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Impact of ATM rs1801516 on late skin reactions of radiotherapy for breast cancer: Evidences from a cohort study and a trial sequential meta-analysis.

ABSTRACT: The relationship between the ataxia-telangiectasia mutated (ATM) rs1801516 gene polymorphism and risk of radiation-induced late skin side effects remains a highly debated issue. In the present study, we assessed the role of ATM rs1801516 as risk factor for radiation-induced fibrosis and telangiectasia, using the LENT-SOMA scoring scale in 285 breast cancer patients who received radiotherapy after breast conserving surgery. A systematic review with meta-analysis and trial sequential analysis (TSA) was then conducted to assess reliability of the accumulated evidence in breast cancer patients. In our cohort study, no association was found between ATM rs1801516 and grade ? 2 telangiectasia (GA+AA vs GG, HRadjusted: 0.699; 95%CI: 0.273-1.792, P = 0.459) or grade ? 2 fibrosis (GA+AA vs GG, HRadjusted: 1.175; 95%CI: 0.641-2.154, P = 0.604). Twelve independent cohorts of breast cancer patients were identified through the systematic review, of which 11 and 9 cohorts focused respectively on the association with radiation-induced fibrosis and radiation-induced telangiectasia. Pooled analyses of 10 (n = 2928 patients) and 12 (n = 2783) cohorts revealed, respectively, no association of ATM rs1801516 with radiation-induced telangiectasia (OR: 1.14; 95%CI: 0.88-1.48, P = 0.316) and a significant correlation with radiation-induced fibrosis (OR: 1.23; 95%CI: 1.00-1.51, P = 0.049), which however did not remain significant after TSA adjustment (TSA-adjusted 95%CI: 0.85-1.78). These results do not support an impact of ATM rs1801516 on late skin reactions of radiotherapy for breast cancer, nevertheless further large studies are still required for conclusive evidences.

SUBMITTER: Terrazzino S

PROVIDER: S-EPMC6874351 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Impact of ATM rs1801516 on late skin reactions of radiotherapy for breast cancer: Evidences from a cohort study and a trial sequential meta-analysis.

Terrazzino Salvatore S Cargnin Sarah S Deantonio Letizia L Pisani Carla C Masini Laura L Canonico Pier Luigi PL Genazzani Armando A AA Krengli Marco M

PloS one 20191122 11

The relationship between the ataxia-telangiectasia mutated (ATM) rs1801516 gene polymorphism and risk of radiation-induced late skin side effects remains a highly debated issue. In the present study, we assessed the role of ATM rs1801516 as risk factor for radiation-induced fibrosis and telangiectasia, using the LENT-SOMA scoring scale in 285 breast cancer patients who received radiotherapy after breast conserving surgery. A systematic review with meta-analysis and trial sequential analysis (TSA ...[more]

PMID: 31756226

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Project description:Studies on associations between ataxia telangiectasia-mutated (ATM) polymorphisms and late radiotherapy-induced adverse events vary in clinical settings, and the results are inconsistent.We conducted the first meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to investigate the role of the ATM polymorphism rs1801516 in the development of radiotherapy-induced late fibrosis.We searched PubMed, Embase, Web of Science, and Chinese National Knowledge Infrastructure databases to identify studies that investigated the effect of the ATM polymorphism rs1801516 on radiotherapy-induced late fibrosis before September 8, 2015. Summary odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were used to assess the association between late fibrosis and the rs1801516 polymorphism. Subgroup analyses were conducted to evaluate the influence of clinical features on the genetic association. Tests of interaction were used to compare differences in the effect estimates between subgroups.The overall meta-analysis of 2000 patients from 9 studies showed that the minor allele of the rs1801516 polymorphism was associated with a significantly increased risk of developing late fibrosis (OR = 1.78, 95% CI: 1.07, 2.94), with high between-study heterogeneity (I = 66.6%, P = 0.002). In subgroup analyses, we identified that the incidence of late fibrosis was a major source of heterogeneity across studies. The OR for patients with a high incidence of late fibrosis was 3.19 (95% CI: 1.86, 5.47), in contrast to 1.09 (95% CI: 1.01, 1.17) for those with a low incidence. There was a significant difference in the effect estimates between the 2 subgroups (ratio of OR = 2.94, 95% CI 1.70, 5.08, P = 0.031).This meta-analysis supported previously reported effect of the ATM polymorphism rs1801516 on radiotherapy-induced late fibrosis. This finding encouraged further researches to identify more genetic polymorphisms that were predictive for radiotherapy-induced adverse events. In addition, we showed that the inconsistency of the associations seen in these studies might be related to variations in the incidence of late fibrosis in the patients. This suggested that future studies should consider the incidence of radiotherapy-induced adverse events when investigating radiosensitivity signature genes.

