Aberrant methylation of the HIC1 promoter is a frequent event in specific pediatric neoplasms

Asha Rathi, Arvind K. Virmani, Kenichi Harada, Charles F. Timmons, Kuniharu Miyajima, Robert J. Hay, Domenico Mastrangelo, Anirban Maitra, Gail Tomlinson, Adi F. Gazdar

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3674-3678
Number of pages5
JournalClinical Cancer Research
Volume9
Issue number10 I
StatePublished - Oct 1 2003
Externally publishedYes

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Methylation
Pediatrics
Neoplasms
Tumor Cell Line
Ganglioneuroblastoma
Alveolar Rhabdomyosarcoma
Ganglioneuroma
Hepatoblastoma
Polymerase Chain Reaction
Messenger RNA
Medulloblastoma
Ewing's Sarcoma
Wilms Tumor
Rhabdomyosarcoma
Retinoblastoma
Germ Cell and Embryonal Neoplasms
Osteosarcoma
Tumor Suppressor Genes
Neuroblastoma
Reverse Transcription

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Rathi, A., Virmani, A. K., Harada, K., Timmons, C. F., Miyajima, K., Hay, R. J., ... Gazdar, A. F. (2003). Aberrant methylation of the HIC1 promoter is a frequent event in specific pediatric neoplasms. Clinical Cancer Research, 9(10 I), 3674-3678.

Aberrant methylation of the HIC1 promoter is a frequent event in specific pediatric neoplasms. / Rathi, Asha; Virmani, Arvind K.; Harada, Kenichi; Timmons, Charles F.; Miyajima, Kuniharu; Hay, Robert J.; Mastrangelo, Domenico; Maitra, Anirban; Tomlinson, Gail; Gazdar, Adi F.

In: Clinical Cancer Research, Vol. 9, No. 10 I, 01.10.2003, p. 3674-3678.

Research output: Contribution to journalArticle

Rathi, A, Virmani, AK, Harada, K, Timmons, CF, Miyajima, K, Hay, RJ, Mastrangelo, D, Maitra, A, Tomlinson, G & Gazdar, AF 2003, 'Aberrant methylation of the HIC1 promoter is a frequent event in specific pediatric neoplasms', Clinical Cancer Research, vol. 9, no. 10 I, pp. 3674-3678.
Rathi A, Virmani AK, Harada K, Timmons CF, Miyajima K, Hay RJ et al. Aberrant methylation of the HIC1 promoter is a frequent event in specific pediatric neoplasms. Clinical Cancer Research. 2003 Oct 1;9(10 I):3674-3678.
Rathi, Asha ; Virmani, Arvind K. ; Harada, Kenichi ; Timmons, Charles F. ; Miyajima, Kuniharu ; Hay, Robert J. ; Mastrangelo, Domenico ; Maitra, Anirban ; Tomlinson, Gail ; Gazdar, Adi F. / Aberrant methylation of the HIC1 promoter is a frequent event in specific pediatric neoplasms. In: Clinical Cancer Research. 2003 ; Vol. 9, No. 10 I. pp. 3674-3678.
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abstract = "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.",
author = "Asha Rathi and Virmani, {Arvind K.} and Kenichi Harada and Timmons, {Charles F.} and Kuniharu Miyajima and Hay, {Robert J.} and Domenico Mastrangelo and Anirban Maitra and Gail Tomlinson and Gazdar, {Adi F.}",
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T1 - Aberrant methylation of the HIC1 promoter is a frequent event in specific pediatric neoplasms

AU - Rathi, Asha

AU - Virmani, Arvind K.

AU - Harada, Kenichi

AU - Timmons, Charles F.

AU - Miyajima, Kuniharu

AU - Hay, Robert J.

AU - Mastrangelo, Domenico

AU - Maitra, Anirban

AU - Tomlinson, Gail

AU - Gazdar, Adi F.

PY - 2003/10/1

Y1 - 2003/10/1

N2 - 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.

AB - 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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