Kamalesh Dattaram Mumbrekar1, Satish Rao Bola Sadashiva1, Shama Prasada Kabekkodu2, Donald Jerard Fernandes3, Bejadi Manjunath Vadhiraja4, Tomo Suga5, Yoshimi Shoji5, Fumiaki Nakayama5, Takashi Imai5, Kapaettu Satyamoorthy6. 1. Department of Radiation Biology and Toxicology, School of Life Sciences, Manipal University, Manipal, Karnataka, India. 2. Department of Biotechnology, School of Life Sciences, Manipal University, Manipal, Karnataka, India. 3. Department of Radiotherapy and Oncology, Shirdi Saibaba Cancer Hospital and Research Centre, Kasturba Hospital, Manipal, Karnataka, India. 4. Department of Radiation Oncology, Manipal Hospital, Bengaluru, Karnataka, India. 5. Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan. 6. Department of Biotechnology, School of Life Sciences, Manipal University, Manipal, Karnataka, India. Electronic address: ksatyamoorthy@yahoo.com.
Abstract
PURPOSE: Heterogeneity in radiation therapy (RT)-induced normal tissue toxicity is observed in 10% of cancer patients, limiting the therapeutic outcomes. In addition to treatment-related factors, normal tissue adverse reactions also manifest from genetic alterations in distinct pathways majorly involving DNA damage-repair genes, inflammatory cytokine genes, cell cycle regulation, and antioxidant response. Therefore, the common sequence variants in these radioresponsive genes might modify the severity of normal tissue toxicity, and the identification of the same could have clinical relevance as a predictive biomarker. METHODS AND MATERIALS: The present study was conducted in a cohort of patients with breast cancer to evaluate the possible associations between genetic variants in radioresponsive genes described previously and the risk of developing RT-induced acute skin adverse reactions. We tested 22 genetic variants reported in 18 genes (ie, NFE2L2, OGG1, NEIL3, RAD17, PTTG1, REV3L, ALAD, CD44, RAD9A, TGFβR3, MAD2L2, MAP3K7, MAT1A, RPS6KB2, ZNF830, SH3GL1, BAX, and XRCC1) using TaqMan assay-based real-time polymerase chain reaction. At the end of RT, the severity of skin damage was scored, and the subjects were dichotomized as nonoverresponders (Radiation Therapy Oncology Group grade <2) and overresponders (Radiation Therapy Oncology Group grade ≥2) for analysis. RESULTS: Of the 22 single nucleotide polymorphisms studied, the rs8193 polymorphism lying in the micro-RNA binding site of 3'-UTR of CD44 was significantly (P=.0270) associated with RT-induced adverse skin reactions. Generalized multifactor dimensionality reduction analysis showed significant (P=.0107) gene-gene interactions between MAT1A and CD44. Furthermore, an increase in the total number of risk alleles was associated with increasing occurrence of overresponses (P=.0302). CONCLUSIONS: The genetic polymorphisms in radioresponsive genes act as genetic modifiers of acute normal tissue toxicity outcomes after RT by acting individually (rs8193), by gene-gene interactions (MAT1A and CD44), and/or by the additive effects of risk alleles.
PURPOSE: Heterogeneity in radiation therapy (RT)-induced normal tissue toxicity is observed in 10% of cancerpatients, limiting the therapeutic outcomes. In addition to treatment-related factors, normal tissue adverse reactions also manifest from genetic alterations in distinct pathways majorly involving DNA damage-repair genes, inflammatory cytokine genes, cell cycle regulation, and antioxidant response. Therefore, the common sequence variants in these radioresponsive genes might modify the severity of normal tissue toxicity, and the identification of the same could have clinical relevance as a predictive biomarker. METHODS AND MATERIALS: The present study was conducted in a cohort of patients with breast cancer to evaluate the possible associations between genetic variants in radioresponsive genes described previously and the risk of developing RT-induced acute skin adverse reactions. We tested 22 genetic variants reported in 18 genes (ie, NFE2L2, OGG1, NEIL3, RAD17, PTTG1, REV3L, ALAD, CD44, RAD9A, TGFβR3, MAD2L2, MAP3K7, MAT1A, RPS6KB2, ZNF830, SH3GL1, BAX, and XRCC1) using TaqMan assay-based real-time polymerase chain reaction. At the end of RT, the severity of skin damage was scored, and the subjects were dichotomized as nonoverresponders (Radiation Therapy Oncology Group grade <2) and overresponders (Radiation Therapy Oncology Group grade ≥2) for analysis. RESULTS: Of the 22 single nucleotide polymorphisms studied, the rs8193 polymorphism lying in the micro-RNA binding site of 3'-UTR of CD44 was significantly (P=.0270) associated with RT-induced adverse skin reactions. Generalized multifactor dimensionality reduction analysis showed significant (P=.0107) gene-gene interactions between MAT1A and CD44. Furthermore, an increase in the total number of risk alleles was associated with increasing occurrence of overresponses (P=.0302). CONCLUSIONS: The genetic polymorphisms in radioresponsive genes act as genetic modifiers of acute normal tissue toxicity outcomes after RT by acting individually (rs8193), by gene-gene interactions (MAT1A and CD44), and/or by the additive effects of risk alleles.
Authors: Alyssa A Rodriguez; Jessica L Wojtaszek; Briana H Greer; Tuhin Haldar; Kent S Gates; R Scott Williams; Brandt F Eichman Journal: J Biol Chem Date: 2020-09-02 Impact factor: 5.157
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Authors: K E Applegate; W Rühm; A Wojcik; M Bourguignon; A Brenner; K Hamasaki; T Imai; M Imaizumi; T Imaoka; S Kakinuma; T Kamada; N Nishimura; N Okonogi; K Ozasa; C E Rübe; A Sadakane; R Sakata; Y Shimada; K Yoshida; S Bouffler Journal: Radiat Environ Biophys Date: 2020-03-07 Impact factor: 1.925