We have developed a multidisciplinary program to investigate genetic events leading to childhood cancer using molecular, cytogenetic, and genetic epidemiologic techniques. The hypotheses are based on a multistage model for cancer. The overall goal is to investigate the role of each of 3 classes of genes in childhood cancer, including a) those genes which are inherited in an autosomal dominant manner and predispose to tumor, but permit tumor development at the cellular level in a recessive manner, after loss of the wild type allele; b) those genes which affect the mutation rate, affecting the frequency of initiated mutations as in class 1 or 3 genes, or of subsequent events such as recombination, deletion, insertion, amplification, etc; c) those genes (oncogenes) associated with tumor-specific activation and cell transformation, exerting an active or dominant effect at the cell level. To date we have defined a familial cancer syndrome attributable to a rare autosomal dominant gene which may account for 6 to 7% of childhood soft tissue sarcoma, and may account for most second malignant neoplasms. We are now trying to map the gene by genetic linkage in families, and to determine whether the genetic abnormality is associated with differential transforming activity. We will determine whether the same or other genetic factors are involved in adolescent soft tissue sarcoma, and in osteosarcoma, by survey and segregation analysis of the family history of cancer of those patients. Studies of a presumed class 1 gene for Wilms' tumor on 11p have revealed that most typical Wilms' tumors show loss of heterozygosity specific for chromosome 11p. This loss occurs by various mechanisms, including chromosome loss, chromosome 11p deletion, and most often somatic recombination. Further studies will define the frequency of each mechanism and the critical DNA sequences involved. To study class 2 genes, 6 different human DNA repair genes which complement CHO DNA repair mutants have been identified and localized to specific chromosomes. We will further characterize and map these genes regionally, determine the frequency of polymorphism for these genes and examine their role in genetic predisposition to childhood cancer.
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