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

Abstract

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.

Molecular Profile of Important Genes for Radiogenomics in the Amazon Indigenous Population

“…Polymorphisms in the RAD51 gene have been associated in previous studies with symptoms of heart failure and the appearance of a new primary tumor in patients with breast cancer treated with trastuzumab and RT [6], suggesting an important gene for RTX; however, such polymorphisms were not detected in the population studied. Other studies have also investigated variations in DNA repair genes-such as ATM, RAD51, and XRCC4-that cause differences in the response to radiation between individuals.…”

“…Gene expression is more frequent in certain tumor tissues and implies a lower survival rate, tumor progression, immunosuppression, radioresistance, and worse prognosis [29,30]. It is associated with radiotoxicity in HER2-positive breast cancer [6].…”

“…Mucositis, xerostomia, subcutaneous fibrosis, and dysphagia [4] occur with squamous cell carcinoma; esophagitis may occur with radiation to the lung [5]. RT to the chest can cause pain, fibrosis, upper limb edema, pericarditis, and ischemic and valvular heart disease [6]. RT in the prostate can lead to dermatitis, urinary incontinence, and bladder and erectile dysfunction [7].…”

Harnessing Epigenetics for Breast Cancer Therapy: The Role of DNA Methylation, Histone Modifications, and MicroRNA

“…Mutations and polymorphisms in them can lead to abnormal cell growth, which can lead to the development of cancer. Among the genes that are associated with the development and progression of breast cancer, the following are currently listed [ 8 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]: BRCA1 and BRCA2 genes, which have the best documented association with breast cancer; having a mutation in these genes is responsible for a 50–80% risk of breast cancer and a 45% risk of ovarian cancer before the age of 85—with a mutation in the BRCA1 gene and a 31–56% risk of breast cancer and 11–27% of ovarian cancer in BRCA2 mutation [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]; the PALB2 gene, which is responsible for the repair of damaged DNA; carriers of the defective gene have a 35% risk of developing breast cancer before the age of 70 [ 31 , 32 , 33 , 34 , 35 , 36 ]; the CHEK2 gene, which is responsible for the production of a protein that inhibits tumor growth; women with a mutation in this gene have a twice as high a risk of developing breast cancer compared to the general population [ 37 , 38 , 39 , 40 , 41 , 42 ]; the NBN gene, which encodes a protein regulating the DNA repair process and maintaining chromosome stability [ 43 , 44 , 45 , 46 , ...…”

“…the NBN gene, which encodes a protein regulating the DNA repair process and maintaining chromosome stability [ 43 , 44 , 45 , 46 , 47 ];…”