Genomic Analysis of Exceptional Responders to Low-Dose Radiation Therapy Reveals Somatic Mutations in ATM

Abstract

Molecular determinants of clinical response to radiation therapy (RT) are poorly understood. Exceptional responders achieving long-term disease control (LTDC) in response to palliative RT allow for investigation of tumor response to genetic alterations. Double-strand breaks (DSBs) are thought to be the most lethal RT-induced DNA aberration. ATM is critical in the DSB damage response (DDR), and germline ATM mutations result in ataxia-telangiectasia (A-T) syndrome. ATM loss sensitizes to ionizing radiation (IR). We investigate two institutional databases (IDB) to identify exceptional responders to RT and their associated genetic alterations. We hypothesize that mutations in DDR genes, specifically ATM, will exhibit marked radiosensitivity to low-dose RT. Analysis of an IDB of 75 head and neck (H&N) RT cases identified 1 patient (pt) with LTDC. Targeted sequencing of this pt identified a frameshift mutation in ATM. We then searched an IDB of 2,250 pts with targeted panel sequencing to identify additional ATM mutated tumors. Inclusion criteria included low-dose RT to gross disease, >3 months follow-up, adequate imaging, and only one active malignancy. The Cancer Genome Atlas (TCGA) data was then analyzed to identify the frequency of DNA repair gene mutations. We identified 7 pts with LTDC to low-dose RT and truncating ATM mutations (Table 1). The pt identified by the H&N DB presented with an invasive squamous cell carcinoma (SCC) of the oral tongue. She demonstrated complete metabolic resolution of disease and remains disease-free 34 months post-RT, without subsequent therapy. The remaining pts also demonstrated exceptional responses, with a median time to LR of 3.6 years, with 29% developing LR. Analysis of 26 DNA repair genes involved in non-homologous end joining, which are similarly linked to in vitro RT sensitivity, was performed on TCGA data. Mutations were observed in 22% of 7981 tumors across 24 cancers, with ATM mutations being the most prevalent (16.7%). This small cohort suggests that exceptional response to radiotherapy may be determined by mutations in DNA repair genes such as ATM. Identifying patients with alterations in DNA repair genes may offer novel opportunities for RT in previously palliative settings.Tabled 1Abstract 1076; Table 1. Characteristics of Patients with ATM Mutations. LC: local control. FB: had two sites treated at two time points. Mutation Types:∗ Nonsense ‡: Frameshift ¥: Splice SitePatientCancer TypeATM MutationRT TargetRT Dose / Fraction (Gy)In-Field RecurrenceDuration of LC (Months)QRH&N SCCI1453‡Oral Tongue44.4 / 12No34.5FBEndometrialG1370¥L3-L436 / 12No52.5Right Presacral36 / 12No33.7AMNon-Small Cell LungQ71‡Whole Brain37.5 / 15Yes43.2NOBreastD1548M‡Whole Brain37.5 / 15Yes41.0CAColonR1875*Abdominal Metastasis30 / 10No3.8AAColonR1898*Pelvis37.5 / 15No3.9GKJNon-Small Cell LungI1441‡ Q1331HNeck & Upper Mediastinum50.4 / 28No3.1 Open table in a new tab