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Admixture mapping of mosaic copy number alterations for identification of cancer drivers

Award Number: K22CA258678
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/15/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Admixture mapping of mosaic copy number alterations for identification of cancer drivers - PROJECT SUMMARY/ABSTRACT Background: Somatic mosaicism arises due to the clonal expansion of a cell with an acquired mutation, which leads to genetically distinct sub-populations of cells in an organism derived from a single zygote. As a clone proliferates, its subclones can accumulate further molecular changes that seed cancer. A better understanding of acquired point mutations and copy number changes in these clonal expansions can help elucidate the earliest stages of cancer development. Studies of tissues from healthy individuals have found that those with clonal mosaicism in blood, specifically copy number alterations (CNAs), have a ~10-fold higher risk of developing hematological malignancies, thus underscoring the translational potential of mosaicism studies for the development of improved risk assessment and cancer prevention strategies. Research up to now has mainly focused on persons of European ancestry. My own preliminary results show differences in the genomic landscape of CNAs between individuals of African American or Latino ancestry when compared with Europeans. Understanding these differences and the underlying molecular mechanisms is critical in order to include these still under-researched populations in translational mosaicism studies for early detection and prevention of hematological and potentially other cancers. Proposed Research: Aim 1 is to address the great need for comprehensive studies of mosaicism in American minority populations through a large-scale analyses of CNAs in African American and Latino whole genome sequencing (WGS) data sets. This approach will enable a robust comparison of mosaicism profiles across populations; WGS will allow for joint analysis of CNAs and somatic point mutations to gain insights into mechanisms that underlie different rates and subtypes of hematological malignancies across populations. Aim 2 is to develop novel methods to combine CNA and haplotype level ancestry data for detection of variants associated with increased mosaicism rates. I will use these methods to identify genetic variants that are associated with mosaicism and with increased cancer risk in Latinos and African Americans. Candidate: I have led projects to discover and analyze acquired CNAs in thousands of non-malignant tissues – first of their kind studies for pathologically normal and premalignant tissues – as well as in cancer tissues that complement these. This expertise and my established track record in the development of computational methods for human/cancer genomics, will ensure the successful completion of these aims. As larger volumes of normal tissues are molecularly profiled, I will be able to extend methods developed in Aim 2 to additional normal tissue types, and conduct integrative omics analyses. I will follow up this work and the associated publications with an R01 proposal focused on translational applications of mosaic mutations in normal tissues as markers for cancer risk assessment, early detection, and prognosis. The K22 award will be fundamental as I launch my independent investigator career, offering management and grant writing training, helping to hone my skills as a mentor/PI and establish a long-term funded research program.


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 = $181,348 )
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cancer Research Manpower	000	3	3/11/2024	NON-COMPETING CONTINUATION	$181,348
														Subtotal = $181,348

Issue Date FY: 2023 ( Subtotal = $181,348 )
2023	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cancer Research Manpower	000	2	4/13/2023	NON-COMPETING CONTINUATION	$181,348
														Subtotal = $181,348

Issue Date FY: 2022 ( Subtotal = $177,806 )
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cancer Research Manpower	000	1	4/12/2022	NEW	$177,806
														Subtotal = $177,806

Grand Total All Awards = $540,502

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Admixture mapping of mosaic copy number alterations for identification of cancer drivers

Award Number: K22CA258678

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/15/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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