Abstract
PurposeTo 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.Materials and MethodsPatients 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.Results179 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) (p=0.013*, OR 2.350, 95% CI 1.089-5.382), Homozygous AA genotype of ERCC4 Ex8 (1244G>A, rs1800067) (p=0.001**, OR 11.626, 95% CI 2.490-275.901) and Homozygous TT genotype of XRCC5 (1401G>T, rs828907) (p=0.020*, 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) (p=0.010*, OR 26.340, 95% CI 4.014-76.568).ConclusionWe 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.
Highlights
India has the highest incidence rate of oropharyngeal carcinoma (OPC) in the world, with majority (68.6%) of the patients presenting in locoregionally advanced stages of the disease [1]
We aim to identify genetic biomarkers which can be incorporated into predictive models of radiation-induced subcutaneous fibrosis
Andreassen et al reported that Thr/Thr genotype in XRCC3 codon 241 correlated with an increased risk of subcutaneous fibrosis as well as telangiectasia in breast cancer [33]
Summary
India has the highest incidence rate of oropharyngeal carcinoma (OPC) in the world, with majority (68.6%) of the patients presenting in locoregionally advanced stages of the disease [1]. The toxicity of intensive treatment regimens contributes to a substantial increase in patient morbidity and mortality, especially in developing countries like India, with patient profiles distinct from the western world. Most patients present with poor performance and nutritional status and inadequate support systems. This leads to poor compliance and treatment tolerability and poor disease outcomes. Majority of our patients receive definitive radiotherapy alone with conventional or altered fractionation schedules in order to achieve acceptable outcomes with minimum morbidity. 2-dimensional conventional radiotherapy continues to be used for a significant proportion of our patients [6, 7]
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