Poster Sessions

ENDO -7

Geoffrey Rezvani

G. Rezvani, J. C. K Lui, J. Baron

The ZAC1 Imprinted Gene Network: A Possible Link Between Normal Growth in Childhood and Growth of Embryonal Tumors

We recently found evidence that the ZAC1 imprinted gene network, which includes Mest, Plag1/Zac1, Peg3, and Igf2, is expressed at high levels in the mouse embryo but is downregulated postnatally, contributing to normal growth deceleration. One member of this network, IGF2, has previously been shown to be overexpressed in rhabdomyosarcomas and Wilms tumor. We hypothesized that some embryonal tumors show persistent high expression levels of genes in this network, contributing to persistent proliferation. We analyzed microarray data available from an NCI database (Whiteford et. al., Cancer Research, 2007) comparing the expression of over 13,000 genes in 182 different pediatric cancer tumor samples, xenografts, and tumor cell lines (normalized to a reference mRNA sample from 7 cancer cell lines). Elevated expression of MEST ( 4-16 fold), PLAGL1 ( 2-4 fold), PEG3 ( 4 fold), and IGF2 ( 4-16 fold) were observed in rhabdomyosarcoma tumor samples, xenografts, and cell lines compared to the reference RNA mixture and compared to non-embryonal tumors of childhood. Similar elevations were seen in Wilms tumor xenografts. Increased expression of these genes was less consistent in medulloblastoma and neuroblastoma. Among individual samples, levels of IGF2 expression in rhabdomyosarcoma correlated with levels of MEST (P<0.005), PLAGL1 (P<0.05), and PEG3 (P<0.0005). We then cultured 6 different cell lines of rhabdomyosarcoma and 10 non-embryonal cancer cell lines and used real-time PCR to study expression levels of 4 genes, IGF2, MEST, PLAGL1, and PEG3. We found elevated mRNA expression of IGF2 (P<0.001) and MEST (P<0.01) in rhabdomyosarcoma cells compared to the adult and pediatric non-embryonal cancer cell lines. No significant differences were seen for PEG3 and PLAGL1. Our findings suggest that some genes within the ZAC1 imprinted gene network are consistently elevated in specific types of embryonal tumors, and these levels correlate with expression of IGF2. Since downregulation of these genes appears to contribute to physiological growth deceleration, persistent expression in these tumors may contribute to their persistent pathological proliferation, suggesting a possible link between the mechanisms that regulate normal childhood growth and those that cause the aberrant growth of childhood cancers.