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Allele selective enrichment for targeted profiling of rare cancer mutations via low-depth sequencing

Award Number: R43CA236103
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2019

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Allele selective enrichment for targeted profiling of rare cancer mutations via low-depth sequencing - Summary Cell-free DNA (cfDNA) in peripheral blood contain tumor-derived DNA and are promising non- invasive bi- omarkers for cancer therapy selection and recurrence monitoring. However, the high cost of current commercial next-generation sequencing (NGS) panels for profiling cancer mutations in cfDNA prevents them from being routinely used. Furthermore, the high sequencing depth and reads required means that cfDNA profiling is es- sentially only possible in specialized centralized reference laboratories and inaccessible to hospitals with lower- throughput sequencing instruments. Here, we propose to use allele-selective enrichment sequencing (ASES) to develop NGS panels that are capable of profiling rare cancer mutations in cfDNA with less than 0.1% variant allele frequency (VAF) using low-depth sequencing. We achieve this using allele-specific toehold probes that deplete wildtype DNA sequences and/or enrich for known mutations, increasing the VAF of rare cancer mutations by roughly 100-fold. Unlike other hy- bridization- based probes, toehold probes discriminate single nucleotide variants based on molecular competition rather than melting temperature optimization, and thus is uniquely scalable to high multiplexing. We have ob- tained preliminary data on a NGS panel that includes 118 amplicons, and observed similar mutation sensitivity using 98% fewer NGS reads. In this Phase I SBIR application, we will first develop an ASES NGS panel for cfDNA profiling covering 7 genes bearing 150 frequent mutations in non-small cell lung cancer patients. Subsequently, we will scale up to a 150 kb hypothesis-free panel covering 50 genes.


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: 2020 ( Subtotal = $0 )
2020	2019	NUPROBE USA, INC.	85 BOLTON ST	CAMBRIDGE	MA	02140	MIDDLESEX	USA	Cancer Detection and Diagnosis Research	000	1	7/29/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $300,000 )
2019	2019	NUPROBE USA, INC.	85 BOLTON ST	CAMBRIDGE	MA	02140	MIDDLESEX	USA	Cancer Detection and Diagnosis Research	000	1	5/13/2019	NEW	$300,000
2019	2019	NUPROBE USA, INC.	85 BOLTON ST	CAMBRIDGE	MA	02140	MIDDLESEX	USA	Cancer Detection and Diagnosis Research	001	1	8/27/2019	NEW	$0
														Subtotal = $300,000

Grand Total All Awards = $300,000

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Allele selective enrichment for targeted profiling of rare cancer mutations via low-depth sequencing

Award Number: R43CA236103

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2019

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