title: 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.
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Setton
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Luc
authors.initials: L
authors.lastname: Morris
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Pedro Blecua Carrillo
authors.initials: PB
authors.lastname: Albornoz
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Barker
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lok
authors.affiliation: Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Sherman
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Nora
authors.initials: N
authors.lastname: Katabi
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Beal
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Ganly
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Powell
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Lee
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Human Oncology and Pathogenesis, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Riaz
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D019295:Computational Biology; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D016889:Endometrial Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D005260:Female; D006258:Head and Neck Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D008875:Middle Aged; D009154:Mutation; D010166:Palliative Care; D018579:Patient Selection; D057285:Precision Medicine; D011836:Radiation Tolerance / Q000235:genetics*; D011879:Radiotherapy Dosage; D012189:Retrospective Studies; D000077195:Squamous Cell Carcinoma of Head and Neck; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: radiation therapy; somatic ATM mutations