Germline Predisposition to Pediatric Cancer, from Next Generation Sequencing to Medical Care

Abstract

Knowledge about genetic predisposition to pediatric cancer is constantly expanding. The categorization and clinical management of the best-known syndromes has been refined over the years. Meanwhile, new genes for pediatric cancer susceptibility are discovered every year. Our current work shares the results of genetically studying the germline of 170 pediatric patients diagnosed with cancer. Patients were prospectively recruited and studied using a custom panel, OncoNano V2. The well-categorized predisposing syndromes incidence was 9.4%. Likely pathogenic variants for predisposition to the patient's tumor were identified in an additional 5.9% of cases. Additionally, a high number of pathogenic variants associated with recessive diseases was detected, which required family genetic counseling as well. The clinical utility of the Jongmans MC tool was evaluated, showing a high sensitivity for detecting the best-known predisposing syndromes. Our study confirms that the Jongmans MC tool is appropriate for a rapid assessment of patients; however, the updated version of Ripperger T criteria would be more accurate. Meaningfully, based on our findings, up to 9.4% of patients would present genetic alterations predisposing to cancer. Notably, up to 20% of all patients carry germline pathogenic or likely pathogenic variants in genes related to cancer and, thereby, they also require expert genetic counseling. The most important consideration is that the detection rate of genetic causality outside Jongmans MC et al. criteria was very low.

Keywords: genetic counseling; genetic predisposition; genetic syndrome; germline; hereditary cancer; pediatric oncology; working tool.

Figure 1

Workflow established for the study.

Figure 2

Distribution of patients (%) by tumor type.

Figure 3

Genes and tumor types whereby pathogenic or likely pathogenic variants were identified.

Figure 4

Family tree of patient number 15. Despite not fulfilling the Jongmans MC criteria nor the revised criteria by Ripperger, the patient’s family history of cancer was still suggestive for genetic cancer predisposition and the genetic counseling was advised based on this information. The adolescent was diagnosed with extraosseous Ewing sarcoma. A CHEK2 variant was detected by the NGS OncoNano V2 panel. The variant was described in the general population (gnomAD reports three total heterozygotes). However, it was described six times in ClinVar and three times in cancer patients (uncertain clinical significance (ID 233261)). It was not found in other databases. In addition, it is a variant studied functionally on one occasion. It was reported in the literature in a patient with hereditary breast cancer, with functional in vitro study that demonstrated a 50% reduction in kinase activity [45], although the location of the variant was outside of a functional domain. The variant was found to be of maternal origin and family history of melanoma was identified in the grandfather and great-uncle in this branch of the family. In addition, the grandfather had had a second tumor at an older age. Based on the ACGM criteria and family information, the variant was classified as likely pathogenic.