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Aberrant Methylation of the HIC1 Promoter Is a Frequent Event in Specific Pediatric Neoplasms¹

Hamon Center for Therapeutic Oncology Research [A. R., A. K. V., K. H., K. M., G. E. T., A. F. G.], Departments of Pathology [A. K. V., A. M., A. F. G.] and Pediatrics [G. E. T.], University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Pathology, Children’s Medical Center, Dallas, Texas 75235 [C. F. T.]; Department of Opthalmology, University of Siena, 53100 Siena, Italy [D. M.]; and American Type Culture Collection, Manassas, Virginia 20110 [R. J. H.]

Purpose: To determine the role of methylation of HIC1, a candidate tumor suppressor gene on 17p13.3, in various types of pediatric tumors.

Experimental Design: We examined the methylation status of the HIC1 promoter by methylation specific PCR in 157 pediatric tumors and 27 nonmalignant tissues. We correlated methylation with mRNA expression by reverse transcription-PCR in eight tumor-derived cell lines.

Results: HIC1 methylation was frequent in medulloblastomas (80%, 12 of 15), retinoblastomas (67%, 6 of 9), rhabdomyosarcomas (59%, 13 of 22), germ cell tumors (55%, 6 of 11), and neurouroblastic tumors (36%, 14 of 39); neuroblastomas (43%, 12 of 28); ganglioneuromas (17%, 1 of 6); and ganglioneuroblastomas (20%, 1 of 5). In contrast, a low incidence of methylation was observed in osteosarcomas (17%, 2 of 12), Ewing’s tumors (9%, 1 of 11), Wilms’ tumors (3%, 1 of 31), and hepatoblastomas (0%, 0 of 7). HIC1 methylation was more frequent in the aggressive alveolar subtype of rhabdomyosarcomas (100%, 8 of 8) than the embryonal subtype (33%, 4 of 12; P < 0.005) and was rare in the nonmalignant tissues examined. Methylation was also demonstrated by sequencing in nine randomly selected tumor samples. Seven of eight pediatric tumor cell lines examined were methylated and showed loss or reduced HIC1 mRNA. Expression was strongly induced in all cell lines by treatment with the demethylating agent 5-aza 2'deoxycytidine.

Conclusions: Our data suggest that aberrant methylation of HIC1 may play a role in the pathogenesis of specific pediatric tumors.

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