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Genomic Biology of the Tandem Duplicator Phenotype in Mouse and Human Cancers

Award Number: R01CA255705
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Genomic Biology of the Tandem Duplicator Phenotype in Mouse and Human Cancers - PROJECT SUMMARY We have identified a group of genome instability configurations called the Tandem Duplicator Phenotypes (TDPs) that are found in ~50% of triple negative breast, ovarian and endometrial cancers and are characterized by the massive genome-wide distribution of somatic tandem duplications (TDs) of specific span sizes. We have identified the bona fide genetic drivers of these configurations, demonstrated that loss of Trp53 and Brca1 in the mouse mammary gland is sufficient to induce tumors with the short-span TDP configuration found in TP53- and BRCA1-deficient human cancers, and shown that upon loss of Brca1, TDs are formed through the aberrant repair of stalled replication forks. Here, we propose to deploy a combination of computational analyses, in vivo modelling and in vitro experimentation to achieve a deep mechanistic understanding of how the distinct TDP genomic configurations emerge and impact the course of breast tumorigenesis. Specifically, we will investigate the molecular mechanisms leading to de novo TD formation across the different TDP groups by exploring how local DNA features associated with DNA replication and fork stalling contribute to the generation of new TDs across a large pan-cancer dataset representing all TDP groups and all TDP genetic drivers (Aim 1A) and how loss of BRCA1 activity may modulate the spread and location of the de novo TDs formed in the context of the short-span TDP (Aim 1B). We will establish new genetically engineered mouse models (GEMMs) of breast cancer to validate that activation of the Ccne1 pathway or loss of Cdk12 activity, both in conjunction with Trp53 loss of function, induces medium- and long-span TDP configurations that mimic their human counterparts both in terms of TD span size and distribution (Aim 2A) and of the genomic features and genetic elements that are associated with and affected by TD formation (Aim 2B). We will also assess the tumor neo-antigen load of the TDP tumors emerging from the newly developed GEMMs and test whether immuno-oncology agents are effective against mammary tumors with the TDP configuration, as suggested by recently emerging clinical observations (Aim 2A). We will then use isogenic human cancer cell lines that are either proficient or deficient for BRCA1 activity, to determine the dynamics of de novo TD formation under different modes of cellular perturbation and as a function of BRCA1 status (Aim 3A). Finally, we will use the newly developed GEMMs to understand the evolutionary path to genome-wide TD distribution in the mammary gland, and to discern the dynamics of TDP emergence, both in terms of the rate of de novo TD formation and with respect to the timeline of breast tumorigenesis (Aim 3B). If successful, this proposal will uncover the root causes of a significant form of genomic instability in human cancer, the TDP, define the mutational dynamics leading to cancer formation in this condition, and generate model systems that can lead to the development of new and directed therapeutics against cancer growth.


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 = $633,594 )
2025	2025	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Cause and Prevention Research	000	5	11/25/2024	NON-COMPETING CONTINUATION	$633,594
														Subtotal = $633,594

Issue Date FY: 2024 ( Subtotal = $668,795 )
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Cause and Prevention Research	000	4	11/20/2023	NON-COMPETING CONTINUATION	$633,594
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Cause and Prevention Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$35,201
														Subtotal = $668,795

Issue Date FY: 2023 ( Subtotal = $689,912 )
2023	2023	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Cause and Prevention Research	000	3	11/9/2022	NON-COMPETING CONTINUATION	$633,594
2023	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Cause and Prevention Research	001	3	3/14/2023	NON-COMPETING CONTINUATION	$56,318
														Subtotal = $689,912

Issue Date FY: 2022 ( Subtotal = $689,912 )
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Cause and Prevention Research	001	2	6/23/2022	NON-COMPETING CONTINUATION	$56,319
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Cause and Prevention Research	000	2	11/30/2021	NON-COMPETING CONTINUATION	$633,593
														Subtotal = $689,912

Issue Date FY: 2021 ( Subtotal = $703,993 )
2021	2021	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Cause and Prevention Research	000	1	12/1/2020	NEW	$703,993
														Subtotal = $703,993

Grand Total All Awards = $3,386,206

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Genomic Biology of the Tandem Duplicator Phenotype in Mouse and Human Cancers

Award Number: R01CA255705

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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