Project description:Neuroblastoma is the most common solid tumor in children under the age of one. It displays remarkable phenotypic heterogeneity, resulting in differences in outcomes that correlate with clinical and biologic features at diagnosis. While neuroblastoma accounts for approximately 5% of all cancer diagnoses in pediatrics, it disproportionately results in about 9% of all childhood deaths. Research advances over the decades have led to an improved understanding of neuroblastoma biology. However, the initiating events that lead to the development of neuroblastoma remain to be fully elucidated. It has only been recently that advances in genetics and genomics have allowed researchers to unravel the predisposing factors enabling the development of neuroblastoma and fully appreciate the interplay between the genetics of tumor and host. In this review, we outline the current understanding of familial neuroblastoma and highlight germline variations that predispose children to sporadic disease. We also discuss promising future directions in neuroblastoma genomic research and potential clinical applications for these advances.
Project description:Kidney cancer is not a single disease but is made up of a number of different types of cancer classified by histology that are disparate in presentation, clinical course, and genetic basis. Studies of families with inherited renal cell carcinoma (RCC) have provided the basis for our understanding of the causative genes and altered metabolic pathways in renal cancer with different histologies. Von Hippel-Lindau disease was the first renal cancer disorder with a defined genetic basis. Over the next two decades, the genes responsible for a number of other inherited renal cancer syndromes including hereditary papillary renal carcinoma, Birt-Hogg-Dube´syndrome, hereditary leiomyomatosis and renal cell carcinoma, and succinate dehydrogenase-associated renal cancer were identified. Recently, renal cell carcinoma has been confirmed as part of the clinical phenotype in individuals from families with BAP1-associated tumor predisposition syndrome and MiTF-associated cancer syndrome. Here we summarize the clinical characteristics of and causative genes for these and other inherited RCC syndromes, the pathways that are dysregulated when the inherited genes are mutated, and recommended clinical management of patients with these inherited renal cancer syndromes.
Project description:Pancreatic adenocarcinoma (PC) is the most deadly of the common cancers. Owing to its rapid progression and almost certain fatal outcome, identifying individuals at risk and detecting early lesions are crucial to improve outcome. Genetic risk factors are believed to play a major role. Approximately 10% of PC is estimated to have familial inheritance. Several germline mutations have been found to be involved in hereditary forms of PC, including both familial PC (FPC) and PC as one of the manifestations of a hereditary cancer syndrome or other hereditary conditions. Although most of the susceptibility genes for FPC have yet to be identified, next-generation sequencing studies are likely to provide important insights. The risk of PC in FPC is sufficiently high to recommend screening of high-risk individuals; thus, defining such individuals appropriately is the key. Candidate genes have been described and patients considered for screening programs under research protocols should first be tested for presence of germline mutations in the BRCA2, PALB2 and ATM genes. In specific PC populations, including in Italy, hereditary cancer predisposition genes such as CDKN2A also explain a considerable fraction of FPC.
Project description:The objective of this study is to review the candidate gene and genome-wide association studies relevant to bronchopulmonary dysplasia, and to discuss the emerging understanding of the complexities involved in genetic predisposition to bronchopulmonary dysplasia and its outcomes. Genetic factors contribute much of the variance in risk for BPD. Studies to date evaluating single or a few candidate genes have not been successful in yielding results that are replicated in GWAS, perhaps due to more stringent p-value thresholds. GWAS studies have identified only a single gene (SPOCK2) at genome-wide significance in a European White and African cohort, which was not replicated in two North American studies. Pathway gene-set analysis in a North American cohort confirmed involvement of known pathways of lung development and repair (e.g., CD44 and phosphorus oxygen lyase activity) and indicated novel molecules and pathways (e.g., adenosine deaminase and targets of miR-219) involved in genetic predisposition to BPD. The genetic basis of severe BPD is different from that of mild/moderate BPD, and the variants/pathways associated with BPD vary by race/ethnicity. A pilot study of whole exome sequencing identified hundreds of genes of interest, and indicated the overall feasibility as well as complexity of this approach. Better phenotyping of BPD by severity and pathophysiology, and careful analysis of race/ethnicity is required to gain a better understanding of the genetic basis of BPD. Future translational studies are required for the identification of potential genetic predispositions (rare variants and dysregulated pathways) by next-generation sequencing methods in individual infants (personalized genomics).
Project description:Progresses over the past years have extensively improved our capacity to use genome-scale analyses-including high-density genotyping and exome and genome sequencing-to identify the genetic basis of pediatric tumors. In particular, exome sequencing has contributed to the evidence that about 10% of children and adolescents with tumors have germline genetic variants associated with cancer predisposition. In this review, we provide an overview of genetic variations predisposing to solid pediatric tumors (medulloblastoma, ependymoma, astrocytoma, neuroblastoma, retinoblastoma, Wilms tumor, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma) and outline the biological processes affected by the involved mutated genes. A careful description of the genetic basis underlying a large number of syndromes associated with an increased risk of pediatric cancer is also reported. We place particular emphasis on the emerging view that interactions between germline and somatic alterations are a key determinant of cancer development. We propose future research directions, which focus on the biological function of pediatric risk alleles and on the potential links between the germline genome and somatic changes. Finally, the importance of developing new molecular diagnostic tests including all the identified risk germline mutations and of considering the genetic predisposition in screening tests and novel therapies is emphasized.
Project description:Purpose of reviewBronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease in premature infants. Twin studies have shown strong heritability underlying this disease; however, the genetic architecture of BPD remains unclear.Recent findingsA number of studies employed different approaches to characterize the genetic aberrations associated with BPD, including candidate gene studies, genome-wide association studies, exome sequencing, integrative omics analysis, and pathway analysis. Candidate gene studies identified a number of genes potentially involved with the development of BPD, but the etiological contribution from each gene is not substantial. Copy number variation studies and three independent genome-wide association studies did not identify genetic variations significantly and consistently associated with BPD. A recent exome-sequencing study pointed to rare variants implicated in the disease. In this review, we summarize these studies' methodology and findings, and suggest future research directions to better understand the genetic underpinnings of this potentially life-long lung disease.SummaryGenetic factors play a significant role in the development of BPD. Recent studies suggested that rare variants in genes participating in lung development pathways could contribute to BPD susceptibility.