Chromosomal and telomeric biomarkers of normal tissue injury to evaluate risk of degenerative health effects (secondary malignancy, cardiovascular disease) post radiation therapy

An overall intent of radiotherapy is to precisely target tumor cells, while minimizing exposures to surrounding normal tissue. Despite successes in this area, there is growing concern that an unacceptably large volume of normal tissue is unavoidably exposed. Chromosome aberrations provide a direct measure of ionizing radiation (IR)-induced DNA damage, as well as an indirect measure of future risk since they are associated with virtually all known cancers. Such structural variants (SVs) include translocations (rearrangements between chromosomes) and inversions (rearrangements within chromosomes), the latter being recently identified as part of a distinctive mutational signature associated with radiation therapyinduced second malignancies. Directional Genomic Hybridization (dGH), is a strand-specific cytogenomicsbased methodology for cell-by-cell, high-resolution detection of all SVs—particularly inversions—which when combined with compatible telomere probes, can also be used to assess telomere length dynamics, as well as validate a variety of changes involving chromosomal termini. Telomeres are critical structural elements that serve to protect the physical ends of chromosomes. Dysfunctional telomeres are associated with instability and carcinogenesis, as well as with a variety of other age-related degenerative pathologies, including cardiovascular disease (CVD). We introduce Telomere-dGH (Telo-dGH) as a prospective “personalized” approach for monitoring of radiation oncology patients, in order to evaluate chromosomal and telomeric alterations as biomarkers of normal tissue injury. Such a strategy has the potential to improve both evaluation and management of risk associated with degenerative late effects across a variety of cancer types (e.g., prostate, pediatric brain), and in connection with various radiation treatment modalities [e.g., intensity-modulated radiation therapy (IMRT), protons, carbon ions].