New Type of Genetic Testing Aims To Benefit Children and Young Adults With Cancer

MSK scientists Andrew Kung and Elli Papaemmanouil

MSK scientists Andrew Kung and Elli Papaemmanouil

DNA sequencing tests that look for mutations in cancer-associated genes have become the standard of care at leading centers, including at Memorial Sloan Kettering Cancer Center (MSK). MSK’s test, called MSK-IMPACT™, can detect mutations in 500-plus cancer-related genes. This information can refine diagnoses and can help doctors determine if an available drug might benefit a particular patient, based on the tumor’s genetic profile.

This cancer-gene-panel approach works very well for adults with common types of cancer, like breast, colorectal, lung, and prostate cancer. But for children and young adults, whose tumors tend to be rare, these panel tests have not been as useful for matching patients to appropriate therapies. That’s because, as researchers are coming to realize, the mutations that drive tumors in young patients tend to be different.

“Adult cancers are usually caused by a lifelong accumulation of mutations from exposure to things like sunlight, cigarette smoke, and carcinogens in the diet,” explains physician-scientist Andrew Kung, who is Chair of the Department of Pediatrics at MSK and who researches the molecular causes of childhood cancers. “Those mutations are usually what are called point mutations — where a single letter of DNA is changed in a gene.”

“With pediatric cancers,” he continues, “the driving mutations tend to be structural changes affecting whole sections of chromosomes. These are often located outside of the boundaries of known cancer genes, where they go undetected by existing tests.”

To better visualize these structural variants, researchers need a way of reading not only the changes to the spellings of particular “words,” or cancer genes, but also the organization of those words in the context of paragraphs and chapters. That’s what a technique called whole genome DNA and RNA sequencing provides, and Dr. Kung and his colleagues believe it may make an important difference in the care of children with cancer.

Such whole genome sequencing has been available for about 10 years, but the high price tag and the time it takes to analyze and interpret such vast amounts of data have prevented this type of sequencing from meaningfully impacting cancer care. Now, with the cost of whole genome sequencing coming down — it will soon cost less than $1,000 per genome — Dr. Kung, MSK computational oncologist Elli Papaemmanouil, and their colleagues have been considering how to make clinical use of this information to benefit patients.

“Everyone agrees that whole genome sequencing will eventually become the go-to diagnostic test to profile tumors,” says Dr. Papaemmanouil. “But there have been several obstacles standing in the way.”

Everyone agrees that whole genome sequencing will eventually become the go-to diagnostic test to profile tumors. But there have been several obstacles standing in the way.
Elli Papaemmanouil computational oncologist

The biggest one, she says, is being able to make sense of the vast amount of data that comes from sequencing the billions of DNA letters making up an entire genome — pinpointing and, relatedly, conveying the clinically relevant information to doctors in a timeframe that could help with care decisions.

Now, in a paper published May 18, 2022, in the journal Nature Communications, Drs. Papaemmanouil and Kung and their colleagues report on the performance of a whole genome sequencing platform that they believe solves these challenges.

“We show that it’s possible for a single institution, using our platform, to provide relevant information to clinicians in about a week,” she says. “This is significantly faster — by a matter of weeks — than existing approaches.”

Making a Difference for Children and Adolescents

In their paper, the researchers report the results of using their sequencing approach on 114 pediatric, adolescent, and young adult patients with solid tumors, and comparing those results with ones obtained from MSK-IMPACT.

They found that their approach identified at least one additional cancer-associated oncogenic variant in 54% of patients (62 out of 114), compared with MSK-IMPACT. Of these, 33 patients had one or more findings that were of direct clinical relevance.

In one case, the additional genetic information led doctors to put a 13-year-old patient on an immunotherapy drug that caused his refractory adrenal cortical carcinoma to go into a complete remission.

Alex Kentsis, a pediatric tumor researcher at MSK who was not involved in the study, said that this whole genome sequencing approach “not only substantially improves the accuracy of diagnosis of patients with diverse cancers but also, for the first time, enables clinical detection of specific types of tumor genetic rearrangements that predominate and cause many childhood and young adult cancers.”

Dr. Papaemmanouil notes this test may have an additional benefit for patients with a significant amount of cancer in their body. “There is the possibility of deriving a whole genome tumor profile from a blood sample,” she says. “This would be an advantage when a patient’s tumor is in a hard-to-biopsy place, like the brain.”

The test is offered patients treated in the Department of Pediatrics.

Not Yet a Replacement for Other Tests

The researchers emphasize that the new platform is not currently a replacement for panel-based tests, such as MSK-IMPACT, which work well for capturing relevant mutations in adult patients with common tumors — and have made a difference in their outcomes.

“What we’re trying to do is to bring a more comprehensive approach to pediatric patients and others with rare cancers, a minority of whom benefit from panel-based testing,” says Dr. Kung. “We want to make precision medicine more inclusive and a possibility for every cancer patient.”

The study authors say the benefits for pediatric patients are so compelling that this type of testing is now being made available to every pediatric patient at MSK through philanthropic funding. So that patients outside of MSK can benefit from it too, MSK has licensed the technology to a company, Isabl Inc., that will be developing and making it available to other cancer centers and hospitals.


Funding for this study was provided by the Olayan Fund for Precision Pediatric Cancer Medicine. Memorial Sloan Kettering Cancer Center has intellectual property rights and financial interests related to Isabl Inc., the company licensing the technology described in this post. Drs. Papaemmanouil and Kung have intellectual property rights related to the technology. Dr. Papaemmanouil is a co-founder of Isabl Inc., serves as CEO of Isabl Inc., and holds equity in the company. Dr. Kung is a co-founder of Isabl Inc., serves on the Board of Directors of Isabl Inc., and holds equity in the company.