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Genomic and functional approaches to characterize Chr1q gains in cancer

Award Number: R01CA276666
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/18/2023
PERIOD OF PERFORMANCE END DATE: 07/11/2025

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Genomic and functional approaches to characterize Chr1q gains in cancer - Aneuploidy is a ubiquitous but poorly-understood feature of tumor genomes. For instance, approximately 25% of human cancers harbor extra copies of the “q” arm of chromosome 1, making this amplification more common across cancer types than mutations in KRAS, PIK3CA, RB1, and many other widely-studied cancer driver genes. Despite the prevalence of 1q aneuploidy in cancer, we have little insight into its role in tumorigenesis. While evolutionary studies have defined consistent patterns in which single nucleotide substitutions occur in oncogenes and tumor suppressors during cancer development, the relative timing of most copy number alterations remains unknown. Additionally, while multiple approaches have been developed to experimentally manipulate single genes in cancer, our ability to alter and study chromosome-scale dosage changes is extremely limited. Thus, we lack genetic strategies that would allow us to develop a mechanistic understanding of how aneuploidies like Chr1q gains influence cancer biology. We hypothesize that certain commonly observed aneuploidies like Chr1q-amplifications may function as cancer “addictions”, in the same way that some cancers can be addicted to oncogenes like KRAS and PIK3CA. Eliminating these aneuploidy “addictions” could therefore block cancer growth and suppress various malignant phenotypes. To investigate this hypothesis, and to uncover the role of 1q-gains in cancer biology more broadly, we have developed novel computational and functional approaches to study cancer aneuploidy. In preliminary work, we discovered that Chr1q gains are commonly the first arm-scale copy number change that occurs during tumor development, and we found that genetically eliminating Chr1q aneuploidy prevents malignant growth in human cancers. To build on these findings, in Aim 1, we will optimize and apply a strategy to reconstruct the evolutionary timing of somatic copy number alterations from multi-sample sequencing studies of human tumors. In Aim 2, we will apply a novel chromosome-engineering approach to eliminate Chr1q aneuploidy from human cancers, and then we will characterize how aneuploidy-loss affects various malignant phenotypes. In Aim 3, we will identify the dosage-sensitive driver genes encoded on Chr1q that contribute to this “aneuploidy addiction” phenotype. In total, these aims will shed light on the functional consequences of an enigmatic genomic alteration found in many cancers. As 1q gains commonly arise during malignant growth but are extremely rare in normal tissue, a greater understanding of this aneuploidy could point toward treatment strategies that are effective against a wide range of tumors but that have little effect on normal diploid tissue.


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 = $515,870 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Cause and Prevention Research	001	4	2/9/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$515,870
2026	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Cause and Prevention Research	002	3	3/3/2026	NON-COMPETING CONTINUATION	$0
2026	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Cause and Prevention Research	000	3	2/9/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $515,870

Issue Date FY: 2025 ( Subtotal = $520,332 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Cause and Prevention Research	001	3	6/4/2025	NON-COMPETING CONTINUATION	$52,033
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Cause and Prevention Research	000	3	12/12/2024	NON-COMPETING CONTINUATION	$468,299
														Subtotal = $520,332

Issue Date FY: 2024 ( Subtotal = $791,853 )
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Cause and Prevention Research	000	2	1/9/2024	NON-COMPETING CONTINUATION	$464,545
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Cause and Prevention Research	002	2	9/25/2024	SUPPLEMENT FOR EXPANSION	$301,500
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Cause and Prevention Research	001	2	4/17/2024	NON-COMPETING CONTINUATION	$25,808
														Subtotal = $791,853

Issue Date FY: 2023 ( Subtotal = $533,035 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Cause and Prevention Research	000	1	1/18/2023	NEW	$533,035
														Subtotal = $533,035

Grand Total All Awards = $2,361,090

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Genomic and functional approaches to characterize Chr1q gains in cancer

Award Number: R01CA276666

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/18/2023

PERIOD OF PERFORMANCE END DATE: 07/11/2025

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