AS603 – PREcision Disease preventIon via somatiC muTagenesis enumeratION (PREDICTION)
Investigator Names and Contact Information
Jason Bielas (jbielas@fredhutch.org)
Introduction/Intent
In order to realize the promise of precision medicine, the ability to predict individuals at a high-risk for
developing a disease who may benefit from a particular intervention, more and better biomarkers are needed
to guide clinical decision making. Focusing on markers of mutagenesis is a promising strategy given that
mutation is the ultimate source of all genetic variation and genes are drivers of a number of important
pathogenic processes that can result in the development of diseases such as cancer. However, key elements
missing in the current literature evaluating mutagenesis in relation to disease risk are. We overcome these
issues through a synergistic collaboration between laboratory, clinical, and population scientists that leverages
the exceptionally sensitive next generation sequencing (NGS)-based mutational assay we developed, and
applies it to biological samples of the highest quality from both a clinical trial and the landmark Women’s Health
Initiative (WHI) study. Our overarching goal is to contribute to the realization of the promise of precision
prevention through completion of the following specific aims: 1. Characterize the frequency, distribution,
and spectrum of mutations in humans. The proposed experiments will provide the first available
measurements of random mutations throughout the genome in humans, and are designed to delineate the
impact that genomic architecture, sequence context, replication timing and transcription have on genome-wide
mutation frequency and spectra. This will be evaluated within the context of a glioblastoma clinical trial where
serial samples were collected from patients during their course of treatment with the highly mutagenic
chemotherapeutic agent temozolomide. 2. Examine the utility of somatic mutation induction as a
biomarker of mutagenic exposure and its potential to stratify smokers that develop lung cancer versus
those that do not. We will first test this hypothesis using a nested case-control design within the WHI cohort.
We will evaluate if smoking-induced mutations are directly correlated to exposure, and if mutation induction is
significantly higher in smokers that ultimately develop fatal lung cancer. 3. To test if mutation rate can be
used as a susceptibility/risk biomarker to identify individuals who will develop cancer. Cancer and other
chronic diseases develop predominantly from a combination of environmental exposures and an individual’s
genetic background. We will employ a case-cohort design within WHI to assess whether the accumulation of
somatic mutations can stratify subjects that are subsequently diagnosed with lethal breast, colorectal, ovarian,
pancreas, or bladder cancer versus those that are not. This proposal is innovative with respect to the
technology used and its application to highly curated human samples. If successful, this project could lead to
the development of clinical grade assays for multiple applications and have significant impact on reducing the
morbidity and mortality associated with cancer and potentially other diseases driven by mutagenesis.
