transcription factor. Specifically, allele G had low binding affinity with E2F1 whose expression positively correlates with PARP1 expression and associated with poor prognosis of patients with NB. By contrast, we did not find genetic association for the SNP rs2048426. These data reveal rs907187 as a novel potential risk variant associated with the failure of induction therapy for high-risk NB.
AB - The genetic aetiology and the molecular mechanisms that characterize high-risk neuroblastoma are still little understood. The majority of high-risk neuroblastoma patients do not take advantage of current induction therapy. So far, one of the main reasons liable for cancer therapeutic failure is the acquisition of resistance to cytotoxic anticancer drugs, because of the DNA repair system of tumour cells. PARP1 is one of the main DNA damage sensors involved in the DNA repair system and genomic stability. We observed that high PARP1 mRNA level is associated with unfavourable prognosis in 3 public gene expression NB patients’ datasets and in 20 neuroblastomas analysed by qRT-PCR. Among 4983 SNPs in PARP1, we selected two potential functional SNPs. We investigated the association of rs907187, in PARP1 promoter, and rs2048426 in non-coding region with response chemotherapy in 121 Italian patients with high-risk NB. Results showed that minor G allele of rs907187 associated with induction response of patients (P =.02) and with decrease PARP1 mRNA levels in NB cell line (P =.003). Furthermore, rs907187 was predicted to alter the binding site of E2F1 transcription factor. Specifically, allele G had low binding affinity with E2F1 whose expression positively correlates with PARP1 expression and associated with poor prognosis of patients with NB. By contrast, we did not find genetic association for the SNP rs2048426. These data reveal rs907187 as a novel potential risk variant associated with the failure of induction therapy for high-risk NB.
KW - chemotherapy
KW - neuroblastoma
KW - oncology
KW - PARP1
KW - pharmacogenomics
KW - SNP
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U2 - 10.1111/jcmm.15058
DO - 10.1111/jcmm.15058
M3 - Article
C2 - 32103589
AN - SCOPUS:85080067027
VL - 24
SP - 4072
EP - 4081
JO - Journal of Cellular and Molecular Medicine
JF - Journal of Cellular and Molecular Medicine
SN - 1582-1838
IS - 7
ER -