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Discovery and verification of methylated circulating tumor DNA markers for the detection of colorectal cancer in subjects under 50 years of age

Award Number: R01CA252042
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Discovery and verification of methylated circulating tumor DNA markers for the detection of colorectal cancer in subjects under 50 years of age - Abstract In recent years, the incidence of colorectal cancer (CRC) under the age of 50 years has increased significantly and population-based screening is currently not offered to persons under 50 years. Consequently, persons with early-onset (<50 years) CRC (EOCRC) more frequently present with symptomatic disease at advanced stages (III/IV) resulting in greater loss of life in young cases. In 2020, the U.S. Preventive Services Task Force recommended the age for CRC screening by colonoscopy or fecal tests be reduced to 45 years. However, the uptake of screening by these methods in all screen-eligible populations is low, including in those <50 years who are genetically at high risk, so adherence in the asymptomatic population <50 years is also likely to be low. Also, over half of EOCRC occur in persons under <45 years of age, where no such screening would be offered. A minimally invasive, blood-based screening test for EOCRC would provide a cost-effective and patient-friendly option for triaging and identifying those warranting a follow-up colonoscopy, while increasing screening adherence in the younger population. Cancer-specific methylated DNA biomarkers are highly suited for population-based cancer screening via the detection of circulating tumor DNA (ctDNA) in blood plasma because they are more prevalent across patients with a given cancer type than tumor mutations and are more stable (nuclease-resistant) in plasma. The methylated SEPTIN9 plasma ctDNA test, “mSEPT9” (Epi proColon V2.0, Epigenomics), is FDA-approved for CRC screening in persons aged ≥50 years who decline colonoscopy and fecal tests. This test urgently needs to be assessed in persons <50 years to determine its suitability for the detection of EOCRC. Even so, a multi-marker test is likely to have superior sensitivity to a single-marker test. Thus, the objectives of our study are to identify and confirm a panel of methylated ctDNA markers for the plasma-based detection of EOCRC, and to compare the diagnostic performance of this panel to the mSEPT9 test in persons <50 years of age. In Aim 1, we will identify the most prevalent differentially-methylated (tumor vs. normal) DNA markers in CRC cases <50 years by performing deep Methyl-Seq across 4.2 million CpG sites in paired primary tumor vs. normal colon tissues from EOCRC cases, and leukocytes from healthy controls (to filter out non-specific markers). The identified markers will be validated in independent sample series. For the top-ranked markers, we will then develop methylation-specific real-time PCR assays with high analytical sensitivity and test these in pooled plasma from metastatic CRC cases (to select markers producing the strongest signals) and healthy controls (to eliminate any producing low-level non-specific signals) to finalize the marker panel. In Aim 2, we will evaluate the diagnostic performance characteristics of the mSEPT9 test vs. the multi-marker panel test in plasma from colonoscopy-verified CRC cases and controls <50 years. This study will yield a multi-marker methylated ctDNA panel with improved diagnostic performance over the single-marker mSEPT9 test for cost-effective, blood-based, CRC screening in asymptomatic persons <50 years of age.


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 = $663,923 )
2025	2025	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Detection and Diagnosis Research	001	5	9/12/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$663,923
2025	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	000	4	9/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $663,923

Issue Date FY: 2024 ( Subtotal = $632,610 )
2024	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	000	4	6/4/2024	NON-COMPETING CONTINUATION	$632,610
														Subtotal = $632,610

Issue Date FY: 2023 ( Subtotal = $658,771 )
2023	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	000	3	7/3/2023	NON-COMPETING CONTINUATION	$658,771
														Subtotal = $658,771

Issue Date FY: 2022 ( Subtotal = $671,056 )
2022	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	000	2	7/1/2022	NON-COMPETING CONTINUATION	$671,056
														Subtotal = $671,056

Issue Date FY: 2021 ( Subtotal = $685,529 )
2021	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	000	1	6/23/2021	NEW	$685,529
														Subtotal = $685,529

Grand Total All Awards = $3,311,889

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Discovery and verification of methylated circulating tumor DNA markers for the detection of colorectal cancer in subjects under 50 years of age

Award Number: R01CA252042

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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