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BMC Cancer
Published in: BMC Cancer 1/2006

Open Access 01-12-2006 | Research article

Frequent promoter hypermethylation of RASSF1A and CASP8 in neuroblastoma

Authors: Paula Lázcoz, Jorge Muñoz, Manuel Nistal, Ángel Pestaña, Ignacio Encío, Javier S Castresana

Published in: BMC Cancer | Issue 1/2006

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Abstract

Background

Epigenetic alterations and loss of heterozygosity are mechanisms of tumor suppressor gene inactivation. A new carcinogenic pathway, targeting the RAS effectors has recently been documented. RASSF1A, on 3p21.3, and NORE1A, on 1q32.1, are among the most important, representative RAS effectors.

Methods

We screened the 3p21 locus for the loss of heterozygosity and the hypermethylation status of RASSF1A, NORE1A and BLU (the latter located at 3p21.3) in 41 neuroblastic tumors. The statistical relationship of these data was correlated with CASP8 hypermethylation. The expression levels of these genes, in cell lines, were analyzed by RT-PCR.

Results

Loss of heterozygosity and microsatellite instability at 3p21 were detected in 14% of the analyzed tumors. Methylation was different for tumors and cell lines (tumors: 83% in RASSF1A, 3% in NORE1A, 8% in BLU and 60% in CASP8; cell lines: 100% in RASSF1A, 50% in NORE1A, 66% in BLU and 92% in CASP8). In cell lines, a correlation with lack of expression was evident for RASSF1A, but less clear for NORE1A, BLU and CASP8. We could only demonstrate a statistically significant association between hypermethylation of RASSF1A and hypermethylation of CASP8, while no association with MYCN amplification, 1p deletion, and/or aggressive histological pattern of the tumor was demonstrated.

