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Ubiquitous Aberrant RASSF1A Promoter Methylation in Childhood Neoplasia1

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Ubiquitous Aberrant RASSF1A Promoter Methylation in Childhood Neoplasia1 994 Vol. 10, 994–1002, February 1, 2004 Clinical Cancer Research Ubiquitous Aberrant RASSF1A Promoter Methylation in Childhood Neoplasia1 Ivy H. N. Wong,1 Jacqueline Chan,1 Joyce Wong,2 during, and after treatment, correspondingly, from pediat- and Paul K. H. Tam2 ric patients with neuroblastoma, thyroid carcinoma, hepa- Departments of 1Biochemistry and 2Surgery, Faculty of Medicine, tocellular carcinoma, rhabdomyosarcoma, Burkitt’s lym- The University of Hong Kong, Hong Kong Special Administrative phoma, T-cell lymphoma, or acute lymphoblastic leukemia. Region Concordantly, RASSF1A methylation was found during treatment in plasma of the same patients, suggesting cell death and good response to chemotherapy. ABSTRACT Conclusions: RASSF1A methylation in tumor or buffy Purpose and Experimental Design: The role of coat did not correlate strongly with age, tumor size, recur- RASSF1A has been elucidated recently in regulating apo- rence/metastasis, or overall survival in this cohort of pedi- ptosis and cell cycle progression by inhibiting cyclin D1 atric cancer patients. Of importance, epigenetic inactivation accumulation. Aberrant RASSF1A promoter methylation of RASSF1A may potentially be crucial in pediatric tumor has been found frequently in multiple adult cancer types. initiation. Using methylation-specific PCR and reverse transcription- PCR, we investigated epigenetic deregulation of RASSF1A in primary tumors, adjacent nontumor tissues, secondary INTRODUCTION metastases, peripheral blood cells, and plasma samples from Childhood neoplasms are biologically different from adult children with 18 different cancer types, in association with tumors, in that childhood neoplasms resemble the embryonic their clinicopathologic features. precursors of the cell types they arise, similar to undifferentiated Results: Regardless of the tumor size, ubiquitous cells appearing during normal embryonic development (1, 2). RASSF1A promoter methylation was found in 67% (16 of Genetic or epigenetic alterations in pediatric tumors may poten- 24) of pediatric tumors, including neuroblastoma, thyroid tially lead to arrested differentiation or dedifferentiation. The carcinoma, hepatocellular carcinoma, pancreatoblastoma, biological characteristics of pediatric malignancies, such as the adrenocortical carcinoma, Wilms’ tumor, Burkitt’s lym- ability to proliferate, invade, migrate, and exhibit differential phoma, and T-cell lymphoma. A majority (75%) of pediatric sensitivity to cytotoxic agents, may provide insights into normal cancer patients with tumoral RASSF1A methylation was cellular and developmental processes. Pediatric tumors are very male. Methylated RASSF1A alleles were also detected in 4 of often highly invasive, metastasizing early in the course of the 13 adjacent nontumor tissues, suggesting that this epigenetic development, but they are very responsive to current therapies change is potentially an early and critical event in childhood (1, 2). neoplasia. RASSF1A promoter methylation found in 92% In contrast to inconsistent chromosomal aberrations found (11 of 12) of cell lines largely derived from pediatric cancer in various adult cancer types, recurring cytogenetic abnormali- patients was significantly associated with transcriptional ties are observed in pediatric cancers (1, 2). As opposed to adult silencing/repression. After demethylation treatment with epithelial tumors, pediatric solid tumors possessing only a few .(5-aza-2؅-deoxycytidine, transcriptional reactivation was genetic mutations can develop after short latent periods (2, 3 shown in KELLY, RD, and Namalwa cell lines as analyzed The methylation patterns in adult tumors have been studied by reverse transcription-PCR. For the first time, RASSF1A extensively, and each tumor type appears to have a distinct methylation was detected in 54% (7 of 13), 40% (4 of 10), methylation profile (4). However, little has been known about and 9% (1 of 11) of buffy coat samples collected before, the methylation profiles in childhood malignancies. RAS plays an important role in the signal transduction from cell surface receptors to an array of intracellular signaling pathways. Mutations leading to constitutive activation of RAS Received 3/12/03; revised 9/19/03; accepted 10/23/03. are commonly found in human cancers (4, 5). RAS binds and Grant support: Research Grants Council Grant No. HKU7484/03M activates a diverse array of effectors and mediates tumor sup- from the Hong Kong Research Grants Council and Research Grants pressive effects in addition to oncogenic effects (6). Activated Council Direct Allocation No. 10204245 from the University