# Role of Base Excision Repair in Limiting Hepatocellular Carcinomas -Administrative Supplement

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $222,468

## Abstract

Summary for Administrative Supplemental Funding Request
The combination of chronic dietary exposure to the fungal toxin, aflatoxin B1 (AFB1), and hepatitis B viral (HBV)
infection is associated with a significant increased risk for early onset hepatocellular carcinomas (HCCs) in
millions of people living in East Asia, Central and South America, and sub-Saharan Africa. Even though dietary
exposures to aflatoxins constitute the second largest global environmental risk factor for cancer development,
there are still significant questions concerning the molecular mechanisms driving carcinogenesis. In-depth
knowledge of these mechanisms is critical for the identification of genetic risk factors that affect individual
susceptibility for people who are HBV infected and AFB1 exposed. In this regard, since AFB1 carcinogenesis is
driven by high frequency mutagenesis of G to T transversions, the DNA repair pathways that initiate and
complete repair of persistent AFB1-induced DNA adducts and base damage from HBV-induced inflammation
have strong biological significance. These pathways define the mutagenic burden in the target tissues and
ultimately limit cellular progression to cancer. Although the nucleotide excision repair (NER) pathway has been
shown to repair AFB1 DNA adducts, murine data presented herein demonstrate that knockout of the DNA base
excision repair (BER) pathway, initiated by the DNA glycosylase NEIL1, is significantly more important than
NER relative to the removal of the highly mutagenic AFB1-Fapy-dG adducts. Thus, our data suggest that
deficiencies in NEIL1 could contribute to the initiation of HCCs in humans. To maximize relevance to human
health, all known variants of NEIL1 will be characterized from regions of the world where aflatoxin ingestion
and HBV infection are prevalent. All variants will be characterized for their biochemical properties relative to
WT NEIL1 and expressed in cells and transgenic mice to understand the potential for catalytically-
compromised variants of NEIL1 to alter susceptibility to aflatoxin exposures. These aims will test the
hypothesis that expression of the oncogenic and other catalytically-compromised variants of NEIL1 can
efficiently block repair and promote increased mutagenesis and carcinogenesis. Characterization of
phenotypically dominant oncogenic variants of NEIL1 will provide the molecular basis from which to design
human epidemiological studies in at-risk populations and early onset HCC cohorts. Further, this application
proposes to establish the molecular mechanisms by which the combination of chronic inflammation driven by
the hepatitis B surface antigen and deficiencies in DNA repair could synergistically drive AFB1-induced
mutagenesis and carcinogenesis. Overall, these studies have direct human health relevance pertaining to
understanding a global environmental health problem by identifying genetic risk factors and biochemical
pathways previously not recognized as germane to AFB1-induced carc...

## Key facts

- **NIH application ID:** 10378947
- **Project number:** 3R01ES031086-02S1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** R. Stephen Lloyd
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $222,468
- **Award type:** 3
- **Project period:** 2020-01-01 → 2024-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10378947

## Citation

> US National Institutes of Health, RePORTER application 10378947, Role of Base Excision Repair in Limiting Hepatocellular Carcinomas -Administrative Supplement (3R01ES031086-02S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10378947. Licensed CC0.

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