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      Genetic Polymorphisms in ERCC1 Gene and Their Association with Response to Radiotherapy in Moroccan Patients with Nasopharyngeal Carcinoma

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          Abstract

          Objective:

          Nasopharyngeal carcinoma (NPC) is a severe malignant disease. Despite its low frequency, NPC is very common in North African population. Radiotherapy is the standard therapeutic treatment of NPC. However, radioresistance hampers the success of treatment. At the molecular scale, radioresistance is due to genetic variations involved in DNA repair pathways in NPC patients. Several studies reported that single nucleotide polymorphisms (SNPs) in excision repair cross complementing group 1 ( ERCC1) could be associated with radioresistance. In this optic, the present study aimed to evaluate the association between DNA repair gene polymorphisms ERCC1 C8092A and ERCC1 C118T and radiotherapy response of patients with NPC.

          Methods:

          A total of 95 patients with confirmed NPC were recruited at the Mohammed VI Center for Cancer Treatment, Casablanca - Morocco between 2016 and 2018. Two single nucleotide polymorphisms in ERCC1 gene were genotyped. Multiple analysis software was used to assess the correlation between these SNPs and radio-therapeutic response.

          Results:

          Sequencing of ERCC1 C8092A polymorphism revealed that CC and CA genotypes were found in 51.6% and 45.3% of cases, respectively, whereas the homozygote AA genotype was reported in only 3.1% of cases. For ERCC1 C118T polymorphism, the heterozygote CT genotype was identified in 49.5% of cases. Homozygotes genotypes CC and TT were detected in 17.9% and 32.6% respectively of NPC cases. Of note, no significant association was found between the ERCC1 C8092A polymorphism and response to radiation therapy (p=0.81). Similarly, there was no significant association between the response to radiotherapy and allelic distribution (p=0.56). Likewise, no correlation was observed neither with genotypes (p=0.07) nor with alleles (p=0.09) of ERCC1 C118T polymorphism and response to radiation therapy.

          Conclusion:

          Our results clearly showed that ERCC1 C8092A and ERCC1 C118T polymorphisms were not associated with response to radiotherapy in Moroccan NPC patients. Large studies are warranted to confirm the role of these SNPs in therapeutic response of NPC patients.

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          Most cited references37

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          Current Perspectives on Nasopharyngeal Carcinoma.

          Hui Mei Lee, Kazuhida Okuda, Fermín E. González … (2019)
          Of the ~129,079 new cases of nasopharyngeal carcinoma (NPC) and 72,987 associated deaths estimated for 2018, the majority will be geographically localized to South East Asia, and likely to show an upward trend annually. It is thought that disparities in dietary habits, lifestyle, and exposures to harmful environmental factors are likely the root cause of NPC incidence rates to differ geographically. Genetic differences due to ethnicity and the Epstein Barr virus (EBV) are likely contributing factors. Pertinently, NPC is associated with poor prognosis which is largely attributed to lack of awareness of the salient symptoms of NPC. These include nose hemorrhage and headaches and coupled with detection and the limited therapeutic options. Treatment options include radiotherapy or chemotherapy or combination of both. Surgical excision is generally the last option considered for advanced and metastatic disease, given the close proximity of nasopharynx to brain stem cell area, major blood vessels, and nerves. To improve outcome of NPC patients, novel cellular and in vivo systems are needed to allow an understanding of the underling molecular events causal for NPC pathogenesis and for identifying novel therapeutic targets and effective therapies. While challenges and gaps in current NPC research are noted, some advances in targeted therapies and immunotherapies targeting EBV NPCs are discussed in this chapter, which may offer improvements in outcome of NPC patients.
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            Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans.

