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Genomic drivers of pediatric and early-onset solid tumors

Abstract

Recent advances in genomics have enabled the recognition of several novel cancer predisposing genes. Although genetic screening is currently well established for more common hereditary cancers, there is a number of rare tumors (annual incidence of less than 6 per 100,000 individuals) that are highly associated with cancer syndromes, but are often neglected due to its infrequency. The identification of the genetic causes of pediatric and early-onset rare tumors is important for the definition of better protocols for patient screening, clinical follow-up and familial management. In addition, knowledge of the molecular basis of the tumorigenesis in these tumors contributes to the understanding of different pathways and cellular processes involved in cell transformation and may become relevant for the definition of new therapies not only in hereditary tumors, but also in their sporadic counterparts. Thus, the present study aims to evaluate the frequency of pathogenic germline mutations in known genes predisposing to cancer in young patients (children, adolescents and young adults) with rare tumors and to apply comprehensive genomic approaches to determine novel genetic causes and underlying biological pathways of these cancers. To accomplish that, we will evaluate the coding sequences of 113 moderate to high penetrance genes associated to hereditary cancers using next generation sequence (NGS) in 200 pediatric and early-onset patients with rare solid tumors. Furthermore, in a subset of these patients in which no relevant germline variants are identified, we will perform whole exome sequencing of the germline and tumor DNA and tumor RNA sequencing in order to identify germline and somatic mutations in novel genes and to correlate these findings to altered molecular pathways in the tumor, resulting into insights into tumor biology. This proposal will contribute to establish a collaborative research project and promote an international scientific exchange between the Bellvitge Biomedical Research Institute (IDIBELL) in Barcelona, Spain and the A.C.Camargo Cancer Center (ACCCC), in São Paulo, Brazil. Pediatric and early-onset rare solid tumors were selected for this initiative because: they are still unwell understood regarding its hereditary risk; they require collaborative efforts to achieve a significant number of patients for each tumor type; they have a scarce number of comprehensive genomic studies; and they are a topic of common interest between the involved groups. With the establishment of this collaboration, we also expect to prepare and submit a proposal to establish a protocol for screening of pediatric and early onset hereditary tumors, including a standard pipeline for screening and analysis of germline and somatic and prediction of therapeutical candidates. (AU)

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