The RASSF gene family members RASSF5, RASSF6 and RASSF7 show frequent DNA methylation in neuroblastoma

Molecular Cancer (Impact Factor: 4.26). 06/2012; 11(1):40. DOI: 10.1186/1476-4598-11-40
Source: PubMed


Hypermethylation of promotor CpG islands is a common mechanism that inactivates tumor suppressor genes in cancer. Genes belonging to the RASSF gene family have frequently been reported as epigenetically silenced by promotor methylation in human cancers. Two members of this gene family, RASSF1A and RASSF5A have been reported as methylated in neuroblastoma. Data from our previously performed genome-wide DNA methylation array analysis indicated that other members of the RASSF gene family are targeted by DNA methylation in neuroblastoma.

In the current study, we found that several of the RASSF family genes (RASSF2, RASSF4, RASSF5, RASSF6, RASSF7, and RASSF10) to various degrees were methylated in neuroblastoma cell lines and primary tumors. In addition, several of the RASSF family genes showed low or absent mRNA expression in neuroblastoma cell lines. RASSF5 and RASSF6 were to various degrees methylated in a large portion of neuroblastoma tumors and RASSF7 was heavily methylated in most tumors. Further, CpG methylation sites in the CpG islands of some RASSF family members could be used to significantly discriminate between biological subgroups of neuroblastoma tumors. For example, RASSF5 methylation highly correlated to MYCN amplification and INRG stage M. Furthermore, high methylation of RASSF6 was correlated to unfavorable outcome, 1p deletion and MYCN amplification in our tumor material.

In conclusion
This study shows that several genes belonging to the RASSF gene family are methylated in neuroblastoma. The genes RASSF5, RASSF6 and RASSF7 stand out as the most promising candidate genes for further investigations in neuroblastoma.

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Available from: Helena Carén, Feb 14, 2014
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    • "It has been reported that the global patterns of DNA methylation are altered in many cancers, including HCC [34-36]. To explore the mechanism by HBx and survivin up-regulate HBXIP, we observed the promoter region of HBXIP using epigenetics analysis. "
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    • "Rassf4A Widely expressed in most normal tissues (heart, brain, placenta, lung, liver, skeletal muscle, pancreas) Epigenetically silenced in nasopharyngeal carcinoma, breast, lung, colorectal, kidney tumour cell lines Chow et al. (2004); Eckfeld et al. (2004) RASSF5 1q32.1 Rassf5A Rassf5C Widely expressed in normal tissues Rassf5A epigenetically silenced in lung NSCLC, breast, kidney, primary tumours, colorectal, hepatocellular carcinoma, leukaemia, melanoma, neuroblastoma cell lines Calvisi et al. (2009); Lee et al. (2010); Macheiner et al. (2006); van der Weyden and Adams (2007); Djos et al. (2012) RASSF6 4q13.3 Rassf6A Varying levels of expression in colon, thymus, kidney, small intestine, placenta, lung Downregulated by gene deletion and epigenetic silencing in 30–60% of breast, colon, kidney, liver, rectum, pancreas, stomach and thyroid primary tumours Epigenetically silenced in many childhood leukaemias, neuroblastoma Allen et al. (2007); Djos et al. (2012); Hesson et al. (2009) RASSF7 11p15.5 Rassf7A Varying levels of expression in normal tissues, high levels in lung and brain Epigenetically silenced in neuroblastoma Upregulated in pancreatic ductal adecnocarcinoma, islet cell tumours, endometrial cancers due to hypoxia Djos et al. (2012); Recino et al. (2010); Sherwood et al. (2010) "
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    • "Promoter hypermethylation induced silencing of RASSF1A, the fist member of the RASSF family, is an early and widespread event in many tumors [13], [16]–[22]. Other members of the RASSF family, such as RASSF2A, RASSF5, RASSF6, RASSF7, and RASSF10, also show frequent DNA methylation in some tumors [23]–[25]. RASSF3 is considered to be responsible in part for resistance to mammary tumor development in neu transgenic mice [26]. However, to the best of our knowledge, there have been no previous studies about the methylation status of RASSF3 in any tumor. "
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