Abstract
Cancer is the second most common cause of death in developed nations, and incidence is rising among
developing nations. An estimated 70% of cancers are attributable to “modifiable” risk factors, including obesity,
chronic inflammatory diseases, and poor diet, all of which have been associated with increased oxidative
stress. These are not themselves “carcinogenetic”, but they are thought to act as “cancer promoters”,
increasing the probability of developing cancer. With advances in whole genome sequencing and development
of computational techniques to examine the cancer genome, we can now use mathematical profiling of somatic
mutational profiles (termed mutational signatures) to identify potential causes underlying a given tumor (e.g.,
smoking versus UV light). It remains unclear, however, if there is a mutational signature that is a biomarker of
cumulative lifetime exposure to reactive oxygen species (ROS)-mediated DNA damage and if this correlates
with cancer-associated lifestyle factors. Here, we will utilize cutting-edge multi-omic profiling and molecular
biology and computational tools to better understand the contribution/mechanism of oxidative stress as a
cancer promoter.
To examine the correlation of ROS mutational signature levels and inflammation-related cancer risk
factors, we will perform whole genome sequencing and mutational signature analysis of a large cohort of
colorectal tumors from patients with detailed, longitudinally collected lifestyle data (e.g., smoking, caloric
intake, red meat intake, exercise level, etc.) collected by the Molecular Epidemiology of Colorectal Cancer
study. We will also evaluate whether accumulation of ROS-generated mutations is biased toward CTCF
binding loci and whether chromosomal architecture is modified by exposure to carcinogens or cancer-
associated processes, thereby mediating unique “epigenomic signatures”. These aims will also provide data
that can be used in the development of two novel computational tools for the analysis of cancer driver
mutational signatures and epigenomic signatures of carcinogen exposure.
Finally, we will test the molecular and clinical benefit of intermittent fasting during daily radiation therapy
based on the hypothesis that lifestyle factors could modulate susceptibility to ROS mutagenesis. Patient-
reported quality of life and clinician-reported adverse events, as well as molecular assay for tissue-specific
levels of ROS-associated DNA damage, will allow us to assess whether intermittent fasting can reduce normal
tissue toxicity. Successful completion of the proposed research will provide a comprehensive examination of
the epidemiology and mechanism of ROS-mediated DNA damage in human cancers and demonstrate the
safety and potential efficacy of intermittent fasting as a clinically translatable and easily adaptable approach to
reducing both acute and chronic side effects associated with radiotherapy.