Enrichment of Targetable Mutations in the Relapsed Neuroblastoma Genome.

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.

Telomerase in cancer and aging.

The telomere-telomerase hypothesis is the science of cellular aging (senescence) and cancer. The ends of chromosomes, telomeres, count the number of divisions a cell can undergo before entering permanent growth arrest. As divisions are being counted, events occur on the cellular and molecular level, which may either delay or hasten this arrest. As humans age, a particular concern is the accumulation of events that lead to the progression of cancer. Telomerase is a mechanism that most normal cells do not possess, but almost all cancer cells acquire, to overcome their mortality and extend their lifespan. This review aims to provide a comprehensive understanding of the role of telomerase in cancer development, progression, diagnosis, and in the future, treatment. The ultimate goal of telomerase research is to use our understanding to develop anti-telomerase therapies, an almost universal tumor target.