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Treatment-specific genetic risk scores for late effects prediction in childhood,adolescent, and young adult cancer survivors

Award Number: R21CA261833
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Treatment-specific genetic risk scores for late effects prediction in childhood,adolescent, and young adult cancer survivors - PROJECT SUMMARY OR ABSTRACT There is growing evidence that polygenic risk scores (PRS), or aggregate measures of genetic risk for disease based on findings from genome-wide association studies (GWAS), may be useful in predicting risks for a wide array of chronic health conditions (CHCs) in the general population. But are PRS useful for predicting late effects risks in survivors of childhood, adolescent, and young adult (CAYA) cancer? Recently, we have shown that PRS based on GWAS conducted in the general population are relatively poor predictors of risks for various CHCs in survivors, in part because they do not consider the modifying effects of specific curative therapies for cancer on genetic risks for CHCs, i.e., treatment-specific genetic effects. To date, no existing analytic method bridges this research gap: this project is innovative because it aims to develop a new method for PRS that can also incorporate treatment-specific genetic effects. The overall objective of the proposed project is to create novel genetic risk predictors that combine established genetic risk signals identified in general population GWAS with treatment-specific genetic effects to equitably predict CHC risks in CAYA cancer survivors. We will investigate this approach using a preliminary set of ten CHCs and complex traits, including subsequent cancers and cardiovascular and endocrine diseases. The long-term goal of this project is to apply these newly developed treatment-specific genetic risk predictors to inform personalized follow-up care programs for survivors, which responds to RFA-CA-20-028 application domains 5 (development of risk predictors of late effects) and 6 (development of targeted interventions to reduce the burden of cancer). Utilizing existing genetic/phenotype data from ~13,000 survivors, the proposed study will pursue the following specific aims: (1) compile a comprehensive catalog of treatment-specific genetic effects for each of the selected phenotypes; (2) develop and evaluate corresponding “survivor-enriched” PRS that incorporate these treatment-specific genetic effects; and (3) assess whether survivor-enriched PRS can decrease disparities in late effects risk prediction in survivors from racial/ethnic minority populations. To accomplish the first aim, we will perform strategic genome-wide association analyses to identify genetic variants whose risk associations with CHCs are modified by therapeutic exposures. We then intend to adapt existing methods shown to improve the cross-population generalizability of PRS to combine discoveries from general population GWAS with results from genetic analyses in survivors. The relative predictive ability of these survivor-enriched PRS will be evaluated in an independent survivor sample. Lastly, given that treatment-specific genetic effects may be trans-ethnic, we will assess survivor-enriched PRS in racial/ethnic minority survivor subgroups that have been traditionally excluded from Eurocentric GWAS. The proposed research is significant in its potential to help identify survivors at high risk for adverse health outcomes with treatment-specific genetic risk scores, which would represent an important advance over current guidelines for survivorship care.


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: 2026 ( Subtotal = $0 )
2026	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cancer Cause and Prevention Research	000	2	12/22/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Cause and Prevention Research	000	2	8/14/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Cause and Prevention Research	001	2	9/14/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2021	THE GOVERNORS OF THE UNIVERSITY OF ALBERTA	114 STREET AND 89 AVENUE	EDMONTON	AB			CAN	Cancer Cause and Prevention Research	000	1	5/12/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	116 ST & 85 AVE	EDMONTON	AB			CAN	Cancer Cause and Prevention Research	000	1	11/8/2021	NEW	$0
2022	2021	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	116 ST & 85 AVE	EDMONTON	AB			CAN	Cancer Cause and Prevention Research	001	1	9/12/2022	NEW	-$256,537
2022	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Cause and Prevention Research	002	2	9/12/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$256,537
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $279,068 )
2021	2021	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	116 ST & 85 AVE	EDMONTON	AB			CAN	Cancer Cause and Prevention Research	000	1	8/30/2021	NEW	$279,068
														Subtotal = $279,068

Grand Total All Awards = $279,068

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Treatment-specific genetic risk scores for late effects prediction in childhood,adolescent, and young adult cancer survivors

Award Number: R21CA261833

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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