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A pan-cancer atlas of driver mutations in >100,000 patients based on a hypothesis-driven combined computational and experimental approach

Award Number: R00CA262152
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Most mutations in cancer genomes are random passengers that do not contribute to oncogenesis, whereas only a few are drivers critical for tumor development. Existing cancer therapies interfere directly with the biology of drivers, which have been characterized extensively in protein-coding regions but remain largely uncharacterized outside coding regions. Most tumors harbor a combination of several driver mutations, but it is unclear how multiple events are coordinated in tumor development. The applicant's long-term goal is to advance cancer medicine by identifying new drug targets and clinical markers for therapies in complex pathways. The overall objectives in this application are to (i) reveal the biological role of noncoding drivers, (ii) capture the coordination of driver events at a pathway level, and (iii) profile the effects of noncoding drivers on cancer gene expression. The central hypothesis is that refining the biological assumptions of computational methods will enhance their statistical power. The rationale is that defining the biology of noncoding drivers and their combination will offer a strong foundation for new therapies. The central hypothesis will be tested in three specific aims: 1) Determine the impact of integrating biological mechanisms into statistical methods for localizing noncoding drivers; 2) Evaluate mechanisms by which promoter mutations increase the expression of cancer genes; and 3) Assess the coordination of multiple driver events in tumor development. The proposed research is innovative, in the applicant's opinion, because it will allow for an unbiased characterization of driver mutations across the entire genome, address the limitations of existing cancer genomics methods in noncoding regions, and facilitate the usage of statistical concepts for non-computational scientists. The proposal is significant because it will enable a systematic interrogation of noncoding drivers and their combinations. Ultimately, this will pave the way for new targeted therapies. Dr. Dietlein will be mentored by Dr. Van Allen, an Associate Professor of Medicine at Harvard Medical School with considerable experience in cancer genomics methods that require statistical innovation for clinically focused questions. His co-mentor, Dr. Meyerson, is a Professor of Genetics and Medicine at Harvard Medical School and a pioneer in developing targeted therapies based on driver mutations. Additional support will be provided by 4 computational and 2 experimental collaborators. Dr. Dietlein's training plan contains four goals, which will be pursued by hands-on experiential training, conference meetings, and structured coursework: 1) Acquire computational skills for interpreting drivers in noncoding regions; 2) Experimental techniques to validate driver mutations by CRISPR interference; 3) Develop professional leadership skills for interdisciplinary teams of scientists; and 4) Use machine-learning methods for interpreting drivers in cancer genomes. Dana-Farber, Harvard Medical School, and the Broad Institute provide an ideal environment to execute the applicant's career development plan.


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 = $224,101 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	4	3/6/2024	NON-COMPETING CONTINUATION	$224,101
														Subtotal = $224,101

Issue Date FY: 2023 ( Subtotal = $214,480 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	3	2/27/2023	NON-COMPETING CONTINUATION	$214,480
														Subtotal = $214,480

Issue Date FY: 2022 ( Subtotal = $283,521 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	001	2	6/21/2022	EXTENSION WITH OR WITHOUT FUNDS	$34,521
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	2	5/11/2022	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $283,521

Grand Total All Awards = $722,102

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A pan-cancer atlas of driver mutations in >100,000 patients based on a hypothesis-driven combined computational and experimental approach

Award Number: R00CA262152

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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