# Ultrasensitive measure of human mutagenesis: Connecting the exposome to disease

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2020 · $143,362

## Abstract

PROJECT SUMMARY
Somatic mutations are the driving force behind carcinogenesis and other age-related diseases, yet the
mechanisms underlying their genesis in humans are ambiguous. This proposal seeks to resolve fundamental
processes of nuclear mutagenesis and ascertain the utility of monitoring somatic mutation as a biomarker of
individual environmental exposure within a well-characterized population. These objectives are now feasible
thanks to the development of a novel mutation detection technology termed CypherSeq, which utilizes circular
barcoded templates, rolling circle amplification, and massively parallel sequencing to accurately quantify
somatic mutation throughout the genome with unprecedented sensitivity. First, the CypherSeq method will be
used to establish a genome-wide profile of somatic mutation in disease-free humans, and test how the
frequency, distribution, and spectrum of mutation change with age throughout the genome. Second,
proliferating and quiescent human cells will be treated with known mutagens, and induced mutagenesis will be
tracked by CypherSeq. These experiments will explore the relationships between cell proliferation,
transcription, DNA repair, and somatic mutation, while also uncovering highly mutable regions of the genome,
which might serve as sites to monitor acute and chronic mutagen exposure in human populations. Further, this
Aim will also test the hypothesis that proliferation is required for repair and mutation fixation within non-
transcribed regions of the genome. Lastly, in the third Aim, robust mutational target sites will be characterized
and used to monitor mutation frequency in blood draws from individuals who have endured a long-term,
carcinogenic exposure to smoky coal. This cross-sectional study will test the hypothesis that underlying the
carcinogenicity of smoky coal is its potential to increase the frequency of somatic mutation in exposed
individuals. As such, it is expected that increased lifetime exposure to smoky coal will positively correlate with
mutation induction. Successful completion of the proposed Aims would provide new insights into human
mutagenesis, and highlight the potential utility of monitoring in vivo mutation induction as a biomarker of
mutagenic environmental exposure; and thus identify individuals with an elevated risk of developing cancer.
Ultimately, mutation-based biomarkers have the potential to stratify cancer risk, providing a basis to direct
medical intervention, lifestyle changes (i.e. limiting mutagen exposure), early diagnosis, and/or the application
of chemopreventive measures, and thus save lives.

## Key facts

- **NIH application ID:** 10649751
- **Project number:** 6R01ES026222-06
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Eric C. Holland
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $143,362
- **Award type:** 6
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10649751

## Citation

> US National Institutes of Health, RePORTER application 10649751, Ultrasensitive measure of human mutagenesis: Connecting the exposome to disease (6R01ES026222-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10649751. Licensed CC0.

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