Pediatric Oncology Patients With Germline Pathogenic Variants in Adult-Onset Cancer Predisposition Genes

Cancer predisposition syndromes caused by germline pathogenic variants (GPV) in adult-onset cancer predisposition genes (aoCPG) are those for which there is low risk of cancer in children, with genetic testing and screening for these conditions typically deferred until adulthood. GPV in aoCPG have been identified in pediatric oncology patients, but in these cases the potential contribution of the aoCPG to cancer development is often unknown. We investigated the role GPV in aoCPG may play in childhood cancer development.

Results of paired tumor-germline sequencing from pediatric oncology patients enrolled from May 2012 to October 2023 were analyzed for frequency of GPV in aoCPG. Germline testing included analysis of up to 182 cancer predisposition genes. Tumor loss-of-heterozygosity, presence of second somatic pathogenic variant, immunohistochemical stain for protein expression, and/or tumor mutation burden were used to determine possible causation.

Of the 954 participants, 42 (4.4%) had GPV in aoCPG. Six (14.3%) of these 42 participants had tumor findings indicating their GPV in an aoCPG likely contributed to cancer development: three patients with Lynch syndrome (two anaplastic astrocytomas, one giant cell glioblastoma) and one each with GPV in ATM (craniopharyngioma and diffuse high-grade glioma), BRIP1 (atypical teratoid rhabdoid tumor), and CHEK2 (mixed germ cell tumor of pineal gland).

These findings contribute to the literature suggesting that, rarely, GPV in aoCPG may contribute to cancer diagnoses in children, raising the question of how tumors in these cases may present differently in children than adults. Increased knowledge about potential childhood cancer risks related to what have historically been considered aoCPG could modify predictive genetic testing recommendations for children and enhance existing cancer screening protocols.