Clinical and molecular characterization of childhood cancer susceptibility syndromes
12 / 2007 - unknown
The OBJECTIVES OF THE STUDY are to:1) Identify novel childhood cancer-predisposing genes in children with a malignancy and one or more phenotypic abnormalities.2) Identify novel childhood cancer predisposing genes in patients with a malformation syndrome (such as Noonan syndrome) and malignancy.Since patients with a malignancy and phenotypic abnormalities are likely to exhibit genomic anomalies (microdeletions and/or duplications), we propose to apply our whole genome tiling resolution arrayCGH technology to the identification of novel cancer-predisposing candidate genes in these patients. In addition, we will search for mutations in genes operating within oncogenetic pathways, such as genes from the WT1 or the Ras signaling pathway, in patients with a malignancy and one or more phenotypic abnormalities (e.g. Noonan syndrome). The identification of children with a malignancy and a germline mutation in a malignancy causing gene, but milder or fewer phenotypic features, may enable us to develop comprehensive cancer preventive programs within families of children with a malignancy.The RESEARCH QUESTIONS are: Which novel genes or group of genes within a defined chromosomal region may have caused malignancy in children with phenotypic abnormalities? Which germline mutations in known and novel genes of oncogenetic pathways associated with congenital malformation syndromes (such as genes associated with the WT1 gene or the Ras signaling pathway) may have caused malignancy in children with phenotypic abnormalities? Can physical appearance help to identify children at risk for malignancy? At present, the etiology of most childhood malignancies is unknown. Based on an overall increase in the Standard Incidence Ratio (SIR; 1.1-1.8) of first-degree relatives in the population of children with malignancies, a certain degree of genetic predisposition is anticipated. In specific subgroups of childhood malignancies hereditary factors appear to be likely, since there is a higher incidence of phenotypic abnormalities present in children with malignancies, and an increased incidence of childhood malignancies, is seen in children with various congenital malformation syndromes. Recently it was established that 8% of the children with a malignancy suffer from an additional congenital malformation syndrome. This coincidence is higher in children with solid tumors than in those with leukemia, and is highest in children with neonatal tumors (~30%). These percentages are significantly higher than the 1 % observed in the general population, and strongly underline the notion that constitutional anomalies may be associated with the occurrence of pediatric malignancies. Since patients with a malignancy and a congenital malformation syndrome are likely to exhibit genomic anomalies (microdeletions and/or duplications) that are within the limits of detection by microarray-based comparative genomic hybridization (arrayCGH) array, such patients are particularly well-suited for the discovery of novel cancer-predisposing genes. We have, as one of a few groups worldwide, developed and validated a human whole genome tiling resolution BAC microarray ( 32k set ) for the efficient detection of sub-microscopic anomalies. Here we propose to apply our whole genome arrayCGH technology to the identification of novel candidate genes in children with a malignancy and one or more phenotypic abnormalities.Typical examples of known congenital malformation syndromes that co-incide with a relatively high risk for childhood cancer are Noonan syndrome, Costello syndrome and Cardio-Facio-Cutaneous (CFC) syndrome. The most prominent malignancies associated with these malformation syndromes are neuroblastoma, rhabdomyosarcoma and leukemia (juvenile myelo-monocytic leukemia, JMML). Very recently, it was shown that a considerable proportion of these syndromes is due to mutations in genes that act in the ras proto-oncogene signaling pathway, i.e., PTPN11 and KRAS (Noonan syndrome), HRAS (Costello syndrome), and BRAF and KRAS (CFC syndrome). However, in 50% of the patients with Noonan syndrome, such mutations could not be found. Probably, other genes operating within the ras-signaling pathway are affected in these as yet unresolved cases. Similarly, some children with an inherited mutation in a ras pathway gene might have only a limited number of abnormalities that do not allow for a confident syndrome diagnosis. In addition to the ras signaling pathway, other oncogenetic pathways are associated with congenital malformation syndromes, for example the tumor suppressor gene Wilms Tumor1 (WT1). Here we propose to perform a mutation scan, searching for novel genes in known and unknown oncogenetic pathways. These scans will be performed in children with a malignancy and one or more congenital phenotypic abnormalities. RELEVANCE: The identification of known and novel cancer-predisposing genes, as suggested in this proposal, will significantly improve diagnostic possibilities for children with a malignancy. In particular, the establishment of a correlation between a molecular defect and the risk to develop cancer will enable us to develop comprehensive cancer preventive programs within families of children with a malignancy. A firm genetic diagnosis will allow genetic counseling within families and may answer questions concerning the risk to develop malignancies in other children within such families.