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Published on: August 21, 2013
Association of PARP1 polymorphisms with response to chemotherapy in patients with high-risk neuroblastoma
Marianna Avitabile1,2, Vito Alessandro Lasorsa1,2, Sueva Cantalupo3
1Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy.
Abstract:
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.
Insights
A specific gene variant (rs907187) in the PARP1 gene is linked to poor treatment response in high-risk neuroblastoma (NB). This finding may explain therapeutic failures and guide future neuroblastoma treatment strategies.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- High-risk neuroblastoma (NB) lacks understanding regarding its genetic causes and molecular mechanisms.
- Many high-risk NB patients do not respond to current induction therapy, often due to tumor cell resistance mediated by DNA repair systems.
- Poly(ADP-ribose) polymerase 1 (PARP1) is a key DNA damage sensor crucial for genomic stability.
Purpose of the Study:
- To investigate the role of PARP1 in high-risk neuroblastoma.
- To identify genetic variants within PARP1 associated with chemotherapy response and patient prognosis.
- To explore the functional impact of identified single nucleotide polymorphisms (SNPs) on PARP1 expression and transcription factor binding.
Main Methods:
- Analysis of PARP1 mRNA levels in neuroblastoma patient datasets and cell lines.
- Genotyping of two selected PARP1 SNPs (rs907187 and rs2048426) in 121 Italian high-risk NB patients.
- Correlation analysis between SNP genotypes, PARP1 mRNA levels, and clinical response to induction therapy.
- In silico prediction of SNP effects on transcription factor binding sites (E2F1).
Main Results:
- Elevated PARP1 mRNA levels were associated with unfavorable prognosis in multiple neuroblastoma datasets.
- The minor G allele of the PARP1 promoter SNP rs907187 was significantly associated with a poorer response to induction chemotherapy (P = 0.02).
- The G allele of rs907187 was linked to decreased PARP1 mRNA levels in NB cell lines (P = 0.003) and predicted to reduce E2F1 transcription factor binding.
- No significant association was found for the SNP rs2048426.
Conclusions:
- The PARP1 genetic variant rs907187 is a potential risk factor associated with induction therapy failure in high-risk neuroblastoma.
- Altered E2F1 binding due to rs907187 may influence PARP1 expression, contributing to poor prognosis in neuroblastoma patients.
- These findings highlight the importance of genetic factors in neuroblastoma treatment resistance and suggest rs907187 as a potential biomarker.
