# Mechanisms of cancer mutations

> **NIH NIH R01** · VAN ANDEL RESEARCH INSTITUTE · 2024 · $458,421

## Abstract

PROJECT SUMMARY:
Cancer genome sequencing has identified thousands of somatic mutations in different types of human
cancer. These mutations provide a valuable source of information as to the potential mutagenic events
that have occurred and created the mutations, sometimes decades before the tumor develops. For certain
cancers, convincing links between an exposure and cancer mutations have been established, best
exemplified by typical sunlight-induced mutations (C to T mutations at dipyrimidine sequences) that are
prevalent in melanoma and in non-melanoma skin cancers and by smoking- related G to T transversion
mutations that are common in lung cancers from smokers but not nonsmokers. The types and frequencies of
mutations in different tumor types is called the mutational signature. Several signatures also have a
characteristic DNA strand bias related to, for example, the direction of transcription. In several human
cancers, there are unusual and characteristic mutational signatures of unknown origin. These signatures are
thought to arise from specific DNA damage, defective DNA repair or from endogenous processes. We
hypothesize that we can identify and recreate mutagenic signatures using DNA damage mapping, a
procedure in which we determine DNA lesions of a specific type at all sequence positions of the human
genome, combined with mutational analysis, with the goal of assigning mutational signatures to etiological
agents relevant for specific human cancers. One key challenge in this field is method development. The
method needs to be sufficiently sensitive to detect rare DNA lesions and must be capable of doing so at all
positions of the genome. We have developed such a method, which we named circle-damage-sequencing
(CD-seq). We propose three Specific Aims. In the first Aim, we will use our new method to characterize and
map reactive aldehyde-derived DNA adducts that we hypothesize play a crucial role in liver cancer. In the
second Aim, we will test the hypothesis that 8-oxo-dG incorporated from the nucleotide pool is responsible
for sequence-specific A to C transversion mutations observed as a dominant mutation type in human
esophageal adenocarcinomas. The last Aim will have the goal of understanding the mechanisms of targeted
mutagenesis by tobacco smoke carcinogens of the PAH class and how this targeting relates to lung and oral
squamous cell carcinomas in tobacco users. Our DNA damage studies will be complemented by mutation
assays to confirm that the relevant pathways induce the expected types of mutations. Our proposed work will
provide mechanistic insights into the potential origin of human cancer mutations. We anticipate that our
methods will aid in many future studies of DNA damage and repair and will help identify other mutagenic
mechanisms.

## Key facts

- **NIH application ID:** 10746849
- **Project number:** 5R01CA276031-02
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Gerd P Pfeifer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $458,421
- **Award type:** 5
- **Project period:** 2022-12-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10746849

## Citation

> US National Institutes of Health, RePORTER application 10746849, Mechanisms of cancer mutations (5R01CA276031-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10746849. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*