Genetic Variants of DNA Repair Genes as Predictors of Radiation-Induced Subcutaneous Fibrosis in Oropharyngeal Carcinoma

Gupta, Ankita; Mathew, Don; Bhat, Shabir Ahmad; Ghoshal, Sushmita

doi:10.3389/fonc.2021.652049

Cited by 10 publications

(12 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The candidate variant with the strongest evidence of pathogenicity available is rs25487 (Arg280His) in the DNA repair gene XRCC1, 19,20,24 encoding a protein vital for the efficient repair of single-strand DNA breaks resulting from exposure to ionizing radiation. This variant was associated by multiple studies with an increased risk of severe oral mucositis in patients with oropharyngeal carcinoma treated with radiotherapy 25 and the risk of radiation-induced side effects on normal tissues including acute mucositis. 26 A missense variant (rs861539) in a gene of the same pathway, XRCC3, was also identified.…”

Section: Discussionmentioning

confidence: 99%

Extreme acute radiation‐induced toxicity in a patient with polymorphous low‐grade adenocarcinoma of the nasopharynx and rare variants in DNA repair genes

Nowicka,

Kuna,

Stawiski

et al. 2023

Head & Neck

View full text Add to dashboard Cite

BackgroundPolymorphous low‐grade adenocarcinoma (PLGA) is an extremely rare finding in the nasopharynx. There are no guidelines for the treatment of PLGA in this localization. Radiotherapy may be administered to treat this malignancy; however, in radiosensitive individuals, it is associated with a risk of severe radiotherapy‐induced toxicity.MethodsWe present a case of a 73‐year‐old woman with locally advanced polymorphous low‐grade adenocarcinoma of the nasopharynx who developed a severe adverse acute reaction to radiotherapy leading to treatment discontinuation. Despite intensive treatment, the patient died 40 days after RT initiation. Whole genome sequencing was performed using DNA from peripheral blood mononuclear cells in the search for variants that could explain such extreme toxicity.ResultsWe identified a combination of pathogenic variants that may have contributed to the patient's reaction to radiation therapy, including predisposing variants in XRCC1, XRCC3, and LIG4. We also identified candidate variants, not previously described in this context, which could be associated with radiation toxicity based on plausible mechanisms. We discuss previous reports of this rare tumor from the literature and known contributors to radiation‐induced toxicity.ConclusionsGenetic causes should be considered in cases of extreme radiosensitivity, especially when is not explained by clinical factors.

show abstract

Section: Discussionmentioning

confidence: 99%

Extreme acute radiation‐induced toxicity in a patient with polymorphous low‐grade adenocarcinoma of the nasopharynx and rare variants in DNA repair genes

Nowicka,

Kuna,

Stawiski

et al. 2023

Head & Neck

View full text Add to dashboard Cite

show abstract

“…Previously, enhanced promoter activity was reported for the polymorphic rs1801321 T allele [ 41 ]. In previous studies investigating the association of RAD51 rs1801321 with response to RT, no association was observed with radiation pneumonitis in lung cancer [ 46 ], skin toxicity or mucositis in head and neck cancer [ 47 ] or fibrosis in oropharyngeal carcinoma [ 48 ]. This is consistent with our results regarding skin adverse events.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies investigated the role of this SNP in response to RT in different cancer types. Some studies reported that the polymorphic T allele confers an increased risk for fibrosis or telangiectasia [ 25 , 48 , 61 ], erythema and acute skin toxicity [ 55 , 62 ] in breast and other cancers. Still, other studies did not replicate the results, especially for late toxicity [ 27 , 28 , 63 , 64 , 65 ].…”

Section: Discussionmentioning

confidence: 99%

NBN, RAD51 and XRCC3 Polymorphisms as Potential Predictive Biomarkers of Adjuvant Radiotherapy Toxicity in Early HER2-Positive Breast Cancer

Goričar

Dugar

Dolžan

et al. 2022

Cancers

View full text Add to dashboard Cite

Radiotherapy (RT) for breast cancer significantly impacts patient survival and causes adverse events. Double-strand breaks are the most harmful type of DNA damage associated with RT, which is repaired through homologous recombination (HRR). As genetic variability of DNA repair genes could affect response to RT, we aimed to evaluate the association of polymorphisms in HRR genes with tumor characteristics and the occurrence of RT adverse events in early HER2-positive breast cancer. Our study included 101 breast cancer patients treated with adjuvant RT and trastuzumab. All patients were genotyped for eight single nucleotide polymorphisms in NBN, RAD51 and XRCC3 using competitive allele-specific PCR. Carriers of XRCC3 rs1799794 GG genotype were less likely to have higher tumor differentiation grade (OR = 0.05, 95% CI = 0.01–0.44, p = 0.007). Carriers of RAD51 rs1801321 TT genotype were more likely to have higher NYHA class in univariable (OR = 10.0; 95% CI = 1.63–61.33; p = 0.013) and multivariable (OR = 9.27; 95% CI = 1.28–67.02; p = 0.027) analysis. Carriers of RAD51 rs12593359 GG genotype were less likely to have higher NYHA class in univariable (OR = 0.09; 95% CI = 0.01–0.79; p = 0.030) and multivariable (OR = 0.07; 95% CI = 0.01–0.81; p = 0.034) analysis. Carriers of XRCC3 rs1799794 GG genotypes experienced more skin adverse events based on LENT-SOMA scale in univariable (OR = 5.83; 95% CI = 1.22–28.00; p = 0.028) and multivariable (OR = 10.90; 95% CI = 1.61–73.72; p = 0.014) analysis. In conclusion, XRCC3 and RAD51 polymorphisms might contribute to RT adverse events in early HER2-positive breast cancer patients.

