Genomic analysis of exceptional responders to radiotherapy reveals somatic mutations in ATM

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.

Keywords: radiation therapy; somatic ATM mutations.

Figure 1. Identification of long-term survivors with ATM frameshift or truncating mutations demonstrating good responses to radiotherapy

a. Institutional database of palliative Quad Shot RT revealed 1 SCC patient with long-term disease control. b. Institutional sequencing database (MSK-IMPACT) identifies 8 patients with good responses to RT.

Figure 2. Pre- and post-therapy imaging for patient A

*MIP: Fludeoxyglucose (¹⁸F) positron emission tomography (FDG-PET) maximum intensity projection (MIP). a) Pre-radiotherapy PET/CT demonstrates primary oral tongue SCC with SUV of 35.4 with FDG avid level Ib and II lymph nodes. b) Three month post-RT PET/CT demonstrates complete resolution of FDG avid malignancy.

Figure 3. Pre- and post-therapy imaging for patient B

a. Pre-radiotherapy PET/CT demonstrating a para-spinal mass involving the L4 vertebral body. b. Post-radiotherapy PET/CT and MRI demonstrating treatment response at L3-L4 and an out-of-field recurrence in a right pre-sacral lymph node. d. Post-radiotherapy MRI demonstrating reduction in size of the right pre-sacral lymph node.

Figure 4. Analysis of TCGA data to identify frequency of DNA repair mutations

a. Analysis of 22 DNA repair related genes involved in NHEJ. a) 9064 tumor samples were examined across 24 cancer types, with 15.9% of tumors exhibiting at least one alteration among the 22 genes. ATM was the most highly mutated, with 19.6% of tumors exhibiting some type of ATM alteration. b. Prevalence of NHEJ pathway alterations are listed by cancer type. The most commonly mutated gene within the pathway, for each cancer type, is listed below the corresponding cancer type. ATM was the most commonly mutated gene in fifteen of the 24 cancer types (62.5%). Red text identifies cancers for which radiation is used as standard of care as either definitive or adjuvant treatment. Adrenocortical carcinoma [ACC], Bladder Urothelial Carcinoma [BLCA], Glioblastoma multiforme [GBM], Head and Neck squamous cell carcinoma [HNSC], Kidney Chromophobe [KICH], Kidney renal clear cell carcinoma [KIRC], Kidney renal papillary cell carcinoma [KIRP], Brain Lower Grade Glioma [LGG], Lung adenocarcinoma [LUAD], Lung squamous cell carcinoma [LUSC], Pheochromocytoma and Paraganglioma [PCPG], Skin Cutaneous Melanoma [SKCM], Uterine Corpus Endometrial Carcinoma [UCEC], Uterine Carcinosarcoma [UCS].

Figure 5. Kaplan-Meier analysis of local recurrence data for 8 patients with truncating and frameshift ATM mutations treated with radiotherapy to gross disease, in years

Median time to in-field local recurrence is 4.62 years (range: 0.26-5.64). Two of the eight patients developed an in-field recurrence.