Individual patient data meta-analysis shows a significant association between the ATM rs1801516 SNP and toxicity after radiotherapy in 5456 breast and prostate cancer patients

Abstract

Purpose Several small studies have indicated that the ATM rs1801516 SNP is associated with risk of normal tissue toxicity after radiotherapy. However, the findings have not been consistent. In order to test this SNP in a well-powered study, an individual patient data meta-analysis was carried out by the International Radiogenomics Consortium. Materials and methods The analysis included 5456 patients from 17 different cohorts. 2759 patients were given radiotherapy for breast cancer and 2697 for prostate cancer. Eight toxicity scores (overall toxicity, acute toxicity, late toxicity, acute skin toxicity, acute rectal toxicity, telangiectasia, fibrosis and late rectal toxicity) were analyzed. Adjustments were made for treatment and patient related factors with potential impact on the risk of toxicity. Results For all endpoints except late rectal toxicity, a significantly increased risk of toxicity was found for carriers of the minor (Asn) allele with odds ratios of approximately 1.5 for acute toxicity and 1.2 for late toxicity. The results were consistent with a co-dominant pattern of inheritance. Conclusion This study convincingly showed a significant association between the ATM rs1801516 Asn allele and increased risk of radiation-induced normal tissue toxicity.

Genomics models in radiotherapy: From mechanistic to machine learning

“…RgC members have found and validated SNPs associated with late skin, fibrotic, and overall toxicity after breast cancer radiotherapy upstream to inflammatory cytokine TNFA (rs1800629, rs2857595) and within base‐excision repair gene XRCC1 (rs2682585) . A large meta‐analysis validated the association of rs1801516 in DNA double‐strand break (DSB) repair gene ATM with several acute and late toxicities in breast and prostate cancer, thus mimicking a milder phenotype of ataxia‐telangiectasia syndrome . The Liao group has identified and validated SNPs to predict for Grade ≥ 3 toxicity after lung cancer radiotherapy.…”

Radiogenomics and radiotherapy response modeling

“…SNP rs2868371 in HSPB1 was associated with multiple late complications in lung cancer radiotherapy patients (Pang et al , 2013; Guerra et al , 2012) including pneumonitis and esophagitis. In a large individual patient data meta-analysis of over 5,000 breast and prostate cancer patients, rs1801516, a protein coding SNP in ATM , was associated with overall acute and late toxicity (Andreassen et al , 2016). …”

Radiogenomics: Identification of Genomic Predictors for Radiation Toxicity

“…A study of more than 5,000 patients treated for either breast or prostate cancer with radiotherapy reported an association between the rs1801516 in the ATM gene with ORs of 1.5 for acute and 1.2 for late toxicity 49 .…”