New Genetic Test Effectively Screens for Hereditary Cancers

A single test can identify the multitude of known sources of genetic variation underlying mismatch repair deficiency syndrome in inherited colon, endometrial, and other cancers, researchers report in The Journal of Molecular Diagnostics.

Researchers have developed a new integrated genetic/epigenetic DNA-sequencing protocol known as MultiMMR that can identify the presence and cause of mismatch 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 testing workflows can also determine causes of MMR deficiency often missed by current clinical tests. Their results are presented in The Journal of Molecular Diagnostics, published by Elsevier.

MMR genes monitor and repair errors that can occur in normal cell replication and recombination. In some inherited and acquired cancers, one or more of the MMR genes are deactivated. “The impact of MultiMMR is broad. Tumors with MMR deficiency respond well to new cancer immunotherapies,” explains lead investigator Trevor J. Pugh, PhD, Department of Medical Biophysics, University of Toronto; Princess Margaret Cancer Centre, University Health Network; and Ontario Institute for Cancer Research, Toronto, ON, Canada. “Determining whether an individual has an inherited form of MMR deficiency can also allow clinicians to enroll patients in active surveillance, engage in risk-reduction strategies, and provide genetic testing to relatives – potentially improving patient outcomes.”

Standard clinical testing for MMR deficiency can be inconsistent, requiring multiple tests and types of expertise, resulting in suboptimal care for patients. Next-generation sequencing tests have gained popularity and are being used in clinical laboratories. However, they do not identify all genetic variations for MMR deficiency and additional testing is often required.

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

To detect the presence of MMR deficiency, MultiMMR promoter methylation and microsatellite instability analyses found 95 percent and 97 percent concordance with clinical testing, respectively. In detecting variants responsible for the MMR deficiency, MultiMMR matched the clinical testing results in 23 out of 24 cases. The test identified all 11 mutations in the synthetic mix in multiple sequencing runs and identified the mismatch repair deficiency in 29 patients with incomplete or inconclusive testing. The panel was able to identify causes of MMR 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 aliquot of DNA, thereby making best use of available tissue, streamlining workflows, and improving integrated reporting for Lynch and related hereditary cancers,” comments lead author Leslie Oldfield, MSc, Department of Medical Biophysics, University of Toronto; and Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

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

“Eligibility for immunotherapy is often contingent on MMR status, so timely and robust testing is important,” adds Ms. Oldfield. “MultiMMR streamlines the process and distinguishes the type of MMR deficiency with improved turnaround time, can scale well with increasing demands, and can provide clinicians with important information to inform patient 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 grant 704038, BioCanRx, and Canada Foundation for Innovation Leaders Opportunity Fund grant 32383.

Dr. Jerome Lejeune found the genetic cause of Down's Syndrome caused by an extra copy of Chromosome 21. His discovery led to others using that information to develop tests to weed those babies out.

Dr. Lejeune was devastated that his discovery led to aborting those babies.

How many tests are women going to be coerced into taking just to see how many abnormalities lie within the couples genetic makeup? And then abort those babies who are not "perfect"?

Hitler would be pinching himself with delight.

Even though it wouldn’t fall under pre existing conditions, per current law pre existing conditions are covered. It shouldn’t be a problem. On the other hand this has the potential to *reduce* healthcare costs due to early detection and taking early action.

On the other hand this has the potential to *reduce* healthcare costs due to early detection and taking early action.

Okay, so you get your DNA test results back, and the news isn't so good:

You have a 47% higher-than-average risk of contracting an especially virulent form of Small-Cell Carcinoma; a 95% increased risk of contracting a rare but incurable form of Squamous Cell Carcinoma; and a whopping 350% increased chance of getting Acute Lymphoblastic Leukemia of the "Philadelphia Chromosome" variant for which there is no therapy and which invariably has an extremely unfavorable prognosis in adults.

Boy, aren't you glad you got tested!

Regards,

Just another trick to get your DNA on file.

Did your parents have cancer? No.

Did your grandparents have cancer? No.

Have your siblings had cancer? No.

Your in-laws, non-biological relatives and neighbors’ illnesses don’t count.

I’m not a doctor and didn’t stay at Holiday Inn but my free unprofessional guess, don’t come for me, of you getting cancer is pretty low, imo. Of course, if you sneak into the hospital to play with the x-ray machines or drink toxic water, well, that might change things.

Nothing in this world (except that math is racist) is 100%.

Well..it’s not a pleasant discovery for sure. But think of what you can do with that knowledge. You can get scanned every 6 months or at least every year paying special attention to any “spots” that show up, and if they do then get a biopsy done right away followed by surgery and/or adjuvant therapy. It may *save your life*. As for ALL, there may not be much you can do other than be mentally prepared. Even for Ph+ there are many options available today like CAR-T, bispecifics and other targeted regimens. So it’s not as bad as it used to be. The point is it’s better to know and be prepared (mentally and otherwise) than to bury one’s head in the sand and suddenly receive a dire diagnosis one day.

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