- Using a panel of 11 genes linked to pediatric cancer predisposition syndromes, researchers found pathogenic or likely pathogenic variants in 7% of newborns who later developed a solid or brain tumor.
- Targeted sequencing of this panel would identify approximately 1/27,000 infants who will develop cancer by age 8 years in the setting of a genetic cancer predisposition syndrome.
- Researchers said it is feasible to conduct genomic newborn screening universally.
Adding genomic testing to routine newborn screening identified children at increased risk of developing certain childhood cancers, researchers found.
By analyzing archived newborn dried blood spots from nearly 2,000 children who later developed a solid or brain tumor by age 8 years, and using a panel of 11 genes linked to pediatric cancer predisposition syndromes, pathogenic or likely pathogenic variants were found in 132 children (6.8%), reported Lisa Diller, MD, of the Dana-Farber Cancer Institute in Boston, and colleagues.
The results show that "targeted sequencing of a panel of cancer predisposition genes would identify approximately 1/27,000 infants who will develop cancer by age 8 in the setting of a genetic cancer predisposition syndrome," they wrote in Nature Communications. "Our data support newborn screening for selected cancer-risk genes."
The authors pointed out that the observed prevalence of 1/27,000 is "consistent with, or even higher than, other diseases currently included in newborn screening, such as Pompe disease (1/18,000 births), severe combined immunodeficiency (1/59,000 births), and maple syrup urine disease (1/200,000 births)."
In any case, early identification of these children could alter their survival outcomes, Diller and team noted.
"It's become clear over the past few decades that at least 10% or more of kids who develop cancer have genetic predisposition to cancer, and a good chunk of those kids are diagnosed in the first few years of life," Diller told MedPage Today. "It predisposes them to very-early-onset cancers. So the clinical problem is, can we do anything other than wait for them to develop their cancers?"
Using data from Michigan's Cancer Surveillance and Newborn Screening Programs, the authors identified 1,948 children born in Michigan from 1987 to 2020 who developed a solid or central nervous system malignancy by age 8 years and had archived dried blood spots.
They performed targeted next-generation sequencing of pathogenic or likely pathogenic germline variants in 11 autosomal dominant cancer risk genes -- RB1, TP53, SMARCB1, WT1, RET, SUFU, PTCH1, DICER1, APC, PHOX2B, and ALK.
Variants were most often identified in RB1 (n=69), TP53 (n=24), SMARCB1 (n=8), and WT1 (n=7), while no pathogenic or likely pathogenic germline variants were detected in the ALK gene.
The strongest signals were seen in cancers already known to have clear inherited risks. All six children in the study who developed medullary thyroid carcinoma had a germline RET mutation, while 40% of children with retinoblastoma, the most common eye tumor in childhood, had a germline RB1 mutation.
Across several other cancers, including choroid plexus carcinoma, adrenocortical carcinoma, pineoblastoma, and medulloblastoma, 11% to 30% of cases had a detectable mutation in one of the genes studied.
In 130 of the 132 children with a mutation, the gene was known to be associated with the type of tumor they later developed.
For children who carry these variants, the ability to identify them at birth has potential life-changing, or life-saving, implications, the authors said.
Diller noted that retinoblastoma -- a rare eye cancer that begins in the retina and mostly affects infants and young children -- drove her interest in newborn genomic testing.
"A clinically detected retinoblastoma is often associated with losing sight, needing chemotherapy, or having your eye removed," Diller said. However, if children with an RB1 mutation were identified at birth, they could undergo regular eye exams to detect the tumor earlier, after which they could be treated with laser therapy or cryotherapy, "avoiding the need for chemotherapy, surgery, and radiation, and preserving sight."
"That's true of all the genes that we chose," she added.
For example, the researchers chose genes associated with the development of Wilms tumor -- a rare type of kidney cancer that mostly affects young children under the age of 5 years. "If you know a child's at risk for a Wilms tumor, you do ultrasounds every 3 months," Diller explained. "And if you find the small tumor, they don't have to lose a kidney, they can use minimal chemotherapy, they don't need radiation, and it can be life preserving."
How feasible is it to perform newborn genomic testing universally?
Co-author Richard Parad, MD, MPH, of Brigham and Women's Hospital in Boston, said he believes the elements are in place to make it happen.
States have newborn screening programs in place with public health laboratories, so the question becomes whether "they can learn and do high-throughput genomic sequencing," he told MedPage Today.
Laboratories already extract DNA from the newborn dried blood spot to screen for severe combined immunodeficiency disorder, he said. "What's needed is the sequencing machine, and then putting the DNA in and being able to interpret the sequence. The machines are expensive, but not out of the range of, say, a tandem mass spectrometer that these labs buy now. The interpretation is probably the most difficult part, [but] software programs are available and this is becoming more and more automated."
There are also ways to reduce the cost of testing, he added. "We're using a targeted panel, so we're only focusing on 11 genes in this study, so that's less expensive. We don't need a sledgehammer to look at the whole genome."
"The technology is there, the AI [artificial intelligence] interpretation is there, and then the cost is low enough," Parad said. "And the DNA is already there -- it's already in the laboratory, sitting there waiting for someone to look at it. So, these pieces are going to come together."
Diller and colleagues noted that another piece of the puzzle is whether parents actually want genomic testing, considering the potential risks of early identification, "including psychological distress for families, the burden of surveillance in young children, and the possibility of overdiagnosis or unnecessary interventions arising from indeterminate findings."
The authors also recently published a study in the Journal of Pediatrics that assessed parental experiences following diagnosis of a cancer predisposition syndrome in their children and their perspectives on population-based genomic newborn screening. Parents characterized receiving a cancer predisposition syndrome diagnosis as emotionally challenging but said the process is worthwhile.
"You would think those families, when they go through years of having to go to the clinic over and over and having all these tests done, would be angry or be fed up," Diller said. "But when we asked them what they thought about newborn screening -- even if we didn't find anything -- and whether this should be offered to the public, they all said yes."
Disclosures
Diller, Parad, and several co-authors reported receiving funding for this research through a "Traditional Bridge Grant" from the Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology and the Dana-Farber/Harvard Cancer Center.
There were no other disclosures.
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