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

Context: 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.

Objective: Our objectives were to investigated the potential heritability in the largest childhood NMTC cohort that has been genotyped to date.

Design: Nationwide retrospective cohort study.

Setting: Tertiary referral centers.

Patients: In total, 97 patients diagnosed with pediatric NMTC between 1970-2020 were included in this study.

Intervention: Germline whole genome sequencing (WGS).

Main outcome: The main outcome measures were mutation detection yield in 1) clinically-relevant tumor predisposition genes, and 2) genes previously associated with NMTC.

Results: 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.

Conclusion: 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.