Journal Article

Enrichment of Targetable Mutations in the Relapsed Neuroblastoma Genome

Padovan-Merhar, Olivia M., Miller, Vincent A., Ostrovnaya, Irina, Kalletla, Karthik, Mossé, Yael P., Weiss, Brian, Maris, John M., Rubnitz, Kaitlyn R., Sanford, Eric M., Granger, Meaghan P., Raman, Pichai, Ali, Siraj M., Modak, Shakeel

2016

Overview

Neuroblastoma is characterized by a relative paucity of recurrent somatic mutations at diagnosis. However, recent studies have shown that the mutational burden increases at relapse, likely as a result of clonal evolution of mutation-carrying cells during primary treatment. To inform the development of personalized therapies, we sought to further define the frequency of potentially actionable mutations in neuroblastoma, both at diagnosis and after chemotherapy. We performed a retrospective study to determine mutation frequency, the only inclusion criterion being availability of cancer gene panel sequencing data from Foundation Medicine. We analyzed 151 neuroblastoma tumor samples: 44 obtained at diagnosis, 42 at second look surgery or biopsy for stable disease after chemotherapy, and 59 at relapse (6 were obtained at unknown time points). Nine patients had multiple tumor biopsies. ALK was the most commonly mutated gene in this cohort, and we observed a higher frequency of suspected oncogenic ALK mutations in relapsed disease than at diagnosis. Patients with relapsed disease had, on average, a greater number of mutations reported to be recurrent in cancer, and a greater number of mutations in genes that are potentially targetable with available therapeutics. We also observed an enrichment of reported recurrent RAS/MAPK pathway mutations in tumors obtained after chemotherapy. Our data support recent evidence suggesting that neuroblastomas undergo substantial mutational evolution during therapy, and that relapsed disease is more likely to be driven by a targetable oncogenic pathway, highlighting that it is critical to base treatment decisions on the molecular profile of the tumor at the time of treatment. However, it will be necessary to conduct prospective clinical trials that match sequencing results to targeted therapeutic intervention to determine if cancer genomic profiling improves patient outcomes.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adolescent / Adult / Aged / Anaplastic Lymphoma Kinase / Biology and Life Sciences / Biopsy / Cancer / Cancer therapies / Chemotherapy / Child / Child, Preschool / Children & youth / Clinical outcomes / Clinical trials / Clonal Evolution - genetics / Colleges & universities / Deoxyribonucleic acid / DNA / Female / Funding / Gene amplification / Genomes / High-Throughput Nucleotide Sequencing / Hospitals / Humans / Infant / Infant, Newborn / Male / MAP Kinase Signaling System - genetics / Medical research / Medicine / Medicine and Health Sciences / Middle Aged / Mutation / Mutation - genetics / Neoplasm Recurrence, Local - drug therapy / Neoplasm Recurrence, Local - genetics / Neoplasm Recurrence, Local - pathology / Neuroblastoma / Neuroblastoma - drug therapy / Neuroblastoma - genetics / Neuroblastoma - pathology / Neuroblastoma - surgery / Patients / Pediatrics / Physicians / ras Proteins - genetics / Receptor Protein-Tyrosine Kinases - genetics / Retrospective Studies / Tumors