Mechanisms and Predictors of Unusual Radiation or Chemotherapy Toxicity

In general, the toxicity of radiation therapy and chemotherapy exhibits a strong
dose-response relationship. However, patients receiving similar doses still exhibit a range
of toxicity responses due to a variety of factors, including comorbid conditions, disease
(cancer) specific factors, and inter-individual genetic variation. A very small percentage
of patients experience side effects that are either extremely severe or extremely mild
compared to the majority of patients for the dose of radiation or chemotherapy given.
Currently, the reasons for this are not entirely clear, but likely relate to patient
specific factors such as immune response, cell/tissue repair capacity and other factors that
fundamentally rely on rare genetic variations at loci involved in these responses. For
example, patients with homozygous deletions in DNA damage response genes such as ATM are
uniquely sensitive to DNA damaging agents. Many patients with severe, homozygous mutations
in such genes have other sequela that lead to medical recognition of the syndrome prior to
therapy. The investigators hypothesize that patients with unusually severe toxicity from
therapy that do not exhibit classical signs of homozygous mutation syndromes are
heterozygous for nonfunctional or hypofunctional alleles at these loci, such that the defect
is only uncovered under the relatively acute, severe stress on that pathway by radiation or
chemotherapy. Conversely, patients with very mild reactions could exhibit rare
variants/combinations of variants that make them uniquely resistant to chemotherapy or
radiotherapy toxicity.

The purpose of the study is to better understand these mechanisms with the eventual goal of
developing predictive markers that will allow us to help individually tailor cancer therapy
is in future patients. Will accomplish these goals by studying a variety of factors from a
single vial of blood. These will include circulating proteins and hormones, circulating
cells and the levels and sequences of white blood cell DNA or RNA using a variety of
techniques including but not limited to determination of cytokine/hormone levels, proteomic
analysis, immunocytochemical assays, whole exome sequencing and qPCR.