of Hong RAS mediates the induction of DNA synthesis (7), tumorigenic Kong. transformation (8), metastasis/invasion (9), reduction of growth The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked factor dependence (10), loss of contact inhibition (11), inhibi- advertisement in accordance with 18 U.S.C. Section 1734 solely to tion of terminal differentiation (12), and resistance to apoptosis indicate this fact. (13). On the other hand, RAS can induce growth inhibitory Requests for reprints: Ivy H. N. Wong, at the Department of Biochem- effects, such as senescence (14), necrosis (15), apoptosis (16), istry, 3/F, Laboratory Block, Faculty of Medicine Building, 21 Sassoon Road, The University of Hong Kong, Hong Kong Special Administra- and terminal differentiation. tive Region. Phone: (852) 2819 9472; Fax: (852) 2712 2719; E-mail: Loss of heterozygosity of chromosome 3p21.3 is one of the [email protected]. most frequent alterations in solid tumors (17, 18). Located Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2004 American Association for Cancer Research. Clinical Cancer Research 995 within this 3p21.3 locus, RASSF1 encodes a novel RAS effector, chronic myeloid leukemia (n ϭ 5). With curative intent, these which has been identified recently as a tumor suppressor of patients underwent surgical resection, chemotherapy, radiother- many different cancer types (19–21). The RASSF1 gene has two apy, peripheral blood stem cell or bone marrow transplantation. CpG islands within two known promoters controlling gene Pediatric Tumors, Adjacent Nontumor Tissues, and expression (19). RASSF1 encodes two major transcripts, 1A and Secondary Metastases. A total of 39 surgically resected spec- 1C, by alternative promoter usage and alternative RNA splicing. imens, including 24 primary tumors, 13 matched adjacent non- RASSF1A and 1C transcripts have four common exons, which tumor tissues, and two secondary metastases, were collected encode a COOH-terminal RAS association domain (19, 22). from 24 pediatric patients with neuroblastoma (n ϭ 8), thyroid RASSF1A and RASSF1C have PEST sequences with a serine carcinoma (n ϭ 2), hepatocellular carcinoma (n ϭ 2), Langer- residue as a putative phosphorylation target for ataxia-telangi- hans cell histiocytosis (n ϭ 2), desmoplastic small round cell ectasia-mutation (23). As differed from RASSF1C, RASSF1A tumor (n ϭ 1), pancreatoblastoma (n ϭ 1), adrenocortical car- cinoma (n ϭ 1), Wilms’ tumor/nephroma (n ϭ 2), rhabdomy- has an NH2-terminal SH3 domain and a putative cysteine-rich diacylglycerol/phorbolester-binding domain (24). RASSF1A in- osarcoma (n ϭ 1), Burkitt’s lymphoma (n ϭ 3), or T-cell activation can be a tumorigenic mechanism distinct from the lymphoma (n ϭ 1). oncogenic activation of RAS signaling. Loss of RASSF1A ex- Peripheral Blood Cells and Plasma Samples from Pe- pression may shift the balance of RAS activities toward a diatric Cancer Patients. Forty-nine buffy coat samples (n ϭ growth-promoting effect (25). 34) and plasma samples (n ϭ 15) were collected before, during, Frequent RASSF1A promoter methylation has been ob- and after treatment from 23 pediatric cancer patients, who served recently in tumor types with uncommon RAS mutations suffered from neuroblastoma (n ϭ 5), medulloblastoma (n ϭ 1), and associated with transcriptional silencing of RASSF1A (18, primitive neuroectodermal tumor (n ϭ 1), thyroid carcinoma 19, 26, 27). In fact, RASSF1A blocks cell cycle progression (n ϭ 1), hepatocellular carcinoma (n ϭ 2), adrenocortical car- cinoma (n ϭ 1), ovarian dysgerminoma (n ϭ 1), rhabdomyo- from G1 phase to S phase by controlling the entry at the retinoblastoma restriction point and inhibiting cyclin D1 protein sarcoma (n ϭ 3), Burkitt’s lymphoma (n ϭ 2), T-cell lymphoma accumulation at the post-transcriptional level (28). RASSF1A (n ϭ 1), or acute myeloid leukemia/acute lymphoblastic leuke- has been implicated in suppressing tumorigenesis in vitro and in mia/chronic myeloid leukemia (n ϭ 5). As a control, 20 buffy vivo (19). Reactivation of RASSF1A transcription in lung carci- coat samples and 20 plasma samples were collected from 20 noma cells reduced colony formation, suppressed cell growth pediatric patients with no cancer. dependent or independent of anchorage, and inhibited tumor Cell Lines Derived from Pediatric Cancer Patients. formation in nude mice (19). Oncogenic RAS does not alter Neuroblastoma (SK-N-AS, SK-N-DZ, SK-N-SH, SK-N-MC, RASSF1A-induced growth inhibitory effects in an immortalized and KELLY), hepatocellular carcinoma (Hep3B), hepatoblas- cell line, but the effects of RASSF1A are dominant to oncogenic toma (HepG2), rhabdomyosarcoma, Burkitt’s lymphoma RAS in human mammary epithelial cells (28). Thus, loss of (JIYOYE, DAUDI, Namalwa), and papillary thyroid carcinoma RASSF1A can be a determining
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