Back to Our Technologies

A Liquid Biopsy Method for Detecting Microsatellite Instability (MSI) in Cancer

Select sequencing of relevant DNA regions obviates the need for whole genome sequencing and enables the identification of MSI mutations.

  • Diagnostics

Project Overview

  • Microsatellite instability (MSI) is a pattern of hypermutation, involving insertions and/or deletions, that occurs in microsatellites resulting from defects in the mismatch repair system. The relationship between mismatch repair deficiency and MSI has been well described for several cancers including colorectal, endometrial, and gastric adenocarcinomas.
  • Despite its clinical significance, detection of MSI mutations remains a challenge to this day. 
  • Dana-Farber scientists have developed a liquid biopsy technology for performing genome-wide enrichment of DNA microsatellites.
  • This technology is available for licensing.

Technology

Recent and ongoing advances in high-throughput genomic screening of germline or high-prevalence somatic mutations have proven to be invaluable in a clinical setting. Detection of a low percent of variant DNA (minority alleles) in the presence of a large excess of non-variant sequences (majority alleles), e.g., low-somatic mutations in a heterogeneous tumour mass or in bodily fluids, remains a challenge. Microsatellite analysis is a case in point. Microsatellites, also known as homopolymer repeats, comprise multiple repeats of a single nucleotide, such as polyadenines (poly-A).

Microsatellite instability (MSI) is a pattern of hypermutation, involving insertions and/or deletions, that occurs in microsatellites resulting from defects in the mismatch repair system. The relationship between mismatch repair deficiency and MSI has been well described for several cancers including colorectal, endometrial, and gastric adenocarcinomas. Hence, the MSI mutation level can be predictive for such cancers. The MSI mutation distribution serves as a signature traceable in tumor tissue and in cell-free DNA (cfDNA) circulating in blood enabling measurement of residual disease during and/or post treatment. Despite its clinical significance, detection of MSI mutations remains a challenge to this day. 

To facilitate MSI mutation detection, researchers at Dana-Farber Cancer Institute have developed a technology for performing genome-wide enrichment of DNA microsatellites. The technology uses custom DNA probe sequences that bind selectively to homo-polymer repeats, e.g., a poly-T probe duplexing with a poly-A microsatellite. In the absence of mutations, a duplex with a higher melting temperature is formed. Conversely, if the same probe binds to a microsatellite comprising mutations, a duplex is obtained with a lower melting point. The difference in melting point allows for selective temperature-controlled PCR amplification, and thus enrichment, of the mutated microsatellites only. This procedure obviates the need for extensive sequencing efforts resulting in faster results at a reduced cost. 

Benefits of the technology:

  • Select sequencing of relevant DNA regions obviates the need for whole genome sequencing. 
  • Enables identification of MSI mutations in tumor tissue or cfDNA isolated from liquid biopsies (e.g., buccal-swap, blood, or other bodily fluids). 
  • Supports detection of minimal residual disease, tumor mutational burden, or tumor dynamics. 
  • Reduced sequencing efforts for faster results at reduced cost. 

Further Details: 

Ladas I, Yu F, Leong KW, Fitarelli-Kiehl M, Song C, Ashtaputre R, Kulke M, Mamon H, Makrigiorgos GM. Enhanced detection of microsatellite instability using pre-PCR elimination of wild-type DNA homo-polymers in tissue and liquid biopsies. Nucleic Acids Res. 2018 Jul 6;46(12):e74.

Team Members: G. Mike Makrigiorgos, PhD

Applications

  • Sensitive MSI mutations detection for prognostic and diagnostic use. 
  • Treatment monitoring by detection of minimal residual disease. 
  • Periodic non-invasive blood-sample-based MSI screening of healthy individuals for early signs of cancer. 

Opportunities

Dana-Farber Cancer Institute is looking for the right partner with an interest in licensing this asset for further development into new oncology diagnostics. 

Get in touch

Team Members