Project description:BACKGROUND:Ataxia telangiectasia mutated (ATM) gene plays a key role in response to DNA lesions and is related to the invasion and metastasis of malignancy. Epidemiological studies have indicated associations between ATM rs1801516 polymorphism and different types of cancer, but their results are inconsistent. To further evaluate the effect of ATM rs1801516 polymorphism on cancer risk, we conducted this meta-analysis. METHODS:Studies were identified according to specific inclusion criteria by searching PubMed, Web of Science, and Embase databases. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) under recessive, dominant, codominant, and overdominant models of inheritance were calculated to estimate the association between rs1801516 polymorphism and cancer risk. RESULTS:A total of 37 studies with 12,879 cases and 18,054 controls were included in our study. No significant association was found between rs1801516 polymorphism and cancer risk in overall comparisons (AA vs GG?+?GA: OR?=?0.91, 95% CI, 0.78-1.07; AA+GA vs GG: OR?=?1.00, 95% CI, 0.90-1.11; AA vs GG: OR?=?0.89, 95% CI, 0.75-1.06; GA vs GG: OR?=?1.01, 95% CI, 0.91-1.13; GG?+?AA vs GA: OR?=?1.00, 95% CI, 0.88-1.10). However, after subgroup analyses by region-specified population, significant associations were found in European (AA vs GG?+?GA: OR?=?0.79, 95% CI, 0.65-0.96, P?=?0.017; AA vs GG: OR?=?0.79, 95% CI, 0.65-0.96, P?=?0.017), South American (AA+GA vs GG: OR?=?2.15, 95% CI, 1.37-3.38, P?=?0.001; GA vs GG: OR?=?2.19, 95% CI, 1.38-3.47, P?=?0.001; GG?+?AA vs GA: OR?=?0.46, 95% CI, 0.29-0.72, P?=?0.001), and Asian (AA vs GG?+?GA: OR?=?7.45, 95% CI, 1.31-42.46, P?=?0.024; AA vs GG: OR?=?7.40, 95% CI, 1.30-42.19, P?=?0.024). Subgroup analyses also revealed that compared with subjects carrying a GG genotype, those carrying a homozygote AA had a decreased risk for breast cancer (AA vs GG: OR?=?0.76, 95% CI, 0.59-0.98, P?=?0.035), and the homozygote AA was associated with decreased cancer risk in subjects with family history (AA vs GG: OR?=?0.68, 95% CI, 0.47-0.98, P?=?0.039). CONCLUSIONS:ATM rs1801516 polymorphism is not associated with overall cancer risk in total population. However, for subgroup analyses, this polymorphism is especially associated with breast cancer risk; in addition, it is associated with overall cancer risk in Europeans, South Americans, Asians, and those with family history.

Project description:Radiation-induced normal-tissue toxicities are common, complex, and distressing side effects that affect 90% of patients receiving breast-cancer radiotherapy and 40% of patients post radiotherapy. In this study, the authors investigated the use of spectrophotometry and ultrasound to quantitatively measure radiation-induced skin discoloration and subcutaneous-tissue fibrosis. The study's purpose is to determine whether skin discoloration correlates with the development of fibrosis in breast-cancer radiotherapy.Eighteen breast-cancer patients were enrolled in our initial study. All patients were previously treated with a standard course of radiation, and the median follow-up time was 22 months. The treated and untreated breasts were scanned with a spectrophotometer and an ultrasound. Two spectrophotometer parameters-melanin and erythema indices-were used to quantitatively assess skin discoloration. Two ultrasound parameters-skin thickness and Pearson coefficient of the hypodermis-were used to quantitatively assess severity of fibrosis. These measurements were correlated with clinical assessments (RTOG late morbidity scores).Significant measurement differences between the treated and contralateral breasts were observed among all patients: 27.3% mean increase in skin thickness (p < 0.001), 34.1% mean decrease in Pearson coefficient (p < 0.001), 27.3% mean increase in melanin (p < 0.001), and 22.6% mean increase in erythema (p < 0.001). All parameters except skin thickness correlated with RTOG scores. A moderate correlation exists between melanin and erythema; however, spectrophotometer parameters do not correlate with ultrasound parameters.Spectrophotometry and quantitative ultrasound are objective tools that assess radiation-induced tissue injury. Spectrophotometer parameters did not correlate with those of quantitative ultrasound suggesting that skin discoloration cannot be used as a marker for subcutaneous fibrosis. These tools may prove useful for the reduction of radiation morbidities and improvement of patient quality of life.

Dataset Information

Impact of ATM rs1801516 on late skin reactions of radiotherapy for breast cancer: Evidences from a cohort study and a trial sequential meta-analysis.

Publications

Impact of ATM rs1801516 on late skin reactions of radiotherapy for breast cancer: Evidences from a cohort study and a trial sequential meta-analysis.

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