Gene alterations as predictors of radiation-induced toxicity in head and neck squamous cell carcinoma

Abstract

Background Optimizing the therapeutic ratio for radiation therapy (RT) in head and neck squamous cell carcinoma (HNSCC) is uniquely challenging owing to high rates of early and late toxicity involving nearby organs at risk. These toxicities have a profound impact on treatment compliance and quality of life. Emerging evidence suggests that RT dose alone cannot fully account for the variable severity of RT-related adverse events (rtAEs) observed in HNSCC patients. Next-generation sequencing has become an increasingly valuable tool with widespread use in the oncology field and is being robustly explored for predicting rtAEs beyond dosimetric data. Methods Patients who had Foundation Medicine sequencing data and received RT for primary or locally recurrent HNSCC were selected for this study. Early and late toxicity data were collected and reported based on Common Terminology Criteria for Adverse Events version 5.0. Dosimetric parameters were collected for pertinent structures. Results A total of HNSCC 37 patients were analyzed in this study. Genetic alterations in BRCA2, ERBB3, NOTCH1 and CCND1 were all associated with higher mean grade of toxicity with BRCA2 alteration implicated in all toxicity parameters evaluated including mucositis, early dysphagia, xerostomia and to a lesser extent, late dysphagia. Interestingly, patients who exhibited alterations in both BRCA2 and ERBB3 experienced a twofold or greater increase in early dysphagia, early xerostomia and late dysphagia compared to ERBB3 alteration alone. Furthermore, several gene alterations were associated with improved toxicity outcomes. Within an RT supersensitive patient subset, alterations were found in TNFAIP3, HNF1A, SPTA1 and CASP8. All of these alterations were not found in the RT insensitive patient subset. We found 17 gene alterations in the RT insensitive patient subset that were not found in the RT supersensitive patient subset. Conclusion Despite consistent RT dosimetric parameters, patients with HNSCC experience heterogeneous patterns of rtAEs. Identifying factors associated with toxicity outcomes offers a new avenue for personalized precision RT therapy and prophylactic management. Here, next-generation sequencing in a population of HNSCC patients correlates several genetic alterations with severity of rtAEs. Further analysis is urgently needed to identify genetic patterns associated with rtAEs in order to reduce harmful outcomes in this challenging population.

Evaluating predictive factors for toxicities experienced by head & neck cancer patients undergoing radiotherapy

“…Our results indicate HPV-negative status or having an oropharyngeal cancer may increase a patient's risk of high-grade late dysphagia. Recent studies have shown that the genomics of the primary tumor can have an effect on normal tissue outcomes [18]. Thus, the relationship seen here between cancer type and worsened outcomes may be due to underlying genetics of the tumor effecting the micro-environment though more analysis is needed to evaluate the cause of this effect.…”

Prediction of the Mechanism of Sodium Butyrate against Radiation-Induced Lung Injury in Non-Small Cell Lung Cancer Based on Network Pharmacology and Molecular Dynamic Simulations

“…( 10 ) reported that simvastatin could reverse RILI-associated dysregulated gene expression including TP53. Genetic alterations in NOTCH1 were associated with a high mean grade of radiation-induced toxicity in head and neck squamous cell carcinoma ( 56 ). SIRT1 has a protective effect against radiation injury ( 57 ).…”

Cytoskeletal protein SPTA1 mediating the decrease in erectile function induced by high‐fat diet via Hippo signaling pathway

“…Mutations of the SPTA1 gene cause various inherited erythroid disorders, 53 including elliptocytosis type 2, pyrexia, and spherocytic hemolytic anemia. 54,55 In recent years, the SPTA1 gene has been reported in squamous lung cancer, 56 head-and-neck squamous cell carcinoma, 57 spinal muscular atrophy, 58 risk and diagnosis of type 2 diabetes, 59 brain metastases and primary tumors, 60 and prostate cancer syndrome, 61 and studies about converting immortalized human erythroid cell lines into in vitro manufactured erythrocytes. 62 Transcriptome analysis showed that SPTA1 gene is enriched in the apoptotic signaling pathway.…”