Cancer Research, Oncology, Community

Children’s Mercy Kansas City tackles the unique complexity of pediatric cancer

A new exome-based test will help determine the genetic variants—germline and somatic—driving these rare cancers

Children’s Mercy Kansas City tackles the unique complexity of pediatric cancer
Assistant Clinical Laboratory Director Lisa Lansdon, PhD and Midhat Farooqi, MD, PhD, Director of Molecular Oncology, Genomic Medicine Center at Children’s Mercy Kansas City | Photo: Steve Puppe
9 March 2023

“Pediatricians like to say children are not little adults, and accordingly, pediatric cancer is not just the miniature form of adult cancer,” says Midhat Farooqi, MD, PhD, Director of Molecular Oncology, Genomic Medicine Center at Children’s Mercy Kansas City in Missouri. Historically, less attention and expertise have been devoted to researching cancer in children than adults, but Children’s Mercy is helping lead the effort to change that.

From its humble beginnings in 1897 with just one bed, the hospital has grown to 390 inpatient beds and 16 locations. It had 14,345 pediatric admissions in 2022—60% of them for patients less than 10 years old—who traveled to the hospital with their families from all 50 US states.

Children’s Mercy also pursues leading-edge research. In 2015, it established the Children’s Mercy Research Institute, founded and led by Tom Curran, PhD, FRS, Senior Vice President, Executive Director, Chief Scientific Officer, and Donald J. Hall Eminent Scholar in Pediatric Research. The Institute supports the launch of ambitious initiatives like Genomic Answers for Kids (GA4K), headed by Tomi Pastinen, MD, PhD, Dee Lyons/Missouri Endowed Chair in Pediatric Genomic Medicine.

The program’s goal is to sequence 30,000 children and their parents, and it just passed the milestone of providing more than 1,000 rare disease diagnoses to families; it largely addresses cases of rare genetic disease, but, as Farooqi points out, “Pediatric cancer is also a rare disease,” and the program is enrolling cancer patients as well.

Currently, the hospital is conducting 137 studies and trials—49 of which are in oncology—and developing databases that are crucial for research. In 2017, Erin Guest, MD, Director of the Children’s Mercy Cancer Genomics Program, and Alexander Kats, MD, Director of Nephropathology and Transplantation Pathology Services, set up a pediatric oncology biobank for storing both solid tumor and leukemic samples. This biobank is now part of the Research Institute’s CAP-accredited Biorepository, which is overseen by John David Nolen, MD, PhD, Chair of the Department of Pathology and Laboratory Medicine.

To date, over 500 patients have enrolled and Farooqi and his team have performed whole-genome and whole-exome sequencing on 200 of them. Children’s Mercy, which is the pediatric consortium partner of The University of Kansas Cancer Center, was awarded a grant from the National Cancer Institute to share this genomic data as part of the Childhood Cancer Data Initiative. Farooqi explains, “Collecting and sharing data nationally and beyond is really important for pediatric cancer because the numbers are low—it can take a few years for the university to register a dozen children with a single tumor type, whereas for adults, let’s say, the same number of cases could be accrued within a month. If we all work together, we can amass higher numbers of rare tumor types within pediatrics as well.”

How is pediatric cancer different from cancer in adults?

  • Cancer in children is rare, making it more difficult to study.
  • Genetic mutations differ in pediatric cancer patients compared to adults—even within the same tumor type.
  • Pediatric cancer is driven more often by genetic fusions than genetic mutations, necessitating the development of different targeted therapies.
  • The younger the patient, the more years side effects from chemotherapy could potentially affect them.

Not only does the study and diagnosis of cancer differ with children, but their treatment is more complex, considering how much of their life still lies ahead. This raises the stakes considerably. “Nonpersonalized, general chemotherapy is sort of a poison for all cells,” Farooqi cautions. “It hits cancer cells first because they are dividing faster, but normal cells are also affected, which leads to side effects and sometimes even secondary cancers from the initial therapy itself. We have to be really mindful that after cancer treatment, kids have a much longer lifetime ahead of them, so developing precision therapies that don’t have off-target effects is much more important in pediatrics.”

