Expanding routine newborn screening to include genetic testing could identify genes associated with cancer risk and flag babies who may be at risk of later developing pediatric cancers, according to findings published in Nature Communications.
Newborns in the United States routinely undergo screening for a group of rare, treatable disorders by applying biochemical tests to a few drops of blood collected from a baby’s heel at about 24 hours after birth. Currently, cancer risk is not screened for because it would require DNA sequencing. But researchers say it may be possible, using the same blood samples to detect new or inherited mutations that predispose some children to cancer, much as genetic testing can identify adults at high risk for cancers such as breast or colon cancer.
About 1 in 27,000 newborns develop an early-onset malignancy that is associated with an associated pathogenic or likely-pathogenic variant.
“I take care of families who carry genes associated with increased risks of childhood cancer—they have a predisposition syndrome that ‘runs’ in the family,” said lead study author Lisa Diller, MD, Vice Chair of Pediatric Oncology at Dana-Farber Cancer Institute. “When a new baby is born in that family, we test the child. If that child has the familial mutation, my job is to make sure that if that child develops a tumor, or even a pretumor, we catch it early, which may allow for less toxic therapies and better outcomes.”
Study Methods
Researchers analyzed a Michigan birth cohort of 1,948 babies born between 1987 and 2020 who developed a solid tumor or central nervous system malignancy by age 8 years. They conducted targeted sequencing of 11 cancer predisposition genes with archived newborn dried blood spot DNA to see if genomic screening could identify newborns at risk for early-onset cancers.
Key Findings
Pathogenic or likely-pathogenic germline variants were identified in 132 children—6.8% of these cases—including 69 cases of RB1, 24 of TP53, eight of SMARCB1, seven of WT1, six of RET, six of SUFU, four of PTCH1, four of DICER1, three of APC, and one of PHOX2B.
The strongest signals were seen in cancers already known to have clear inherited risk links. All six children in the study who developed medullary thyroid carcinoma had a germline RET mutation. Forty percent of children with retinoblastoma 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.
Children with these cancer-predisposing mutations tended to develop cancer much earlier than other children in the study. The median age at diagnosis was 14 months for children with a detected mutation, compared with 32 months for children without one, underscoring how quickly these cancers can appear and how valuable advance warning could be.
Retinoblastoma offers a particularly clear example of how this information might change care. The researchers identified RB1 mutations in 69 children, 68 of whom later developed retinoblastoma. Among children with retinoblastoma, those with an RB1 mutation were diagnosed at a median age of 9 months, compared with 23 months for those without a detected germline RB1 mutation. If these children had been identified at birth, they could have undergone regular eye exams to detect tumors earlier, potentially improving vision outcomes and reducing the need for intensive treatments such as eye removal, chemotherapy, or radiation.
“Finding an early tumor or pretumor saves [a] child from a more difficult-to-treat and sometimes fatal diagnosis,” Dr. Diller added.
Germline variance prevalence was more common in certain cancers, including medullary thyroid carcinoma (100%); retinoblastoma (40%); and choroid plexus carcinoma, adrenocortical carcinoma, pineoblastoma, and medulloblastoma (11%–30%), with strong gene–tumor specificity (P < .001).
These findings provide strong evidence that selected pediatric cancer-risk genes could be valuable additions to expanded newborn screening, particularly when early detection can lead to closer surveillance, earlier diagnosis, and less toxic treatment.
DISCLOSURES: Funding was provided by the Bridge Project, a partnership between the Koch Institute at MIT and the Harvard Cancer Center. For full disclosures of the study authors, visit nature.com.
