Gene Curation Expert Panel for Childhood, Adolescent and Young Adult Cancer Predispositions - PROJECT SUMMARY/ABSTRACT Cancer is the most common cause of disease-related death in children in North America, and cancer incidence increases with age, including through adolescence and into young adulthood. Importantly, genetic predisposition contributes to the development of cancer in at least 10-15% of pediatric oncology patients, with similar rates likely in adolescents and young adults, the early detection of which presents opportunities for improved outcomes. Many of the genes with cancer-predisposing deleterious germline variants are shared across all ages, but there are some putative gene-disease associations that are unique to the childhood, adolescent and young adult (CAYA) populations. Establishing the clinical validity of genes and cancer risk in the CAYA population can prove challenging due to the rarity of the syndromes. With increasing use of germline testing in children, there is an urgency in systematically defining gene-disease relationships to ensure appropriate clinical action. Recognizing these challenges, and gaps in current gene curation efforts, we recently established the CAYA Cancer Predisposition Gene Curation Expert Panel (CAYA GCEP) affiliated with the Hereditary Cancer Clinical Domain Working Group. Chaired by 3 experts with strong track records of contributions and leadership in the field of CAYA cancer predisposition, the CAYA GCEP includes an initial team of 36 experts and 19 biocurators, representing 28 institutions. Through our initial review, we have identified 124 genes associated with cancer predisposition disorders that may significantly impact the CAYA population, and which are not being addressed by other GCEPs or have been curated solely for non-oncologic disease associations. Importantly, among these genes, there is considerable enrichment of genes associated with hematopoietic malignancies and bone marrow failure syndromes, which has influenced membership and organization of the CAYA GCEP. Uniquely, the CAYA GCEP will have access to data from several registries for children with cancer predisposition disorders, which will help in gene-disease curation when published data are scant. The goals of the CAYA GCEP will be achieved through the following specific aims: 1) Curate gene-disease validity for candidate genes and predispositions to hematopoietic malignancies and 2) Curate gene-disease validity for candidate genes and predispositions to intracranial and extracranial solid tumors. For Aim 1, prioritization of genes includes collaboration with the leadership of the Myeloid Malignancy VCEP, to ensure gene-disease validity prior to variant curation, including in SAMD9L and SAMD9, for which variant curation is already planned. For Aim 2, genes asserted to be associated with CNS tumors, neuroblastoma and Wilms tumor are prioritized, as these are the most prevalent solid tumors in children and adolescents. We will also perform a pilot study of the use of artificial intelligence to enhance the efficiency of gene-disease curation. The work of the CAYA GCEP will have immediate clinical actionability as it relates to the incorporation of genes in hereditary cancer genetic testing panels and provide the pre-requisite gene-disease validity allowing for subsequent variant curation by the appropriate VCEPs.