Farooqi works in the lab with Assistant Clinical Laboratory Director Lisa Lansdon, PhD, who helps the team look for clinically actionable variants. Her motivation stems from her first encounter with pediatric rare disease and pediatric cancer: When she was in elementary school, a friend was diagnosed with an inherited blood disorder called Diamond-Blackfan anemia. “He ended up passing away in sixth grade after developing leukemia,” she says. “It was a really impressionable experience for me, and I knew that genetics was where I wanted to land.”

Farooqi, too, was inspired by a personal connection. While he was in his residency, his grandfather was diagnosed with cancer. “That made me see the value of genetic testing for oncology,” he says. “Because one of the things we’re finding is that every patient’s cancer is unique, and that there are many, many different roads that a cell can take to become a tumor cell. So, figuring out which path that is can have a really big impact on the diagnosis, prognosis, and treatment for every patient with cancer.”

Why do kids get cancer?

For the most part, the answer to this question is unknown. Relative to adults, children have had much less exposure to environmental toxins and less time to accumulate “somatic mutations,” which generally occur after birth and can lead to cancer. We know that 10%–15% of all childhood cancers occur because of a predisposition—they carry a “germline mutation,” usually inherited from a parent at conception, that gives them a higher risk of cancer in their lifetime. However, this is not much different from the rate of adult cancers stemming from germline mutations, which is thought to be 5%–10%. Overall, more research is needed to answer this question.

A new exome test for patients
Recently, Children’s Mercy launched a clinical exome-based test for newly diagnosed or newly relapsed pediatric oncology patients. The Genomic Medicine Center’s CAP- and CLIA-certified lab runs the exome-based sequencing test at 300× coverage on samples of the patient’s tumor tissue and their healthy tissue (also called tumor/normal testing), analyzing the former for somatic variants and the latter for germline variants.

The advantage of doing this paired tumor/normal testing is that it tells the clinical team which specific variants are present in the tumor—if the healthy tissue also has the variant, then the patient’s blood relatives may benefit from being tested as well. “Otherwise, for some variants you always have this question of, ‘Is this variant in the germline?’” Farooqi says. “And if you’re trying to target mutations only in the tumor, then it helps to be absolutely sure that the variant is somatic.”

In general, most adult reference laboratories tend to do a high volume of tumor-only testing. Some academic institutions and commercial labs will do paired tumor/normal testing, but it’s more the exception than the rule. Children’s Mercy tests both under one roof and also offers a paired germline variant report, all thanks to an enormously supportive clinical group, hospital administration, and the philanthropic community of Kansas City.

“We’re lucky to have the support of the Hematology/Oncology group, under the direction of Alan Gamis, MD, MPH, and the Genetics Division of Pathology, directed by Carol Saunders, PhD,” says Farooqi, “and financial help from local foundations such as Black & Veatch, Big Slick, Braden’s Hope for Childhood Cancer, as well as many others. Plus, our hospital’s Philanthropy department and Senior Vice President of Allied Health Brian O’Neal, PharmD, MS, created a framework to ensure that no patient at Children’s Mercy would have to pay out of pocket for this testing, which is amazing!”

A bright future
Farooqi, who joined the hospital in 2016, is thrilled to be offering the exome-based test with a quicker turnaround mode of operation and the opportunity to share data for research. “Time is of the essence for our patients with cancer, so having accelerated capabilities to do paired tumor-normal analysis clinically in real time, plus the accuracy of the variant calling, makes the integration of our NovaSeq 6000 with Illumina Connected Software critical to our workflow,” he says. “Since we’ve laid a foundation, I am now most excited about getting to grow the program to offer more research insights and clinical tests—we are keenly interested in analyzing the sequence data for microsatellite instability and tumor mutational burden, as well as pharmacogenomics, to look at variants that could impact dosing for chemotherapy medicines.”

“We can see a path toward the future,” Lansdon adds. “We’re going to be able to develop additional tests that we can layer on top, get better insights, and give the latest and greatest information to our clinical teams. We have a laundry list a mile long of all the things that we could do in this vision for the future, and that’s super exciting, because it means that it doesn’t stop here with our new clinical exome test. For us, it really is just the beginning.”

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