Gupta Ankita, Mathew Don, Bhat Shabir Ahmad, Ghoshal Sushmita, Pal Arnab
Department of Radiotherapy, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
Front Oncol. 2021 May 17;11:652049. doi: 10.3389/fonc.2021.652049. eCollection 2021.
To investigate the impact of genetic variants of DNA repair and pro-fibrotic pathway genes on the severity of radiation-induced subcutaneous fibrosis in patients of oropharyngeal carcinoma treated with radical radiotherapy.
Patients of newly diagnosed squamous cell carcinoma of oropharynx being treated with two-dimensional radical radiotherapy were enrolled in the study. Patients who had undergone surgery or were receiving concurrent chemotherapy were excluded. Patients were followed up at 6 weeks post completion of radiotherapy and every 3 months thereafter for a median of 16 months. Subcutaneous fibrosis was graded according to the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) grading system and the maximum grade was recorded over the length of the patient's follow-up. Patients with severe fibrosis (≥G3), were compared to patients with minor (≤G2) fibrotic reactions. Eight single nucleotide polymorphisms of 7 DNA repair genes and 2 polymorphisms of a single pro-fibrotic pathway gene were analyzed by Polymerase Chain Reaction and Restriction Fragment Length Polymorphism and were correlated with the severity of subcutaneous fibrosis.
179 patients were included in the analysis. Subcutaneous fibrosis was seen in 168 (93.9%) patients. 36 (20.1%) patients had severe (grade 3) fibrosis. On multivariate logistic regression analysis, Homozygous CC genotype of XRCC3 (722C>T, rs861539) (, OR 2.350, 95% CI 1.089-5.382), Homozygous AA genotype of ERCC4 Ex8 (1244G>A, rs1800067) (, OR 11.626, 95% CI 2.490-275.901) and Homozygous TT genotype of XRCC5 (1401G>T, rs828907) (, OR 2.188, 95% CI 1.652-7.334) were found to be predictive of severe subcutaneous fibrosis. On haplotype analysis, the cumulative risk of developing severe fibrosis was observed in patients carrying both haplotypes of variant Homozygous AA genotype of ERCC4 Ex8 (1244G>A, rs1800067) and Homozygous TT genotype of XRCC5 (1401 G>T, rs828907) (, OR 26.340, 95% CI 4.014-76.568).
We demonstrated significant associations between single nucleotide polymorphisms of DNA repair genes and radiation-induced subcutaneous fibrosis in patients of oropharyngeal carcinoma treated with radiotherapy. We propose to incorporate these genetic markers into predictive models for identifying patients genetically predisposed to the development of radiation-induced fibrosis, thus guiding personalized treatment protocols.
探讨DNA修复基因和促纤维化通路基因的遗传变异对接受根治性放疗的口咽癌患者放射性皮下纤维化严重程度的影响。
纳入接受二维根治性放疗的新诊断口咽鳞状细胞癌患者。排除接受过手术或正在接受同步化疗的患者。放疗结束后6周进行随访，此后每3个月随访一次，中位随访时间为16个月。根据放射治疗肿瘤学组（RTOG）和欧洲癌症研究与治疗组织（EORTC）的分级系统对皮下纤维化进行分级，并记录患者随访期间的最高分级。将重度纤维化（≥G3）患者与轻度（≤G2）纤维化反应患者进行比较。通过聚合酶链反应和限制性片段长度多态性分析7个DNA修复基因的8个单核苷酸多态性和单个促纤维化通路基因的2个多态性，并将其与皮下纤维化的严重程度相关联。
179例患者纳入分析。168例（93.9%）患者出现皮下纤维化。36例（20.1%）患者出现重度（3级）纤维化。多因素逻辑回归分析显示，XRCC3（722C>T，rs861539）的纯合CC基因型（，OR 2.350，95%CI 1.089 - 5.382）、ERCC4 Ex8（1244G>A，rs1800067）的纯合AA基因型（，OR 11.626，95%CI 2.490 - 275.901）和XRCC5（1401G>T，rs828907）的纯合TT基因型（，OR 2.188，95%CI 1.652 - 7.334）可预测重度皮下纤维化。单倍型分析显示，携带ERCC4 Ex8（1244G>A，rs1800067）纯合AA基因型和XRCC5（1401G>T，rs828907）纯合TT基因型两种单倍型的患者发生重度纤维化的累积风险（，OR 26.340，9５%CI 4.014 - 76.568）。
我们证明了放疗的口咽癌患者中DNA修复基因的单核苷酸多态性与放射性皮下纤维化之间存在显著关联。我们建议将这些遗传标记纳入预测模型，以识别遗传上易发生放射性纤维化的患者，从而指导个性化治疗方案。
