CHEK2 Alterations in Pediatric Malignancy: A Single-Institution Experience

SIMPLE SUMMARY: Pediatric malignancies rarely occur, with 12,000–15,000 cases per year in the United States. Approximately 10% of pediatric cancers are thought to be secondary to germline alterations in cancer-predisposing genes based on numerous germline genomic analyses. CHEK2 germline loss-of-function variants have been reported in certain pediatric cancer patient cohorts, including neuroblastomas, non-Hodgkin lymphomas, thyroid cancer, melanomas, sarcomas, and brain tumors. However, a paucity of data exists surrounding clinical phenotypes and outcomes. In this study, we present our single-institution experience regarding six children and adolescents with CHEK2 germline alterations and cancer or cancer-predisposing conditions, including their clinical presentations and outcomes. We also review the current body of data regarding CHEK2 germline alterations in the pediatric cancer population and future challenges with studies on these alterations. ABSTRACT: Background: Approximately 10% of pediatric malignancies are secondary to germline alterations in cancer-predisposing genes. Checkpoint kinase 2 (CHEK2) germline loss-of-function variants have been reported in pediatric cancer patients, but clinical phenotypes and outcomes are poorly described. We present our single-institution experience of pediatric oncology patients with CHEK2 germline alterations, including clinical presentations and outcomes. Methods: Pediatric oncology patients with CHEK2 germline alterations were identified among those assessed by clinical or translational research at the Institute for Genomic Medicine at Nationwide Children’s Hospital. A chart review of disease course was conducted on identified patients. Results: We identified 6 patients with germline CHEK2 variants from a cohort of 300 individuals, including 1 patient with concurrent presentation of Burkitt lymphoma and neuroblastoma, 3 patients with brain tumors, 1 patient with Ewing sarcoma, and 1 patient with myelodysplastic syndrome. Three patients had a family history of malignancies. Four patients were in remission; one was undergoing treatment; one patient had developed treatment-related meningiomas. We review prior data regarding CHEK2 variants in this population, challenges associated with variant interpretation, and genetic counseling for individuals with CHEK2 variants. Conclusions: CHEK2 germline loss-of-function alterations occur in patients with a variety of pediatric tumors. Larger multicenter studies will improve our understanding of the incidence, phenotype, and molecular biology of CHEK2 germline variants in pediatric cancers.