Oncotarget

Research Papers:

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

Jennifer Ma, Jeremy Setton, Luc Morris, Pedro Blecua Carrillo Albornoz, Christopher Barker, Benjamin H. Lok, Eric Sherman, Nora Katabi, Kathryn Beal, Ian Ganly, Simon N. Powell, Nancy Lee, Timothy A. Chan _ and Nadeem Riaz

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2017; 8:10312-10323. https://doi.org/10.18632/oncotarget.14400

Metrics: PDF 1651 views  |   HTML 2616 views  |   ?  


Abstract

Jennifer Ma1, Jeremy Setton1, Luc Morris2, Pedro Blecua Carrillo Albornoz1, Christopher Barker1, Benjamin H. Lok1, Eric Sherman3, Nora Katabi4, Kathryn Beal1, Ian Ganly2, Simon N. Powell1, Nancy Lee1, Timothy A. Chan1,5, Nadeem Riaz1

1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

2Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA

3Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

4Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

5Human Oncology and Pathogenesis, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Correspondence to:

Nadeem Riaz, email: riazn@mskcc.org

Timothy A. Chan, email: chant@mskcc.org

Keywords: somatic ATM mutations, radiation therapy

Received: May 24, 2016    Accepted: November 30, 2016    Published: December 31, 2016

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 14400