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Enhanced Detection of Clinically Relevant Low-Prevalence Somatic Mutations in Solid Tumors and ctDNA

Novel approach that eliminates wildtype DNA sequences from samples to enrich the clinically relevant mutant DNA regions.

  • Diagnostics

Project Overview

  • In-depth diagnostic information derived from the low percentage of variant DNA sequences (‘minority alleles’) can guide therapeutic strategies in cancer and other indications. 
  • There is a need to develop improved techniques that allow for the identification of low-level minority alleles.
  • To address this unmet need, scientists at Dana-Farber developed a novel approach that eliminates wild-type DNA sequences from samples to enrich the clinically relevant mutant DNA regions.
  • This asset is available for non-exclusive licensing.

Technology

A common challenge in genetic analysis is the identification of a low percentage of variant DNA sequences (‘minority alleles’) in the presence of a large excess of non-variant sequences (‘majority alleles’). Excess wild-type DNA, lacking biological or clinical value, masks rare mutations that contain valuable diagnostic clues. Indications that suffer from these current technical limitations include cancer, early prenatal genetic diseases challenged by very low fractions of fetal alleles in an abundance of maternal DNA, infectious diseases, and organ transplantation. In-depth diagnostic information derived from minority alleles is set to guide therapeutic strategies in cancer and other indications. 

While high throughput sequencing-based methods for detecting low-prevalence somatic mutations in clinical samples have been developed, these are still cumbersome, costly, and not cost-effective in certain cases. Thus, there is a need to develop improved techniques that allow for the identification of low-level minority alleles, including mutated or hypo/hypermethylated alleles, or microsatellite instability in the presence of high-level wildtype DNA. 

To address this unmet need, the labs of Dr. Makrigiorgos at Dana-Farber developed a straightforward and powerful novel approach that eliminates wildtype DNA sequences from samples to enrich the clinically relevant mutant DNA regions. The Nuclease-assisted Mutation Enrichment with Probe overlap (NaME-PrO) method is a one-step process that selectively degrades wild-type DNA/RNA sequences, effectively enriching for the undegraded sites comprising mutations. It is compatible with downstream high-throughput mutation detection methods, thus allowing for robust identification of variant-sequence alleles in the presence of a large excess of non-variant alleles in nucleic acids. 

Team Members: G. Mike Makrigiorgos, PhD, Chen Song, PhD

Applications

  • Enabling detection of low-prevalence somatic mutations in tumor tissues or in circulating tumor DNA.
  • Overcomes challenges associated with tumor heterogeneity and stromal contamination in current approaches.
  • Uniquely suited for enhancing sensitivity of microsatellite instability detection.
  • Overcomes current limitations of mutation detection technologies, thereby enhancing efficiency and reliability of patient-specific mutation screening for heterogeneous tumor samples.
  • Enables high multiplexity of targets that enables coupling with any high-throughput methods for somatic mutation detection.
  • Applicable to identification of low-prevalence methylated alleles in epigenetic analysis.
  • Applicable to detection and genotyping of fetal DNA circulating in maternal blood. 

Opportunities

Dana-Farber Cancer Institute is looking for the right partner with an interest in licensing these assets for use as an internal research tool or for further development as a component of a new diagnostic. This asset is available for non-exclusive licensing 

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Team Members