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Impact of cancer predisposition on oncogenic process, microenvironment, and treatment

Award Number: R01CA260112
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Impact of cancer predisposition on oncogenic process, microenvironment, and treatment - Our previous study of more than 10 thousand tumors across 33 cancer types identified over 800 germline predisposition variants in both tumor suppressors and oncogenes. Although the impact of some of these variants on cancer onset, incidence rate, and clonality have been documented, the effects of these variants (especially when compared to somatic mutations) on molecular characteristics of cancer cells, contributions of non-cancer cells having germline variants, and treatment responses, are far less studied. Our recent single cell(sc) /single nucleus(sn) RNA-seq analyses of cancer samples provided comprehensive expression profiles at a single cell resolution and revealed the expression of key cancer predisposition genes, such as BRCA 112, VHL, BAP1, and c-MET in many non-cancer stromal and immune cells in the tumor microenvironment (TME). Our pilot analyses also revealed significant differential gene expression in cancer and non-cancer cells based on the nature of the driver event being germline or somatic. We hypothesize that tumors with certain germline predisposition variants in tumor suppressors and oncogenes may show differences in tumor progression and treatment responses from those tumors with somatic mutations in the same genes due to differential influence on mutational, transcriptomic, and proteomic profiles of the cancer cells and potentially distinctive contributions from non-cancer cells having those germline changes. To take advantage of the considerable progress over the last few years, namely newly accumulated cancer sequencing data, advances in single cell omics, patient-derived xenografts (PDX), and tumor genetic models, we propose to test these hypotheses by performing the following: compare germline predisposition variants and somatic mutations to dissect their differential biological impacts and interactions using computational analysis (Aim 1); perform single nucleus RNA-seq/ATAC-seq, spatial transcriptomics, and multiplex imaging analysis of human cancer samples to reveal the differential roles of germline predisposition variants and somatic mutations in tumor cells and the TME (Aim 2); use PDX and genetic cancer models to investigate potential functional differences between germline predisposition variants and somatic mutations in tumor cells, TME, and treatment responses (Aim 3). Results from this study will advance our understanding of the unique contributions of germline variants to cancer cells and TME alike, improve genetic counseling and prognosis, and provide guidance for differential treatment of tumors carrying germline variants vs somatic mutations in key cancer driver genes.


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 = $475,364 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	000	5	1/8/2026	NON-COMPETING CONTINUATION	$427,827
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	001	5	4/16/2026	NON-COMPETING CONTINUATION	$47,537
														Subtotal = $475,364

Issue Date FY: 2025 ( Subtotal = $475,364 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	001	4	2/14/2025	NON-COMPETING CONTINUATION	$0
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	000	4	12/23/2024	NON-COMPETING CONTINUATION	$427,827
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	002	4	6/6/2025	NON-COMPETING CONTINUATION	$47,537
														Subtotal = $475,364

Issue Date FY: 2024 ( Subtotal = $451,596 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Biology Research	001	3	4/22/2024	NON-COMPETING CONTINUATION	$23,769
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Biology Research	000	3	12/25/2023	NON-COMPETING CONTINUATION	$427,827
														Subtotal = $451,596

Issue Date FY: 2023 ( Subtotal = $468,852 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	001	2	3/29/2023	NON-COMPETING CONTINUATION	$38,273
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	000	2	12/8/2022	NON-COMPETING CONTINUATION	$430,579
														Subtotal = $468,852

Issue Date FY: 2022 ( Subtotal = $481,478 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	000	1	12/31/2021	NEW	$481,478
														Subtotal = $481,478

Grand Total All Awards = $2,352,654

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Impact of cancer predisposition on oncogenic process, microenvironment, and treatment

Award Number: R01CA260112

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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