Diagnostic Strategies and Algorithms for Investigating Cancer Predisposition Syndromes in Children Presenting with Malignancy

SIMPLE SUMMARY: Here we provide an overview of several genetically determined conditions that predispose to the development of solid and hematologic malignancies in children. Diagnosing these conditions, whose prevalence is estimated around 10% in children with cancer, is useful to warrant personalized oncologic treatment and follow-up, as well as psychological and genetic counseling to these children and their families. We reviewed the most recent studies focusing on the prevalence of cancer predisposition syndromes in cancer-bearing children and the most-used clinical screening tools. Our work highlighted the value of clinical screening tools in the management of young cancer patients, especially in settings where genetic testing is not promptly accessible. ABSTRACT: In the past recent years, the expanding use of next-generation sequencing has led to the discovery of new cancer predisposition syndromes (CPSs), which are now known to be responsible for up to 10% of childhood cancers. As knowledge in the field is in constant evolution, except for a few “classic” CPSs, there is no consensus about when and how to perform germline genetic diagnostic studies in cancer-bearing children. Several clinical screening tools have been proposed to help identify the patients who carry higher risk, with heterogeneous strategies and results. After introducing the main clinical and molecular features of several CPSs predisposing to solid and hematological malignancies, we compare the available clinical evidence on CPS prevalence in pediatric cancer patients and on the most used decision-support tools in identifying the patients who could benefit from genetic counseling and/or direct genetic testing. This analysis highlighted that a personalized stepwise approach employing clinical screening tools followed by sequencing in high-risk patients might be a reasonable and cost-effective strategy in the care of children with cancer.