New genetic tests effective for hereditary cancers

A single test can identify the multitude of known sources of genetic variation underlying the disorder for repairing deficiencies in hereditary colon, endometrial and other cancers The Journal of Molecular Diagnostics.

Researchers have developed a new integrated genetic / epigenetic DNAfollow-up protocol known as MultiMMR that can identify the presence and cause of a lack of repair (MMR) deficiency in a single test from a small sample of DNA in colon, endometrial and other cancers This alternative to complex, multi-step test workflows can also determine the causes of MMR deficiency that are frequently missed by current clinical trials. Their results are in The Journal of Molecular Diagnostics, published by Elsevier.

MMR genes monitor and repair errors that may occur in normal cell replication and recombination. In some inherited and acquired cancers, one or more of the MMR genes is inactivated. ‘The impact of MultiMMR is huge. Tumors with MMR deficiency respond well to new cancer immunotherapies, ”explains lead researcher Trevor J. Pugh, PhD, Department of Medical Biophysics, University of Toronto; Princess Margaret Cancer Center, University Health Network; and the Ontario Institute for Cancer Research, Toronto, ON, Canada. “Determining whether an individual has a hereditary form of MMR deficiency can also allow clinicians to enroll patients in active supervision, conduct risk reduction strategies, and provide genetic testing to family members, showing the patient’s results. can improve. “

Trevor J. Pugh

Researchers have developed a new integrated genetic / epigenetic DNA sequencing protocol, known as MultiMMR, which addresses the presence and cause of lack of repair (MMR) in a single test from a small sample of DNA in colon, endometrial and other can identify cancers. This alternative to complex, multi-step test workflows can also determine the causes of MMR deficiency that are frequently missed by current clinical trials. Their results are presented in The Journal of Molecular Diagnostics, published by Elsevier. Credit: Trevor J. Pugh

Standard clinical trials for MMR deficiency may be inconsistent, requiring multiple tests and expertise, leading to suboptimal patient care. Next generation sequence tests have become popular and are used in clinical laboratories. However, they do not identify all genetic variations for MMR deficiency, and additional testing is often necessary.

The MultiMMR tests simultaneously for promoter methylation, mutations, copy number status, copy-neutral loss of heterozygosity, and microsatellite instability of a small amount of DNA. In this study, the researchers sequenced DNA from 142 samples (82 normal and 60 tumor samples) from 82 patients with MMR-associated colorectal, endometrial, and brain cancer. As a positive control, the results for 45 patients were compared with previous clinical trials using conventional tests. They also used MultiMMR to contain a commercially available DNA control containing 11 variants that are difficult to detect with the next generation sequence.

To detect the presence of MMR deficiency, 95 percent and 97 percent agreement, respectively, were found with clinical trials with MultiMMR promoter methylation and microsatellite instability analyzes. In detecting variants responsible for the MMR deficiency, MultiMMR fits the clinical trial results in 23 out of 24 cases. The test identified all 11 mutations in the synthetic mixture in multiple sequencing and identified the defective repair deficiency in 29 patients with incomplete or unconvincing tests. The panel was able to identify causes of MMR that are often missed by the current clinical cascade.

“We have shown that the presence and cause of MMR can be determined in a single test, from a single amount of DNA, thus making the best use of available tissue, improving the workflow flow and integrating the reporting for Lynch and related hereditary cancers. ” lead author Leslie Oldfield, MSc, Department of Medical Biophysics, University of Toronto; and Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.

The researchers note that current protocols for cascade testing may not be able to meet the increased demand for universal tumor testing in patients with colorectal and endometrial cancer. For example, many next-generation sequencing tests do not look for microsatellite instability and promoter methylation along with somatic mutations.

“Eligibility for immunotherapy is often dependent on MMR status, so it is important to test in a timely and strong manner,” she adds. Oldfield by. “MultiMMR streamlines the process and distinguishes the type of MMR deficiency with improved turnaround time, can increase well with increasing demands and can provide clinicians with important information to inform patients’ management and treatment decisions.”

Reference: “An Integrative DNA Sequencing and Methylation Panel to Assess Mismatch Repair Deficiency” by Leslie E. Oldfield, Tiantian Li, Alicia Tone, Melyssa Aronson, Melissa Edwards, Spring Holter, Rene Quevedo, Emily Van de Laar, Jordan Lerner-Ellis, Aaron Pollett, Blaise Clarke, Uri Tabori, Steven Gallinger, Sarah E. Ferguson and Trevor J. Pugh, 28 November 2021, The Journal of Molecular Diagnostics.
DOI: 10.1016 / j.jmoldx.2020.11.006

This study was supported by the Canada Research Chairs Program, Ontario Institute for Cancer Research Senior Investigator Award IA-063, the Princess Margaret Cancer Foundation Gattuso-Slaight Personalized Cancer Medicine Fund, Canadian Cancer Society Research Institute 704038, BioCanRx and Canada Foundation for Award for Innovation Leaders Opportunity Fund 32383.

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