Pathogenic ATM Mutations in Cancer and a Genetic Basis for Radiotherapeutic Efficacy
| Autor: | Dana L. Casey, Luc G. T. Morris, Nadeem Riaz, Timothy A. Chan, Howard I. Scher, Robert M. Samstein, Lior Z. Braunstein, Xinmao Song, Kenneth L. Pitter, Margaret Hannum, Diana Mandelker, Isabella Pecorari, Paul B. Romesser, Christopher A. Barker, Jeremy Setton, Atif J. Khan, Joachim Yahalom, Nancy Y. Lee, Isaac X Pei, Jennifer Ma, Kaled M. Alektiar, Yue C Lu, Christopher H. Crane, S.N. Powell, Jorge S. Reis-Filho, Biko McMillan, Michael J. Zelefsky, Jonine L. Bernstein, Zhigang Zhang, Andreas Rimner, Britta Weigelt |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
Male Oncology Cancer Research medicine.medical_specialty Adolescent medicine.medical_treatment Mutation Missense Ataxia Telangiectasia Mutated Proteins medicine.disease_cause Radiation Tolerance Germline Cohort Studies Young Adult 03 medical and health sciences 0302 clinical medicine Neoplasms Internal medicine medicine Humans Cumulative incidence Gene Silencing Allele Child Alleles Aged 030304 developmental biology Aged 80 and over 0303 health sciences Mutation business.industry Editorials Cancer Middle Aged medicine.disease Radiation therapy Tumor progression 030220 oncology & carcinogenesis Ataxia-telangiectasia Female Tumor Suppressor Protein p53 business |
| Zdroj: | J Natl Cancer Inst |
| ISSN: | 1460-2105 0027-8874 |
| DOI: | 10.1093/jnci/djaa095 |
| Popis: | Background Radiation therapy is one of the most commonly used cancer therapeutics but genetic determinants of clinical benefit are poorly characterized. Pathogenic germline variants in ATM are known to cause ataxia-telangiectasia, a rare hereditary syndrome notable for marked radiosensitivity. In contrast, somatic inactivation of ATM is a common event in a wide variety of cancers, but its clinical actionability remains obscure. Methods We analyzed 20 107 consecutively treated advanced cancer patients who underwent targeted genomic sequencing as part of an institutional genomic profiling initiative and identified 1085 harboring a somatic or germline ATM mutation, including 357 who received radiotherapy (RT). Outcomes of irradiated tumors harboring ATM loss-of-function (LoF) mutations were compared with those harboring variants of unknown significance. All statistical tests were 2-sided. Results Among 357 pan-cancer patients who received 727 courses of RT, genetic inactivation of ATM was associated with improved radiotherapeutic efficacy. The 2-year cumulative incidence of irradiated tumor progression was 13.2% vs 27.5% for tumors harboring an ATM LoF vs variant of unknown significance allele, respectively (hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.34 to 0.77, P = .001). The greatest clinical benefit was seen in tumors harboring biallelic ATM inactivation (HR = 0.19, 95% CI = 0.06 to 0.60, P = .005), with statistically significant benefit also observed in tumors with monoallelic ATM inactivation (HR = 0.57, 95% CI = 0.35 to 0.92, P = .02). Notably, ATM LoF was highly predictive of outcome in TP53 wild-type tumors but not among TP53-mutant tumors. Conclusions We demonstrate that somatic ATM inactivation is associated with markedly improved tumor control following RT. The identification of a radio-sensitive tumor phenotype across multiple cancer types offers potential clinical opportunities for genomically guided RT. |
| Databáze: | OpenAIRE |
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