Abstract
Radiation therapy is a mainstay of cancer treatment, yet the molecular determinants of clinical response are poorly understood. We identified exceptional responders to radiotherapy based on clinical response, and investigated the associated tumor sequencing data in order to identify additional patients with similar mutations. Among head and neck squamous cell cancer patients receiving palliative radiotherapy at our institution, we identified one patient with documented complete metabolic response. Targeted sequencing analysis of the tumor identified a somatic frame-shift mutation in ATM, a gene known to be associated with radio-sensitivity in the germline. To validate the association of somatic ATM mutation with radiotherapy response, we identified eight patients with ATM truncating mutations who received radiotherapy, all of whom demonstrated excellent responses with a median local control period of 4.62 years. Analysis of 22 DNA repair genes in The Cancer Genome Atlas (TCGA) data revealed mutations in 15.9% of 9064 tumors across 24 cancer types, with ATM mutations being the most prevalent. This is the first study to suggest that exceptional responses to radiotherapy may be determined by mutations in DNA repair genes. Sequencing of DNA repair genes merits attention in larger cohorts and may have significant implications for the personalization of radiotherapy.
Highlights
Patients with metastatic head and neck cancer or locally advanced disease and poor performance status often receive palliative radiotherapy (RT)
We discuss genomic analysis of tumor sequencing data to identify patients with a DNA repair mutation that may be a determinant of clinical response
We examined The Cancer Genome Atlas (TCGA) data to identify the frequency of mutations in 22 DNA repair genes involved in the non-homologous end joining (NHEJ) pathway [8] across 24 cancer types (Table 2)
Summary
Patients with metastatic head and neck cancer or locally advanced disease and poor performance status often receive palliative radiotherapy (RT). Some patients respond better than anticipated to palliative RT and achieve long-term disease control. We examine patients at our institution who received palliative RT for head and neck squamous cell cancers (HNSCC) and identified a patient with long-term disease control (Figure 1a). Targeted sequencing analysis of the tumor revealed a frame-shift mutation in ATM, a gene centrally involved in the DNA damage response. To further investigate the role of ATM in tumor response, we www.impactjournals.com/oncotarget examined a separate institutional database of patients who underwent targeted sequencing analysis and identified eight patients with similar ATM mutations that received palliative RT, all of whom appeared to have excellent responses (Figure 1b)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
