Abstract
Increasing use of genomic sequencing enables standardized screening of all childhood cancer predisposition syndromes (CPS) in children with cancer. Gene panels currently used often include adult-onset CPS genes and genes without substantial evidence linking them to cancer predisposition. We have developed criteria to select genes relevant for childhood-onset CPS and assembled a gene panel for use in children with cancer. We applied our criteria to 381 candidate genes, which were selected through two in-house panels (n = 338), a literature search (n = 39), and by assessing two Genomics England’s PanelApp panels (n = 4). We developed evaluation criteria that determined a gene’s eligibility for inclusion on a childhood-onset CPS gene panel. These criteria assessed (1) relevance in childhood cancer by a minimum of five childhood cancer patients reported carrying a pathogenic variant in the gene and (2) evidence supporting a causal relation between variants in this gene and cancer development. 138 genes fulfilled the criteria. In this study we have developed criteria to compile a childhood cancer predisposition gene panel which might ultimately be used in a clinical setting, regardless of the specific type of childhood cancer. This panel will be evaluated in a prospective study. The panel is available on (pediatric-cancer-predisposition-genepanel.nl) and will be regularly updated.
Highlights
Cancer affects approximately 15,000 children and 20,000 young adults in Europe each year [1]
In order to develop the criteria for selecting genes eligible for the Pediatric cancer predisposition syndrome (CPS) gene panel, we divided the genes into two categories: Category 1 consisted of individual genes: genes causing a CPS that is not associated with variants in other genes, and Category 2 consisted of group genes: genes that can be grouped phenotypically together, as they give rise to the same CPS
The Pediatric CPS gene panel will aid the identification of genetic variants within genes with a proven causal link to childhood cancer which is a prerequisite in a diagnostic setting
Summary
Cancer affects approximately 15,000 children and 20,000 young adults in Europe each year [1]. In a significant percentage of cases, the cancer is caused by a pathogenic germline variant in a cancer predisposition gene. In recent studies, this percentage is estimated to be 7−10% [2,3,4]. This percentage is estimated to be 7−10% [2,3,4] In many of these patients the cancer predisposition syndrome (CPS) is recognizable by additional features or a positive family history. Genetic predisposition might play a role in children without recognizable features of genetic predisposition. In patients with pathogenic de novo variants in the TP53 gene, causing Li-Fraumeni syndrome (LFS), a family history of cancers suggesting the LFS diagnosis will be absent [5]
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