A three-stage genome-wide association study identifies a susceptibility locus for late radiotherapy toxicity at 2q24.1

Abstract

There is increasing evidence supporting the role of genetic variants in the development of radiation-induced toxicity. However, previous candidate gene association studies failed to elucidate the common genetic variation underlying this phenotype, which could emerge years after the completion of treatment. We performed a genome-wide association study on a Spanish cohort of 741 individuals with prostate cancer treated with external beam radiotherapy (EBRT). The replication cohorts consisted of 633 cases from the UK and 368 cases from North America. One locus comprising TANC1 (lowest unadjusted P value for overall late toxicity=6.85×10(-9), odds ratio (OR)=6.61, 95% confidence interval (CI)=2.23-19.63) was replicated in the second stage (lowest unadjusted P value for overall late toxicity=2.08×10(-4), OR=6.17, 95% CI=2.25-16.95; Pcombined=4.16×10(-10)). The inclusion of the third cohort gave unadjusted Pcombined=4.64×10(-11). These results, together with the role of TANC1 in regenerating damaged muscle, suggest that the TANC1 locus influences the development of late radiation-induced damage.

Genetic Risk Factors for Radiation Vasculopathy

“…[23][24][25][26][27][28] None of the genetic variants identified in this study emerged as risk factors in these prior investigations.…”

Integrated proteo-genomic approach for early diagnosis and prognosis of cancer

“…With surgery and chemotherapy, radiation therapy is also one of the highly effective treatments and plays a prominent role in cancer prognosis [78,79]. Studies have identified biomarkers which showed some predictive of patient response to drug treatment [80].…”

“…Radiation induced late toxicity can considerably limit treatment frequency and it has negative impact in tumor control. Moreover, late radiation-induced toxicity negatively impact the quality of life of survivors [79]. It is clinically well established that some of the patients are sensitive to ionizing radiations which may trigger radiation-induced toxicities.…”

In vitro prediction of breast cancer therapy toxicity

“…Directly demonstrating a genetic factor contributing to non-syndromic human radiosensitivity, a large genomewide association study with requisite power demonstrated a novel candidate radiosensitivity gene, TANC1, within a defined genomic region in a RS prostate cancer cohort compared to control (14). Mutations in this gene were associated with late RT toxicity.…”