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DNA repair gene mutations and prostate cancer

Award Number: R01CA233664
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/02/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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DNA repair gene mutations and prostate cancer - Prostate cancer (PCa) is one of the most heritable human cancers, with inherited risk estimates of up to 60%; however, the underlying inherited genetic architecture is still largely unexplained. Our unique access to a collection of 446 blood specimens from 211 PCa families has enabled an innovative family-based approach to identifying novel disease-susceptibility loci. To date, we have collected targeted sequencing data from a panel of 48 “cancer risk genes” using samples from all of the PCa families, and whole-exome sequencing (WES) data using samples from a subset of the PCa families. We identified 45 familial loss-of-function and missense mutations in 32 DNA damage response and repair genes. Most of these gene products are known to participate in homology-directed DNA repair (HDR), an error-free type of DNA double-strand break (DSB) repair. DSBs can result from androgen receptor (AR)-induced transcriptional stress and increase cancer risk in androgen- responsive tissues, such as the prostate. In response to androgen stimulation, both TOP2B topoisomerase and LINE-1 endonuclease are recruited to active transcription sites and induce DSBs. Accumulated evidence suggests that loss of HDR will promote other error-prone repair pathways, such as alternative non-homologous end joining, causing mutation accumulation and genomic instability. The mutations we have identified are all germline mutations, representing potential causal genetic factors. We therefore hypothesize that functional deficiency in the HDR pathway, due to loss-of-function and missense mutations in HDR genes, contributes to genomic instability and PCa. We have designed the following three specific aims to test our central hypothesis: 1) To determine the functional defects in DNA damage response and HDR caused by PCa-associated HDR gene mutations; 2) To define the roles of nucleases EXO5 and EXD2 and helicases HFM1 and FANCM in resecting DNA ends at AR-induced, TOP2B-linked DSBs for HDR in prostate cells; 3) To assess the biological significance of AR signaling and the HDR pathway in PCa tumorigenesis. Our strong research team includes Dr. Binghui Shen (contact PI, City of Hope [COH]) and Dr. Xiaochun Yu (mPI; COH), both experts in the fields of DNA damage repair and cancer genetics, and recognized PCa biologists Dr. Zijie Sun (mPI; COH) and Dr. Ming- Fong Lin (co-I; University of Nebraska Medical Center). We will test the role of HDR gene mutations as risk factors for PCa and define the underlying molecular mechanism(s) linking HDR gene mutations to illegitimate DNA repair and PCa development. Completion of the proposed work will significantly advance our understanding of the role of HDR in cancer, especially PCa. We will use an innovative approach to identify novel PCa-associated HDR defects based on familial inheritance and evaluation of both loss-of-function and missense mutations. These insights will impact the field by increasing the availability of biomarkers for early diagnosis and providing molecular targets for anti-cancer drug development.


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: 2024 ( Subtotal = $662,863 )
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	001	5	4/17/2024	NON-COMPETING CONTINUATION	$34,888
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	5	11/29/2023	NON-COMPETING CONTINUATION	$627,975
														Subtotal = $662,863

Issue Date FY: 2023 ( Subtotal = $683,795 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	4	1/31/2023	NON-COMPETING CONTINUATION	$683,795
														Subtotal = $683,795

Issue Date FY: 2022 ( Subtotal = $683,795 )
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	001	3	4/29/2022	NON-COMPETING CONTINUATION	$55,820
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	3	11/18/2021	NON-COMPETING CONTINUATION	$627,975
														Subtotal = $683,795

Issue Date FY: 2021 ( Subtotal = $697,751 )
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	2	11/24/2020	NON-COMPETING CONTINUATION	$662,863
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	001	2	1/20/2021	NON-COMPETING CONTINUATION	$34,888
														Subtotal = $697,751

Issue Date FY: 2020 ( Subtotal = $716,750 )
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	1	12/2/2019	NEW	$699,936
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	002	1	5/19/2020	NEW	$0
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Cause and Prevention Research	001	1	1/24/2020	NEW	$16,814
														Subtotal = $716,750

Grand Total All Awards = $3,444,954

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DNA repair gene mutations and prostate cancer

Award Number: R01CA233664

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/02/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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