Research IndicatorsGraph generated 31 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (6)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: RASSF10 (cancer-related)
Ras association domain protein 10 (RASSF10) was reported to act as a prognostic indicator in various types of cancer and it was proved to be tumor suppressor gene in colorectal cancer (CRC). The purpose of this study was to evaluate the prognostic significance of RASSF10 in CRC.Quantitative real-time polymerase chain reaction was used to detect the messenger RNA (mRNA) expression while enzyme-linked immunosorbent assay was taken to measure the protein expression of RASSF10 in tumor tissues and adjacent normal tissues from 102 patients with CRC. The relationship between RASSF10 expression level and clinical characteristics of CRC patients was analyzed by chi-squared test. In addition, the association between overall survival of CRC patients and RASSF10 expression was estimated by Kaplan-Meier analysis. Cox regression analysis was used to evaluate the prognostic value of RASSF10.The expression level of RASSF10 in tumor tissues was significantly lower than that in the normal tissues both at mRNA and protein levels. Moreover, the expression level was correlated with lymph-node-metastasis and tumor-node-metastasis stage. Kaplan-Meier analysis suggested that patients with high expression level of RASSF10 had a longer overall survival than those with low level (log-rank test, P < .001). Besides, RASSF10 might be a potential biomarker in the prognosis of CRC according to cox regression analysis.The down regulated of RASSF10 is found in CRC and it may be an ideal prognostic marker.
Xie J, Chen Y, Meng F, et al.Study on the relationship between the RASSF10 gene and the biological behavior of hepatocellular carcinoma cells.
Eur Rev Med Pharmacol Sci. 2017; 21(16):3576-3580 [PubMed
] Related Publications
OBJECTIVE: To investigate the relationship between Ras association domain family gene 10 (RASSF10 gene) and the biological behavior of hepatocellular carcinoma (HCC), including proliferation, invasion, and metastasis.
MATERIALS AND METHODS: HCC cell lines were generated with stable overexpression or low expression of RASSF10 protein. A cell line transfected with an empty vector was treated as control. At 12, 24, 48, and 72 h, the cell proliferation was determined by MTT assay, the invasion ability was determined by Transwell chambers, and the scratch assay was used to assess the migration ability. Additionally, cell lines were injected subcutaneously in the axillary fossa of nude mice aged 5-6 weeks. Tumors were measured weekly for 6 consecutive weeks to observe tumor volume, tumor growth rate, weight, and tumor metastasis in nude mice of the different groups.
RESULTS: In both the control group and low expression group, cell proliferation rates, cell invasion, and migration abilities, increased over time but decreased over time in the overexpression group. At each time point, data in the overexpression group were markedly lower than those in the control group, and highest in the low expression group. The differences were statistically significant (p<0.05). In both control group and low expression group, tumor volume, tumor growth rate, weight, and tumor metastasis number were increased in nude mice over time, while they decreased in the overexpression group (except for tumor metastasis number). At each time point, data in the overexpression group were markedly lower than in the control group, and highest in the low expression group. The differences were statistically significant (p<0.05).
CONCLUSIONS: Like a tumor suppressor gene, RASSF10 can inhibit the proliferation, invasion, and migration of HCC cells.
Younesian S, Shahkarami S, Ghaffari P, et al.DNA hypermethylation of tumor suppressor genes RASSF6 and RASSF10 as independent prognostic factors in adult acute lymphoblastic leukemia.
Leuk Res. 2017; 61:33-38 [PubMed
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BACKGROUND: The Hypermethylation of Ras association domain family (RASSF) often plays a key role in malignant progression of solid tumors; however, their impact on the prognosis and survival of adult ALL patients remain elusive.
METHODS: The frequency of the promoter methylation pattern of RASSF6 and RASSF10 were analyzed in the peripheral blood (PB) samples taken at the time of diagnosis of 45 ALL patients. The methylation-specific PCR (MSP) assay was used to detect the DNA methylation patterns.
RESULTS: RASSF6 was frequently hypermethylated in patients diagnosed with pre-B-ALL (90.9%) and B-ALL (87.5%), followed by T-ALL (66.7%); whereas, RASSF10 methylation was more confined to T-ALL (80%) as compared to B-ALL (25%) and pre-B ALL (9.1%) patients. Moreover, hypermethylation of RASSF6 was significantly associated with a poor prognosis and shorter overall survival (OS) in patients with pre-B-ALL (log-rank test; P=0.041).
