EXPRESSION AND PARENTAL IMPRINTING OF THE H19 GENE IN HUMAN RHABDOMYOSARCOMA

The expression of Insulin-like Growth Factor 2 (IGF-2) and H19, two ge nes located on human chromosome 11p15 and provided with cell growth mo dulating activity, is regulated by parental imprinting, in that the ac tivity of their alleles is dependent on the parental origin. Parental bias in the genetic alterations of chromosome 11p15 observed in severa l pediatric cancers suggests the involvement of imprinted genes in tum or development. We have previously reported that the number of functio nal IGF-2 alleles is frequently increased in rhabdomyosarcoma (RMS), a s a consequence of either relaxation of imprinting (LOI) or gene dupli cation. Here we show that the expression of the H19 gene is significan tly suppressed with respect to normal muscle tissue in 13 out of 15 rh abdomyosarcomas with embryonal histology (ERMS) and in three out of 11 rhabdomyosarcomas classified as alveolar subtype (ARMS). Since a grow th-inhibitory activity has been found associated with the H19 gene, th e extinction of its expression can contribute to RMS development. Pare ntal imprinting of the H19 gene was found conserved in all informative RMSs, including those whose IGF-2 imprinting was relaxed, indicating that LOI is a gene-specific event. Seven ERMSs and one ARMS displaying low H19 RNA levels showed an underrepresentation of the expressed all ele in their genotype. This result is consistent with the paternal imp rinting of the H19 gene and with the preferential loss of the maternal 11p15 alleles in these neoplasms. Low H19 expression was also found i n four out of eight RMSs retaining the heterozygosity at 11p15, but sh owing IGF-2 LOI. These findings suggest that the genetic and epigeneti c alterations affecting chromosome 11p15 in a high number of RMSs caus e deregulation of more than one imprinted gene, possibly affecting tum or growth, including the extinction of H19 expression and an increase in the number of active IGF-2 alleles.