“Pediatricians like to say children are not little adults, and accordingly, pediatric cancer is not just the miniature form of adult cancer,” said 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.
The hospital has grown from its humble beginnings with just one bed in 1897 to 390 inpatient beds and 16 locations today. In 2022, it had 14,345 paediatric admissions, 60% of which were for patients younger than 10 years old and came from all 50 US states.
Children's Mercy is also committed to cutting-edge research. The Children's Mercy Research Institute was 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, in 2015. The Institute encourages the launch of bold initiatives such as Genomic Answers for Kids (GA4K), led 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 recently passed the 1,000 rare disease diagnoses milestone; it primarily 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, as well as developing research databases. Erin Guest, MD, Director of the Children's Mercy Cancer Genomics Program, and Alexander Kats, MD, Director of Nephropathology and Transplant Pathology Services, established a paediatric oncology biobank in 2017 to store both solid tumor and leukemic samples. This biobank is now a part of the CAP-accredited Biorepository at the Research Institute, which is overseen by John David Nolen, MD, PhD, Chair of the Department of Pathology and Laboratory Medicine.
Over 500 patients have enrolled so far, with Farooqi and his team performing whole-genome and whole-exome sequencing on 200 of them. Children's Mercy, The University of Kansas Cancer Center's paediatric consortium partner, 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.”
What distinguishes paediatric cancer from adult cancer?Children's cancer research and diagnosis differ, but their treatment is more complicated, given how much of their life is still ahead of them. This significantly raises the stakes.
“Non-personalized, general chemotherapy is sort of a poison for all cells,”
cautioned Farooqi.
“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 Lisa Lansdon, PhD, Assistant Clinical Laboratory Director, who assists the team in their search for clinically actionable variants. Her motivation stems from her first encounter with paediatric rare disease and paediatric cancer: when she was in elementary school, a friend was diagnosed with Diamond-Blackfan anaemia, an inherited blood disorder.
“He ended up passing away in sixth grade after developing leukemia,” she said. “It was a really impressionable experience for me, and I knew that genetics was where I wanted to land.”
Farooqi was also motivated by a personal connection. His grandfather was diagnosed with cancer while he was in residency.
“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 children get cancer? The majority of the time, the answer to this question is unknown. Children have had much less exposure to environmental toxins and less time to accumulate "somatic mutations," which typically occur after birth and can lead to cancer, than adults. We know that 10%-15% of all childhood cancers are caused by a predisposition—they have a "germline mutation," usually inherited from a parent at conception, that increases their lifetime risk of cancer. However, this is not significantly different from the 5%-10% rate of adult cancers caused by germline mutations. More research is needed to answer this question in general.
A new exome test is available for patients Children's Mercy recently introduced a clinical exome-based test for newly diagnosed or relapsed paediatric oncology patients. The CAP- and CLIA-certified lab at the Genomic Medicine Center performs the exome-based sequencing test at 300 coverage on samples of the patient's tumor tissue and healthy tissue (also known as tumor/normal testing), analyzing the former for somatic variants and the latter for germline variants.
The benefit of performing this paired tumor/normal testing is that it informs the clinical team about which specific variants are present in the tumor—if the variant is also present in the healthy tissue, 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.”
Most adult reference laboratories perform a high volume of tumor-only testing. Some academic and commercial labs will perform paired tumor/normal testing, but this is more of an exception than the rule. Children's Mercy tests both under one roof and provides a paired germline variant report, thanks to an extremely supportive clinical group, hospital administration, and the Kansas City philanthropic community.
“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,” said Farooqi while adding, “Financial assistance from local foundations such as Black & Veatch, Big Slick, Braden’s Hope for Childhood Cancer, as well as many others have been a big help. 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 promising future Farooqi, who joined the hospital in 2016, is overjoyed to be able to offer the exome-based test with a faster turnaround time 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,” said
Farooqi. “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.”
To know more about Illumina’s expanding access to genomics, click
here.