CONCLUSION: RASSF6 and RASSF10 were frequently hypermethylated in the samples at the time of diagnosis of adult ALL patients. Our study represents the first report of methylation of RASSF6 at a high frequency in patients with pre-B ALL. Furthermore, hypermethylation of RASSF6 was significantly associated with inferior overall survival in pre-B ALL patients. It may suggest that the frequent epigenetic inactivation of RASSF6 plays an important role in the pathogenesis and progression of pre-B-ALL.
Fan C, Wang W, Jin J, et al.RASSF10 is Epigenetically Inactivated and Suppresses Cell Proliferation and Induces Cell Apoptosis by Activating the p53 Signalling Pathway in Papillary Thyroid Carcinoma Cancer.
Cell Physiol Biochem. 2017; 41(3):1229-1239 [PubMed
] Related Publications
OBJECTIVES: We aimed to confirm whether RASSF10 activated the p53 signalling pathway, thereby modulating cell proliferation, migration, invasion, and apoptosis in papillary thyroid carcinoma (PTC) cells.
METHODS: A total of 108 PTC tissue samples and normal adjacent tissues were obtained. RT-PCR and Western blotting analyses were performed to detect RASSF10 expression, and methylation levels of RASSF10 were estimated by methylation-specific PCR (MSP). We also detected the expression and methylation status of RASSF10 in both a human PTC cell line (K1) and a normal thyroid cell line (FRTL5). After transfection of cells with empty vector pcDNA3.1, pcDNA3.1-RASSF10, p53 siRNA and shRASSF10, Coulter counter, colony-formation, wound healing, Transwell and flow cytometry analyses were performed to examine the role of RASSF10 in cell proliferation, migration, invasion, and apoptosis. Finally, the expression of p53, p21, Bcl-2 and Bax were detected using Western Blotting analyses.
RESULTS: RASSF10 expression in PTC tissues was significantly lower and hyper-methylated compared to normal adjacent tissues. In addition, RASSF10 was significantly down-regulated and hyper-methylated in K1 cells compared to FRTL5 cells. In addition, suppressed proliferation and significantly induced apoptosis of K1 cells were observed after transfection with pcDNA3.1-RASSF10 (P < 0.05). Furthermore, RASSF10 activated the p53 signalling pathway and regulated the expression of p53, p21, Bcl-2 and Bax. Furthermore, p53 siRNA could antagonize the effects of RASSF10 in K1 cells.
CONCLUSIONS: RASSF10 induces apoptosis in PTC cells by activating the p53 signalling pathway, indicating its role as a treatment target for PTC.
Wang F, Li P, Feng Y, et al.Low expression of RASSF10 is associated with poor survival in patients with colorectal cancer.
Hum Pathol. 2017; 62:108-114 [PubMed
] Related Publications
The RASSF10 has been identified as a tumor suppressor in human colorectal cancer (CRC). However, the expression of RASSF10 in patients with CRC has not been evaluated for its potential use as a biomarker in the diagnosis and prognosis assessment of CRC. We analyzed the expression of RASSF10 mRNA (n=30) and protein (n=205) in CRC and matched noncancerous colon tissue samples to explore the relationships among RASSF10 expression, clinicopathological factors, and prognosis in patients with CRC. Our results showed that the expression of RASSF10 mRNA and protein in CRC-adjacent tissues was higher than that in CRC tissues. Low RASSF10 expression was associated with the T stage (P=.037, odds ratio, 0.664; 95% confidence interval, 0.452-0.975) and the N stage (P<.001, odds ratio, 0.318; 95% confidence interval, 0.184-0.549) of the tumors. In addition, univariate analysis revealed that patients with CRC with lower RASSF10 expression had poorer overall survival (OS; P<.001) and disease-free survival (DFS; P<.001). The 5-year OS and DFS rates were 48.2% and 28.3%, respectively, in patients with low RASSF10 expression and 82.2% and 62.6%, respectively, in patients with high RASSF10 expression. Multivariate Cox regression analysis revealed that the strongest predictors of OS and DFS were RASSF10 expression (P<.001 and P<.001, respectively), T stage (P=.003 and P=.009, respectively), and N stage (P=.005 and P=.026, respectively). These results demonstrate that low expression of RASSF10 in CRC tissues is significantly correlated with poor survival after curative resection and may serve as a useful biomarker predictive of CRC prognosis.
Xue WJ, Feng Y, Wang F, et al.The value of serum RASSF10 hypermethylation as a diagnostic and prognostic tool for gastric cancer.
