2023 ASPHO Conference Paper and Poster Index
Unknown authors
Abstract
Background: Adult-onset hereditary cancer predisposition syndromes (HCPSs) are those for which there is no expected increased risk for cancer in children.Rarely, children in families with adult-onset HCPSs present with cancer, but the potential contribution of the HCPS to these pediatric malignancies is unknown.While predictive testing for adult-onset HCPSs is typically deferred for healthy children until adulthood, when HCPS-related screening is initiated, it is increasingly common for children with cancer to have germline testing including adult-onset HCPSs completed.Objectives: We examined findings from pediatric patients enrolled in one institution's paired tumor-germline sequencing study to inform our knowledge of the potential role these germline pathogenic variants (PVs) may play in childhood cancer development.Design/Method: Paired tumor-germline sequencing results from pediatric oncology patients up to 25 years old (enrolled 5/2012-12/2022) were analyzed for frequency of germline PVs associated with adultonset HCPSs.Germline testing included analysis of 181 cancer predisposition genes associated with both pediatric and adult-onset HCPSs.Tumor loss-of-heterozygosity (LOH), immunohistochemistry (IHC) staining, and/or second somatic PV were used to determine possible association with a HCPS.Results: Of 872 participants, 42 (4.8%)had a total of 43 PVs in genes associated with adult-onset HCPSs, including ATM (3), BARD1 (1), BRCA1 (2), BRCA2 (5), BRIP1 (2), CHEK2 (17), HOXB13 (4), MITF (3), MLH1 (1), MSH6 (2), PALB2 (1), and RAD50 (2).Six (14.3%) had somatic features indicating the adult-onset HCPS likely contributed to their cancer development, rather than the HCPS being an incidental, unrelated finding.These included three patients with Lynch syndrome (two astrocytomas, one glioblastoma) and one each with germline PVs in ATM (glioma), BRIP1 (atypical teratoid rhabdoid tumor), and CHEK2 (mixed germ cell tumor).Conclusion: These findings suggest most pediatric cancer diagnoses in families with adult-onset HCPSs are unrelated to these syndromes, but rarely these "adult-onset" HCPSs may contribute to cancer diagnoses in children.This work may underestimate the role of these adultonset HCPSs in pediatric cancer development, as tumors may have other mechanisms of inactivation not identified in this study.None of the adult-onset HCPS-related tumors would have been identified by screening guidelines recommended for adults with these HCPSs.These findings raise the questions of whether cancer risk is truly restricted to adulthood in these syndromes, and how tumors caused by HCPSs may present differently in children than adults.Increased knowledge about potential childhood cancer risks related to these HCPSs could modify predictive genetic testing recommendations for children and enhance existing HCPS screening protocols.