Clinically-relevant Germline Variants in Children with Non-Medullary Thyroid Cancer.

Abstract

The underlying genetic cause of non-medullary thyroid cancer (NMTC) in children is often unknown, hampering both predictive testing of family members and preventive clinical management. Our objectives were to investigated the potential heritability in the largest childhood NMTC cohort that has been genotyped to date. Nationwide retrospective cohort study. Tertiary referral centers. In total, 97 patients diagnosed with pediatric NMTC between 1970-2020 were included in this study. Germline whole genome sequencing (WGS). The main outcome measures were mutation detection yield in 1) clinically-relevant tumor predisposition genes, and 2) genes previously associated with NMTC. In total, 13 of 97 patients (13%) carried a germline (likely) pathogenic (P/LP) variant in a well-known tumor predisposition gene: APC (n=1), BRCA2 (n=2), CHEK2 (n=4), DICER1 (n=4), HOXB13 (n=1), , and MITF (n=1). In addition, one patient was diagnosed with Pendred syndrome (SLC26A4) and nine variants of high interest were found in other NMTC candidate susceptibility genes. The reported prevalence (13%) of germline variants in well-known tumor predisposing genes and the added value of a revised personal-/family history and histology led us to recommend genetic counseling for all childhood NMTC patients.The detected tumor predisposition syndromes are associated with a risk for second cancers which necessitates additional surveillance of the index patients and pre-symptomatic genetic testing of at risk family members.