Conclusion

1) LOH at 3p21 appears in a small percentage of neuroblastomas, indicating that a candidate tumor suppressor gene of neuroblastic tumors is not located in this region.
2) Promoter hypermethylation of RASSF1A and CASP8 occurs at a high frequency in neuroblastomas.
Appendix
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Literature
1.
Schawb M, Shimada H, Joshi V, Brodeur GM: Pathology and genetics of tumours of the nervous system. World health organization classification of tumours. Lyon, IARC Press. 2000, 153-161.
2.
Brodeur GM: Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 2003, 3: 203-216. 10.1038/nrc1014.CrossRefPubMed
3.
Agathanggelou A, Dallol A, Zochbauer-Muller S, Morrissey C, Honorio S, Hesson L, Martinsson T, Fong KM, Kuo MJ, Yuen PW, Maher ER, Minna JD, Latif F: Epigenetic inactivation of the candidate 3p21.3 suppressor gene BLU in human cancers. Oncogene. 2003, 22: 1580-1588. 10.1038/sj.onc.1206243.CrossRefPubMed
4.
Sekido Y, Ahmadian M, Wistuba II, Latif F, Bader S, Wei MH, Duh FM, Gazdar AF, Lerman MI, Minna JD: Cloning of a breast cancer homozygous deletion junction narrows the region of search for a 3p21.3 tumor suppressor gene. Oncogene. 1998, 16: 3151-3157. 10.1038/sj.onc.1201858.CrossRefPubMed
5.
Lerman MI, Minna JD: The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium. Cancer Res. 2000, 60: 6116-6133.PubMed
6.
Wei MH, Latif F, Bader S, Kashuba V, Chen JY, Duh FM, Sekido Y, Lee CC, Geil L, Kuzmin I, Zabarovsky E, Klein G, Zbar B, Minna JD, Lerman MI: Construction of a 600-kilobase cosmid clone contig and generation of a transcriptional map surrounding the lung cancer tumor suppressor gene (TSG) locus on human chromosome 3p21.3: progress toward the isolation of a lung cancer TSG. Cancer Res. 1996, 56: 1487-1492.PubMed
7.
Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP: Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat Genet. 2000, 25: 315-319. 10.1038/77083.CrossRefPubMed
8.
Liu L., Tommasi S., Lee D.H., Dammann R., Pfeifer G. P.: Control of microtubule stability by the RASSF1A tumor suppressor. Oncogene. 2003, 22: 8125-8136. 10.1038/sj.onc.1206984.CrossRefPubMed
9.
Song MS, Song SJ, Ayad NG, Chang JS, Lee JH, Hong HK, Lee H, Choi N, Kim J, Kim H, Kim JW, Choi EJ, Kirschner MW, Lim DS: The tumour suppressor RASSF1A regulates mitosis by inhibiting the APC-Cdc20 complex. Nat Cell Biol. 2004, 6: 129-137. 10.1038/ncb1091.CrossRefPubMed
10.
Harada K, Toyooka S, Maitra A, Maruyama R, Toyooka KO, Timmons CF, Tomlinson GE, Mastrangelo D, Hay RJ, Minna JD, Gazdar AF: Aberrant promoter methylation and silencing of the RASSF1A gene in pediatric tumors and cell lines. Oncogene. 2002, 21: 4345-4349. 10.1038/sj.onc.1205446.CrossRefPubMed
11.
Dammann R, Yang G, Pfeifer GP: Hypermethylation of the cpG island of Ras association domain family 1A (RASSF1A), a putative tumor suppressor gene from the 3p21.3 locus, occurs in a large percentage of human breast cancers. Cancer Res. 2001, 61: 3105-3109.PubMed
12.
Yoon JH, Dammann R, Pfeifer GP: Hypermethylation of the CpG island of the RASSF1A gene in ovarian and renal cell carcinomas. Int J Cancer. 2001, 94: 212-217. 10.1002/ijc.1466.CrossRefPubMed
13.
Tommasi S, Dammann R, Jin SG, Zhang Xf XF, Avruch J, Pfeifer GP: RASSF3 and NORE1: identification and cloning of two human homologues of the putative tumor suppressor gene RASSF1. Oncogene. 2002, 21: 2713-2720. 10.1038/sj.onc.1205365.CrossRefPubMed
