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Mutational signature analysis: methods and applications to the clinic

Award Number: R01CA269805
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/05/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Mutational signature analysis: methods and applications to the clinic - PROJECT SUMMARY Mutational signature analysis is a recent analytical approach for interpreting somatic mutations in the genome. It utilizes the sequence context of point mutations as well as the size and type of copy number and structural aberrations to decompose the observed mutational patterns into distinct 'signatures', some of which have been associated with speciﬁc biological processes. In this project, we will develop more robust and sensitive com- putational methods for mutational signature analysis and apply them to several clinically important questions. Our initial work has attracted a great deal of attention from clinicians, and we will analyze data from several clinical cohorts in close collaboration. In Aim 1, we will build upon our previous work to devise a method that can identify homologous recombination deﬁciency in cancer patients proﬁled on gene panels. Although whole-genome sequencing offers several advantages, gene panel sequencing remains as a pivotal platform in clinical care. Our method will enable signature analysis for gene panels from which only a small number of mutations can be observed. We will incorporate additional sources of information and identify biomarkers for patient stratiﬁcation. In Aim 2, we will investigate other types of genomic instability such as mismatch repair deﬁciency, replication stress, and APOBEC mutagenesis. For example, although patients with mismatch repair deﬁciency generally respond better to immunotherapy, there is a considerable variation across patients. We will use mutational signatures to identify a subset of patients that respond better. In Aim 3, we will extend our method to data from circulating tumor DNA and single cell RNA sequencing to enable signature-based predictive modelling. In Aim 4, we will develop a generalized analytical framework for whole-genome and whole-exome signature analysis that will overcome the shortcomings of current approaches. We will use this new framework to build a high-quality reference catalog for the community.


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 = $408,071 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	4	3/18/2025	NON-COMPETING CONTINUATION	$408,071
														Subtotal = $408,071

Issue Date FY: 2024 ( Subtotal = $430,741 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	3	4/16/2024	NON-COMPETING CONTINUATION	$430,741
														Subtotal = $430,741

Issue Date FY: 2023 ( Subtotal = $444,343 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	2	3/20/2023	NON-COMPETING CONTINUATION	$444,343
														Subtotal = $444,343

Issue Date FY: 2022 ( Subtotal = $453,188 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	1	5/5/2022	NEW	$453,188
														Subtotal = $453,188

Grand Total All Awards = $1,736,343

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Mutational signature analysis: methods and applications to the clinic

Award Number: R01CA269805

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/05/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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