            Hannah M Jones, H Mohrenweiser, Michael Shen (1998)
            The removal or repair of DNA damage has a key role in protecting the genome of the cell from the insults of cancer-causing agents. This was originally demonstrated in individuals with the rare genetic disease xeroderma pigmentosum, the paradigm of cancer genes, and subsequently in the relationship between mismatch repair and colon cancer. Recent reports suggest that individuals with less dramatic reductions in the capacity to repair DNA damage are observed at polymorphic frequency in the population; these individuals have an increased susceptibility to breast, lung, and skin cancer. We report initial results from a study to estimate the extent of DNA sequence variation among individuals in genes encoding proteins of the DNA repair pathways. Nine different amino acid substitution variants have been identified in resequencing of the exons of three nucleotide excision repair genes (ERCC1, XPD, and XPF), a gene involved in double-strand break repair/recombination genes (XRCC3), and a gene functioning in base excision repair and the repair of radiation-induced damage (XRCCI). The frequencies for the nine different variant alleles range from 0.04 to 0.45 in a group of 12 healthy individuals; the average allele frequency is 0.17. The potential that this variation, and especially the six nonconservative amino acid substitutions occurring at residues that are identical in human and mouse, may cause reductions in DNA repair capacity or the fidelity of DNA repair is intriguing; the role of the variants as cancer risk factors or susceptibility alleles remains to be addressed.
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              Long non-coding RNA PVT1 predicts poor prognosis and induces radioresistance by regulating DNA repair and cell apoptosis in nasopharyngeal carcinoma

              Yi He, Yizhou Jing, Fang Wei … (2018)
              The long non-coding RNA, plasmacytoma variant translocation 1 (PVT1), is highly expressed in a variety of tumors, and is believed to be a potential oncogene. However, the role and mechanism of action of PVT1 in the carcinogenesis and progression of nasopharyngeal carcinomas (NPCs) remains unclear. In this study, for the first time, we have discovered that PVT1 shows higher expression in NPCs than in normal nasopharyngeal epithelial tissue, and patients with NPCs who show higher expression of PVT1 have worse progression-free and overall survivals. Additionally, we observed that the proliferation of NPC cells decreased, and their rate of apoptosis increased; these results indicated that the knockdown of PVT1 expression in the NPC cells induced radiosensitivity. Further, we have shown that the knockdown of PVT1 expression can induce apoptosis in the NPC cells by influencing the DNA damage repair pathway after radiotherapy. In general, our study shows that PVT1 may be a novel biomarker for prognosis and a new target for the treatment of NPCs. Additionally, targeting PVT1 may be a potential strategy for the clinical management of NPC and for the improvement of the curative effect of radiation in NPCs.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Asian Pac J Cancer Prev
                Journal ID (iso-abbrev): Asian Pac J Cancer Prev
                Journal ID (publisher-id): APJCP
                Title: Asian Pacific Journal of Cancer Prevention : APJCP
                Publisher: West Asia Organization for Cancer Prevention (Iran )
                ISSN (Print): 1513-7368
                ISSN (Electronic): 2476-762X
                Publication date (Print): 2023
                Volume: 24
                Issue: 1
                Pages: 93-99
                Affiliations
                [1 ] Biology and Medical Research Unit, National Center of Energy, Sciences and Nuclear Techniques, Rabat, Morocco.
                [2 ] Laboratory of Microbiology and Molecular Biology, Faculty of Sciences, Rabat, Morocco.
                [3 ] Laboratory of Viral Oncology, Institut Pasteur du Maroc, Casablanca, Morocco.
                [4 ] Mohammed VI Center for Cancer Treatment, Ibn Rochd University Hospital, Casablanca, Morocco.
                [5 ] Nuclear Medecine Department, Ibn Rochd University Hospital, Hassan II University, Casablanca, Morocco.
                [6 ] Department of Radiology, Ibn Rochd University Hospital, Hopital 20 Août, Casablanca, Morocco.
                Author notes
                [* ]For Correspondence: mzibri@yahoo.com
                Article
                DOI: 10.31557/APJCP.2023.24.1.93
                PMC ID: 10152845
                PubMed ID: 36708557
                SO-VID: 90cfd07a-eb89-4dcf-922d-98c17da45020
                License:

                This work is licensed under a Creative Commons Attribution-Non Commercial 4.0 International License. https://creativecommons.org/licenses/by-nc/4.0/

                History
                Date received : 8 May 2022
                Date accepted : 12 January 2023
                Categories
                Subject: Research Article

                Keywords: nasopharyngeal carcinoma,ercc1 c8092a,ercc1 c118t,radioresistance,morocco
                Data availability:
                Keywords: nasopharyngeal carcinoma, ercc1 c8092a, ercc1 c118t, radioresistance, morocco

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