14.
Hesson L, Dallol A, Minna JD, Maher ER, Latif F: NORE1A, a homologue of RASSF1A tumour suppressor gene is inactivated in human cancers. Oncogene. 2003, 22: 947-954. 10.1038/sj.onc.1206191.CrossRefPubMed
15.
Ortiz-Vega S, Khokhlatchev A, Nedwidek M, Zhang XF, Dammann R, Pfeifer GP, Avruch J: The putative tumor suppressor RASSF1A homodimerizes and heterodimerizes with the Ras-GTP binding protein Nore1. Oncogene. 2002, 21: 1381-1390. 10.1038/sj.onc.1205192.CrossRefPubMed
16.
Morris MR, Hesson LB, Wagner KJ, Morgan NV, Astuti D, Lees RD, Cooper WN, Lee J, Gentle D, Macdonald F, Kishida T, Grundy R, Yao M, Latif F, Maher ER: Multigene methylation analysis of Wilms' tumour and adult renal cell carcinoma. Oncogene. 2003, 22: 6794-6801. 10.1038/sj.onc.1206914.CrossRefPubMed
17.
Wolf BB, Green DR: Suicidal tendencies: apoptotic cell death by caspase family proteinases. J Biol Chem. 1999, 274: 20049-20052. 10.1074/jbc.274.29.20049.CrossRefPubMed
18.
Steller H: Artificial death switches: induction of apoptosis by chemically induced caspase multimerization. Proc Natl Acad Sci USA. 1998, 95: 5421-5422. 10.1073/pnas.95.10.5421.CrossRefPubMedPubMedCentral
19.
Gonzalez-Gomez P, Bello MJ, Inda MM, Alonso ME, Arjona D, Aminoso C, Lopez-Marin I, de Campos JM, Sarasa JL, Castresana JS, Rey JA: Deletion and aberrant CpG island methylation of Caspase 8 gene in medulloblastoma. Oncol Rep. 2004, 12: 663-666.PubMed
20.
Kim HS, Lee JW, Soung YH, Park WS, Kim SY, Lee JH, Park JY, Cho YG, Kim CJ, Jeong SW, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH: Inactivating mutations of caspase-8 gene in colorectal carcinomas. Gastroenterology. 2003, 125: 708-715. 10.1016/S0016-5085(03)01059-X.CrossRefPubMed
21.
Teitz T, Wei T, M.B. V, Vanin EF, Grenet J, Valentine VA, Behm FG, Look AT, Lahti JM, Kidd VJ: Caspase 8 is deleted or silenced preferentially inchildhood neuroblastomas with amplification of MYCN. Nat Med. 2000, 6: 529-535. 10.1038/75007.CrossRefPubMed
22.
Li LC, Dahiya R: MethPrimer: designing primers for methylation PCRs. Bioinformatics. 2002, 18: 1427-1431. 10.1093/bioinformatics/18.11.1427.CrossRefPubMed
23.
Gonzalez-Gomez P, Bello MJ, Lomas J, Arjona D, Alonso ME, Aminoso C, Lopez-Marin I, Anselmo NP, Sarasa JL, Gutierrez M, Casartelli C, Rey JA: Aberrant methylation of multiple genes in neuroblastic tumours. relationship with MYCN amplification and allelic status at 1p. Eur J Cancer. 2003, 39: 1478-1485. 10.1016/S0959-8049(03)00312-5.CrossRefPubMed
24.
Chang SC, Lin JK, Lin TC, Liang WY: Loss of heterozygosity: An independent prognostic factor of colorectal cancer. World J Gastroenterol. 2005, 11: 778-784.CrossRefPubMedPubMedCentral
25.
Dichamp C, Taillibert S, Aguirre-Cruz L, Lejeune J, Marie Y, Kujas M, Delattre JY, Hoang-Xuan K, Sanson M: Loss of 14q chromosome in oligodendroglial and astrocytic tumors. J Neurooncol. 2004, 67: 281-285. 10.1023/B:NEON.0000024218.68120.8d.CrossRefPubMed
26.
Martinez R, Schackert HK, Appelt H, Plaschke J, Baretton G, Schackert G: Low-level microsatellite instability phenotype in sporadic glioblastoma multiforme. J Cancer Res Clin Oncol. 2005, 131: 87-93. 10.1007/s00432-004-0592-5.CrossRefPubMed
27.
Umetani N, Hoon DS: Frequent LOH at chromosome 12q22-23 and Apaf-1 inactivation in glioblastoma. Brain Pathol. 2004, 14: 224-CrossRefPubMed
28.
