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Deciphering cancer origin from DNA evolution

Award Number: R01CA310281
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/17/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Deciphering cancer origin from DNA evolution - PROJECT SUMMARY/ABSTRACT DNA sequencing holds significant promise for precisely profiling individual tumors, which in turn can guide personalized cancer therapies and improve long-term patient outcomes. A key prognostic factor across tissue types is intra-tumor heterogeneity (ITH), resulting from somatic single-nucleotide variants and copy-number aberrations, that is highly predictive of patient survival and risks of metastasis and relapse. However, accurately estimating ITH and tumor growth from DNA data remains challenging, thereby impeding its broader adoption for clinical decision making. This proposed project will focus on developing DECODE (Deciphering Cancer Origin from DNA Evolution), a novel approach for reconstructing tumor evolution that can predict patient outcomes and facilitate risk stratification and treatment selection in clinical practice (Aim 1). DECODE will integrate the neutral tail in the site frequency spectrum (SFS), comprised of recent mutations that carry signals indicative of a tumor’s expansion mode. DECODE’s enhanced accuracy will be based on mathematical corrections for sample-specific coverage and effects of mutation filtering. This will reduce the risk of overfitting, enhance the detection of overlapping clusters, and render DECODE ideally suited for data generated by current DNA-seq technologies. In Aim 2, DECODE will be used to analyze the tumor heterogeneity and infer tumor evolution history in primary cancers from the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For each sample, the SFS neutral tail will be characterized and the number of subclones and subclonal frequencies will be estimated. The tumor evolution timelines from these samples will then be inferred, using a novel mathematical framework to estimate the age of each tumor’s most recent common ancestor, subclonal arrival times and growth rates from DECODE’s parameters. Finally, the ITH estimates and tumor and subclonal growth rates will be examined for predictive power of patient outcome in specific cancer types, toward finding potential biomarkers. Relapsed and metastatic tumors from the Personalized OncoGenomics (POG) cohort will also be studied (Aim 3). For these samples, a multi-variate DECODE algorithm will be developed to consider mutations with distinct multiplicities occurring on different copy number backgrounds. The multi-variate DECODE will be able to analyze advanced cancers, which often exhibit variable copy numbers due to chromosomal instability. The comparison of ITH estimates and clonal evolutions inferred from DECODE between samples in POG and ICGC/TCGA will enable a deeper understanding into differences in selection forces driving relapses and metastases compared to de novo cancers. In summary, DECODE is a novel approach toward reliable tumor evolution reconstruction, enabled by advances in mathematical modeling and parameter inference. Its accuracy, notably for samples sequenced with currently available technologies, will enable deeper understanding of tumor adaptation, clinical patient stratification and outcome prediction, toward the goal of personalized therapy treatment.


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 = $428,975 )
2026	2026	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Cancer Detection and Diagnosis Research	000	1	4/28/2026	NEW	$428,975
														Subtotal = $428,975

Grand Total All Awards = $428,975

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Deciphering cancer origin from DNA evolution

Award Number: R01CA310281

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/17/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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