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Role of Base Excision Repair in Limiting Hepatocellular Carcinomas

Award Number: R01ES031086
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2020
PERIOD OF PERFORMANCE END DATE: 10/31/2024

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Role of Base Excision Repair in Limiting Hepatocellular Carcinomas - Summary 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 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 carcinogenesis.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Environmental Health	000	5	3/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $357,054 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Environmental Health	000	5	10/26/2023	NON-COMPETING CONTINUATION	$357,054
														Subtotal = $357,054

Issue Date FY: 2023 ( Subtotal = $357,054 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Environmental Health	000	4	10/28/2022	NON-COMPETING CONTINUATION	$357,054
														Subtotal = $357,054

Issue Date FY: 2022 ( Subtotal = $357,054 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Environmental Health	000	3	10/22/2021	NON-COMPETING CONTINUATION	$357,054
														Subtotal = $357,054

Issue Date FY: 2021 ( Subtotal = $579,522 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Environmental Health	001	2	8/25/2021	SUPPLEMENT FOR EXPANSION	$222,468
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Environmental Health	000	2	10/28/2020	NON-COMPETING CONTINUATION	$357,054
														Subtotal = $579,522

Issue Date FY: 2020 ( Subtotal = $377,998 )
2020	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Environmental Health	000	1	12/25/2019	NEW	$377,998
														Subtotal = $377,998

Grand Total All Awards = $2,028,682

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Role of Base Excision Repair in Limiting Hepatocellular Carcinomas

Award Number: R01ES031086

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2020

PERIOD OF PERFORMANCE END DATE: 10/31/2024

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