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Ref Type Journal Article
PMID (28055970)
Authors Ma J, Setton J, Morris L, Albornoz PB, Barker C, Lok BH, Sherman E, Katabi N, Beal K, Ganly I, Powell SN, Lee N, Chan TA, Riaz N
Title Genomic analysis of exceptional responders to radiotherapy reveals somatic mutations in ATM.
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Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ATM Q1331H missense unknown ATM Q1331H does not lie within any known functional domains of the Atm protein (UniProt.org). Q1331H has been identified in the scientific literature (PMID: 28055970), but has not been biochemically characterized and therefore, its effect on Atm protein function is unknown (PubMed, Jul 2024).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ATM Q1331H ATM I1441fs lung non-small cell carcinoma predicted - sensitive Radiotherapy Case Reports/Case Series Actionable In a retrospective analysis, radiotherapy treatment resulted in 3.1 months of local disease control and no in-field recurrence in a patient with non-small cell lung cancer harboring ATM I1441fs and Q1331H (PMID: 28055970). 28055970
ATM L2738* thyroid cancer predicted - sensitive Radiotherapy Case Reports/Case Series Actionable In a retrospective analysis, radiotherapy treatment resulted in 5.16 months of local disease control and no in-field recurrence in a patient with thyroid cancer harboring ATM L2738* (PMID: 28055970). 28055970
ATM R1898* colon cancer predicted - sensitive Radiotherapy Case Reports/Case Series Actionable In a retrospective analysis, radiotherapy treatment resulted in 3.9 months of local disease control and no in-field recurrence in a patient with colon cancer harboring ATM R1898* (PMID: 28055970). 28055970
ATM R1875* colon cancer predicted - sensitive Radiotherapy Case Reports/Case Series Actionable In a retrospective analysis, radiotherapy treatment resulted in 3.8 months of local disease control and no in-field recurrence in a patient with colon cancer harboring ATM R1875* (PMID: 28055970). 28055970
ATM I1453fs tongue squamous cell carcinoma predicted - sensitive Radiotherapy Case Reports/Case Series Actionable In a retrospective analysis, radiotherapy treatment resulted in a complete metabolic response lasting at least 34 months in a patient with squamous cell carcinoma of the tongue, and the patient was found to harbor ATM I1453fs (PMID: 28055970). 28055970