Marsit CJ, Hasegawa M, Hirao T, Kim DH, Aldape K, Hinds PW, Wiencke JK, Nelson HH, Kelsey KT: Loss of heterozygosity of chromosome 3p21 is associated with mutant TP53 and better patient survival in non-small-cell lung cancer. Cancer Res. 2004, 64: 8702-8707. 10.1158/0008-5472.CAN-04-2558.CrossRefPubMed
29.
Pizzi S, Azzoni C, Bassi D, Bottarelli L, Milione M, Bordi C: Genetic alterations in poorly differentiated endocrine carcinomas of the gastrointestinal tract. Cancer. 2003, 98: 1273-1282. 10.1002/cncr.11621.CrossRefPubMed
30.
Sakamoto N, Terai T, Ajioka Y, Abe S, Kobayasi O, Hirai S, Hino O, Watanabe H, Sato N, Shimoda T, Fujii H: Frequent hypermethylation of RASSF1A in early flat-type colorectal tumors. Oncogene. 2004, 23: 8900-8907. 10.1038/sj.onc.1207993.CrossRefPubMed
31.
Xiong W, Zeng ZY, Xia JH, Xia K, Shen SR, Li XL, Hu DX, Tan C, Xiang JJ, Zhou J, Deng H, Fan SQ, Li WF, Wang R, Zhou M, Zhu SG, Lu HB, Qian J, Zhang BC, Wang JR, Ma J, Xiao BY, Huang H, Zhang QH, Zhou YH, Luo XM, Zhou HD, Yang YX, Dai HP, Feng GY, Pan Q, Wu LQ, He L, Li GY: A susceptibility locus at chromosome 3p21 linked to familial nasopharyngeal carcinoma. Cancer Res. 2004, 64: 1972-1974. 10.1158/0008-5472.CAN-03-3253.CrossRefPubMed
32.
Westermann F, Schwab M: Genetic parameters of neuroblastomas. Cancer Lett. 2002, 184: 127-147. 10.1016/S0304-3835(02)00199-4.CrossRefPubMed
33.
Altura RA, Maris JM, Li H, Boyett JM, Brodeur GM, Look AT: Novel regions of chromosomal loss in familial neuroblastoma by comparative genomic hybridization. Genes Chromosomes Cancer. 1997, 19: 176-184. 10.1002/(SICI)1098-2264(199707)19:3<176::AID-GCC7>3.0.CO;2-V.CrossRefPubMed
34.
Chen QR, Bilke S, Wei JS, Whiteford CC, Cenacchi N, Krasnoselsky AL, Greer BT, Son CG, Westermann F, Berthold F, Schwab M, Catchpoole D, Khan J: cDNA array-CGH profiling identifies genomic alterations specific to stage and MYCN-amplification in neuroblastoma. BMC Genomics. 2004, 5: 70-10.1186/1471-2164-5-70.CrossRefPubMedPubMedCentral
35.
Tonini GP, Romani M: Genetic and epigenetic alterations in neuroblastoma. Cancer Lett. 2003, 197: 69-73. 10.1016/S0304-3835(03)00081-8.CrossRefPubMed
36.
Yang Q, Zage P, Kagan D, Tian Y, Seshadri R, Salwen HR, Liu S, Chlenski A, Cohn SL: Association of epigenetic inactivation of RASSF1A with poor outcome in human neuroblastoma. Clin Cancer Res. 2004, 10: 8493-8500. 10.1158/1078-0432.CCR-04-1331.CrossRefPubMed
37.
Yan P, Muhlethaler A, Bourloud KB, Beck MN, Gross N: Hypermethylation-mediated regulation of CD44 gene expression in human neuroblastoma. Genes Chromosomes Cancer. 2003, 36: 129-138. 10.1002/gcc.10150.CrossRefPubMed
38.
Astuti D, Da Silva NF, Dallol A, Gentle D, Martinsson T, Kogner P, Grundy R, Kishida T, Yao M, Latif F, Maher ER: SLIT2 promoter methylation analysis in neuroblastoma, Wilms' tumour and renal cell carcinoma. Br J Cancer. 2004, 90: 515-521. 10.1038/sj.bjc.6601447.CrossRefPubMedPubMedCentral
39.
van Noesel MM, van Bezouw S, Voute PA, Herman JG, Pieters R, Versteeg R: Clustering of hypermethylated genes in neuroblastoma. Genes Chromosomes Cancer. 2003, 38: 226-233. 10.1002/gcc.10278.CrossRefPubMed
40.
Banelli B, Gelvi I, Di Vinci A, Scaruffi P, Casciano I, Allemanni G, Bonassi S, Tonini GP, Romani M: Distinct CpG methylation profiles characterize different clinical groups of neuroblastic tumors. Oncogene. 2005, 24: 5619-5628. 10.1038/sj.onc.1208722.CrossRefPubMed