show abstract

“…Specifically, we identified polymorphisms in XRCC1 / XRCC5 (x-ray repair cross-complementing 1/5), encoding two key genes responsible for base excision repair, that were associated with differential risks of high-grade toxicity. The XRCC1 rs25487 allele has been associated with severe oral mucositis in oropharyngeal carcinoma patients treated with radiotherapy ( 45 ). The XRCC5 rs3835 allele has been implicated in the development of severe radiation pneumonitis in NSCLC patients ( 56 ).…”

Section: Discussionmentioning

confidence: 99%

“…The involvement of SNPs in the various damage and stress-response genes in mediating radiation-induced toxicities has been extensively studied in multiple cancer types (9)(10)(11)(12)(34)(35)(36)(37). Early association studies have employed a candidate gene approach, which has led to the identification of several key genes that may serve as potential predictors of radiation-induced toxicities, including ATM, base excision repair genes (XRCC1-5), mismatch repair genes (MSH2, MLH1), and oxidative damage-detoxification genes (GSTM1, GSTT1) (38)(39)(40)(41)(42)(43)(44)(45). As we shift from candidate gene approach to genome-wide association studies, such as the multi-centered RAPPER (Radiogenomics: Assessment of Polymorphisms for Predicting the Effects of Radiotherapy) study (46), more genetic polymorphisms associated with radio-toxicity have been identified.…”

Section: Discussionmentioning

confidence: 99%

Genomic Profiling Reveals Novel Predictive Biomarkers for Chemo-Radiotherapy Efficacy and Thoracic Toxicity in Non-Small-Cell Lung Cancer

Zhang²,

Pang³

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

Chemo-radiotherapy (CRT) remains the main treatment modality for non-small-cell lung cancer (NSCLC). However, its clinical efficacy is largely limited by individual variations in radio-sensitivity and radiotherapy-associated toxicity. There is an urgent need to identify genetic determinants that can explain patients’ likelihood to develop recurrence and radiotherapy-associated toxicity following CRT. In this study, we performed comprehensive genomic profiling, using a 474-cancer- and radiotherapy-related gene panel, on pretreatment biopsy samples from patients with unresectable stage III NSCLCs who underwent definitive CRT. Patients’ baseline clinical characteristics and genomic features, including tumor genetic, genomic and molecular pathway alterations, as well as single nucleotide polymorphisms (SNPs), were correlated with progression-free survival (PFS), overall survival (OS), and radiotherapy-associated pneumonitis and/or esophagitis development after CRT. A total of 122 patients were enrolled between 2014 and 2019, with 84 (69%) squamous cell carcinomas and 38 (31%) adenocarcinomas. Genetic analysis confirmed the association between the KEAP1-NRF2 pathway gene alterations and unfavorable survival outcome, and revealed alterations in FGFR family genes, MET, PTEN, and NOTCH2 as potential novel and independent risk factors of poor post-CRT survival. Combined analysis of such alterations led to improved stratification of the risk populations. In addition, patients with EGFR activating mutations or any oncogenic driver mutations exhibited improved OS. On the other hand, we also identified genetic markers in relation to radiotherapy-associated thoracic toxicity. SNPs in the DNA repair-associated XRCC5 (rs3835) and XRCC1 (rs25487) were associated with an increased risk of high-grade esophagitis and pneumonitis respectively. MTHFR (rs1801133) and NQO1 (rs1800566) were additional risk alleles related to higher susceptibility to pneumonitis and esophagitis overall. Moreover, through their roles in genome integrity and replicative fidelity, somatic alterations in ZNF217 and POLD1 might also serve as risk predictors of high-grade pneumonitis and esophagitis. Taken together, leveraging targeted next-generating sequencing, we identified a set of novel clinically applicable biomarkers that might enable prediction of survival outcomes and risk of radiotherapy-associated thoracic toxicities. Our findings highlight the value of pre-treatment genetic testing to better inform CRT outcomes and clinical actions in stage III unresectable NSCLCs.

show abstract

Genetic Variants of DNA Repair Genes as Predictors of Radiation-Induced Subcutaneous Fibrosis in Oropharyngeal Carcinoma

Cited by 10 publications

References 51 publications

Extreme acute radiation‐induced toxicity in a patient with polymorphous low‐grade adenocarcinoma of the nasopharynx and rare variants in DNA repair genes

Extreme acute radiation‐induced toxicity in a patient with polymorphous low‐grade adenocarcinoma of the nasopharynx and rare variants in DNA repair genes

NBN, RAD51 and XRCC3 Polymorphisms as Potential Predictive Biomarkers of Adjuvant Radiotherapy Toxicity in Early HER2-Positive Breast Cancer

Genomic Profiling Reveals Novel Predictive Biomarkers for Chemo-Radiotherapy Efficacy and Thoracic Toxicity in Non-Small-Cell Lung Cancer

Contact Info

Product

Resources

About