Genomic newborn screening for cancer risk: A retrospective cohort study.

Abstract

10014 Background: Population-based newborn screening (NBS) improves outcomes through early detection of rare pediatric conditions. Cancer is a leading cause of pediatric morbidity and mortality, but biomarkers for cancer risk are not included in NBS. NBS for detection of germline variants in genes associated with elevated risks of early onset childhood cancer could promote surveillance and early detection. Methods: Infants born in Michigan between 1987 and 2020 who developed a solid or CNS tumor before age 8 were identified through the Michigan Cancer Registry and linked to the state dried blood spot (DBS) biobank. DNA was extracted from 3.2 mm DBS punches and underwent t-NGS of 11 early-onset cancer predisposition genes ( RB1, TP53, WT1, RET, SMARCB1, PTCH1, SUFU, APC, DICER1, ALK and PHOX2b) . Deleterious single nucleotide, short insertion and deletion variants (SNV/indels) and copy number variants (CNVs) were identified using an automated variant classification platform (Fabric Genomics) including Clinvar classification. CNV’s were manually reviewed for evidence of deletion of at least one exon in a targeted gene. Results: 1948 DBS from infants who developed a solid or brain cancer before age 8 were identified. DNA extraction and tNGS with > 20X coverage was successful for 99.9% of DBS. A heterozygous deleterious variant was detected in 133 infants (116 SNV/indels and 17 CNVs), or 6.8% of the cohort. The distribution, by diagnostic group and gene is shown below. No activating ALK variants were detected. Germline deleterious predisposition variants (PV) in RB1 were detected in 40/50 bilateral retinoblastoma cases. 14/132 (11%) of medulloblastoma cases demonstrated a PV involving SUFU (6), PTCH1 (3), SMARCB1 (4) or TP53 (1). Heterozygous PV in RET were detected in 6/6 medullary thyroid carcinoma cases. Median age at cancer diagnosis was 14 months in cases with PV compared to 32 months in cases without PV (p < .001). Lower overall survival was noted in sarcoma cases with PV vs. those without PV and in brain tumor cases with PV vs. those without (Logrank test, p = .04 and p < .004, respectively). PV carriers developed proportionally more second cancers (9.5% vs 5%; p = 0.02) and 20% of PV carriers who received radiation therapy developed second cancers. Conclusions: Population-based genomic NBS could identify newborns at risk for early onset childhood cancers, enabling early surveillance, diagnosis and treatment. Inclusion of RB1 in a NBS test would identify 80% of children at risk for bilateral retinoblastoma. Further research focused on implementation of NBS for cancer risk is needed. Diagnosis Group Overall N=1948 No (%) with a variant Count of deleterious variants (combined CNV and SNV/indel) for each gene RB1 TP53 WT1 PTCH1 SUFU DICER1 SMARCB1 RET PHOX2b APC CNS tumors 667 28 (4%) 1 9 3 6 1 7 1 Renal Tumors 309 10 (3%) 1 7 1 1 Sarcoma 193 13 (7%) 10 1 2 Retinoblastoma 167 67 (40%) 67 Liver Tumors 87 3 (3%) 1 2 Neuroblastoma 450 1 (<1%) 1 Rare/Other 75 11 (15%) 1 3 1 6