41.
Abe M, Ohira M, Kaneda A, Yagi Y, Yamamoto S, Kitano Y, Takato T, Nakagawara A, Ushijima T: CpG island methylator phenotype is a strong determinant of poor prognosis in neuroblastomas. Cancer Res. 2005, 65: 828-834.PubMed
42.
Agathanggelou A, Honorio S, Macartney DP, Martinez A, Dallol A, Rader J, Fullwood P, Chauhan A, Walker R, Shaw JA, Hosoe S, Lerman MI, Minna JD, Maher ER, Latif F: Methylation associated inactivation of RASSF1A from region 3p21.3 in lung, breast and ovarian tumours. Oncogene. 2001, 20: 1509-1518. 10.1038/sj.onc.1204175.CrossRefPubMed
43.
Kuzmin I, Gillespie JW, Protopopov A, Geil L, Dreijerink K, Yang Y, Vocke CD, Duh FM, Zabarovsky E, Minna JD, Rhim JS, Emmert-Buck MR, Linehan WM, Lerman MI: The RASSF1A tumor suppressor gene is inactivated in prostate tumors and suppresses growth of prostate carcinoma cells. Cancer Res. 2002, 62: 3498-3502.PubMed
44.
Hesson L, Bieche I, Krex D, Criniere E, Hoang-Xuan K, Maher ER, Latif F: Frequent epigenetic inactivation of RASSF1A and BLU genes located within the critical 3p21.3 region in gliomas. Oncogene. 2004, 23: 2408-2419. 10.1038/sj.onc.1207407.CrossRefPubMed
45.
Astuti D, Agathanggelou A, Honorio S, Dallol A, Martinsson T, Kogner P, Cummins C, Neumann HP, Voutilainen R, Dahia P, Eng C, Maher ER, Latif F: RASSF1A promoter region CpG island hypermethylation in phaeochromocytomas and neuroblastoma tumours. Oncogene. 2001, 20: 7573-7577. 10.1038/sj.onc.1204968.CrossRefPubMed
46.
Wong IH, Chan J, Wong J, Tam PK: Ubiquitous aberrant RASSF1A promoter methylation in childhood neoplasia. Clin Cancer Res. 2004, 10: 994-1002. 10.1158/1078-0432.CCR-0378-3.CrossRefPubMed
47.
Asada K, Asada R, Yoshiji H, Fukui H, Floyd RA, Kotake Y: DNA cytosine methylation profile in various cancer-related genes is altered in cultured rat hepatocyte cell lines as compared with primary hepatocytes. Oncol Rep. 2006, 15: 1241-1248.PubMed
48.
Harada K, Toyooka S, Shivapurkar N, Maitra A, Reddy JL, Matta H, Miyajima K, Timmons CF, Tomlinson GE, Mastrangelo D, Hay RJ, Chaudhary PM, Gazdar AF: Deregulation of caspase 8 and 10 expression in pediatric tumors and cell lines. Cancer Res. 2002, 62: 5897-5901.PubMed
49.
Iolascon A, Borriello A, Giordani L, Cucciolla V, Moretti A, Monno F, Criniti V, Marzullo A, Criscuolo M, Ragione FD: Caspase 3 and 8 deficiency in human neuroblastoma. Cancer Genet Cytogenet. 2003, 146: 41-47. 10.1016/S0165-4608(03)00125-0.CrossRefPubMed
50.
Banelli B, Casciano I, Croce M, Di Vinci A, Gelvi I, Pagnan G, Brignole C, Allemanni G, Ferrini S, Ponzoni M, Romani M: Expression and methylation of CASP8 in neuroblastoma: identification of a promoter region. Nat Med. 2002, 8: 1333-1335. 10.1038/nm1202-1333.CrossRefPubMed
51.
Casciano I, Banelli B, Croce M, De Ambrosis A, di Vinci A, Gelvi I, Pagnan G, Brignole C, Allemanni G, Ferrini S, Ponzoni M, Romani M: Caspase-8 gene expression in neuroblastoma. Ann N Y Acad Sci. 2004, 1028: 157-167. 10.1196/annals.1322.017.CrossRefPubMed
Metadata
Title
Frequent promoter hypermethylation of RASSF1A and CASP8 in neuroblastoma
Authors
Paula Lázcoz
Jorge Muñoz
Manuel Nistal
Ángel Pestaña
Ignacio Encío
Javier S Castresana
Publication date
01-12-2006
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2006
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-6-254

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