Tumour Biol. 2016; 37(8):11249-57 [PubMed
] Related Publications
The tumor-suppressing role of Ras-association domain family 10 (RASSF10) has been described in several types of cancers. Here, we evaluated the potential use of the hypermethylation status of the RASSF10 promoter in serum as a new diagnostic and prognostic tool in gastric cancer (GC). We used bisulfite sequencing polymerase chain reaction to examine RASSF10 methylation levels in serum and/or tumor samples from 82 GC, 45 chronic atrophic gastritis (CAG), and 50 healthy control patients. In the serum of GC patients, the median level of RASSF10 methylation was higher at 47.84 % than those in the serum of CAG and healthy control patients at 11.89 and 11.35 %, respectively. The median level of RASSF10 methylation in GC tumor tissue was similarly high at 62.70 %. Furthermore, RASSF10 methylation levels were highly correlated between paired serum and tumor samples from GC patients. We performed receiver-operating characteristic curve analyses to verify that serum RASSF10 methylation levels could effectively distinguish GC from control patients. Moreover, multivariate analyses showed that high serum RASSF10 methylation levels in GC patients were associated with large tumors, lymph node metastasis, and high carcinoembryonic antigen (CEA) levels. Survival analyses showed that GC patients with high serum RASSF10 methylation levels had shorter overall and disease-free survival after D2 lymphadenectomy than those with low levels. High serum RASSF10 methylation levels were also an independent predictor of tumor recurrence and GC patient survival. In conclusion, serum RASSF10 promoter methylation levels can serve as a valuable indicator for the diagnosis and prognosis of GC in the clinic.
Methylation of the Ras-association domain family 10 (RASSF10) promoter region correlates with clinicopathological characteristics and poor prognosis in several human cancers. Here, we examined RASSF10 expression in hepatocellular carcinoma (HCC) and its role in hepatocarcinogenesis. RASSF10 mRNA and protein levels were downregulated in both HCC cell lines and patient tissue samples. In patient tissues, low RASSF10 levels correlated with hepatocirrhosis, poor tumor differentiation, tumor thrombus and Barcelona Clinic Liver Cancer stage, and were indicative of increased tumor recurrence and reduced patient survival. Low RASSF10 expression was associated with promoter hypermethylation, which was in turn associated with polycyclic aromatic hydrocarbon and aflatoxin B1 exposure, but not DNA methyltransferase expression. Overexpression of RASSF10 in HCC cell lines suppressed cell growth and colony formation, and induced apoptosis by up- or down-regulating specific Bcl-2 family proteins. RASSF10 overexpression increased pro-apoptotic Bax and Bad levels, but decreased anti-apoptotic Bcl-2 and Bcl-xl expression. Overexpression also inhibited tumor formation in nude mice and reduced cell migration and invasion by inhibiting the epithelial-mesenchymal transition. RASSF10 knockdown promoted cell growth. Our results show that RASSF10 is frequently hypermethylated and down-regulated in HCC and can potentially serve as a useful biomarker predictive of HCC patient prognosis.
Dong T, Zhang M, Dong Y, et al.Methylation of RASSF10 promotes cell proliferation and serves as a docetaxel resistant marker in human breast cancer.
Discov Med. 2015; 20(111):261-71 [PubMed
] Related Publications
Breast cancer is a leading cause of death among females worldwide. However, the mechanisms of breast cancer remain largely unclear. RASSF10 is frequently methylated in certain types of human cancers. To understand the mechanism of RASSF10 in breast cancer, samples of breast cancer cell lines, primary cancer, breast tissue adjacent to cancer, and normal breast tissue were investigated in this study. Methylation specific PCR (MSP), flow cytometry, western blot, and siRNA knockdown assay were used. Complete methylation was found in MCF7, MDA-MB-435, and MDA-MB-468 cells, partial methylation was found in ZR75-1 cells, and unmethylation was revealed in SKBR3 cells. Loss of RASSF10 expression was found in MCF7, MDA-MB-435, and MDA-MB-468 cells, and high expression of RASSF10 was found in ZR75-1 and SKBR3 cells. The expression of RASSF10 was induced by 5-aza-2'-deoxycytidine (5-Aza) in MCF7, MDA-MB-435, and MDA-MB-468 cells. RASSF10 methylation was found in 77.8% (49/63) of primary breast cancer and 17.8% (8/45) of adjacent tissue samples. No methylation was found in normal breast tissue samples. Restoration of RASSF10 expression inhibited cell proliferation and induced G2/M phase arrest in MCF7 and MDA-MB-468 cells. RASSF10 sensitized these cells to docetaxel. RASSF10 induced apoptosis and activated P53 signaling in breast cancer cells. In conclusion, RASSF10 is frequently methylated in human breast cancer and infrequently in adjacent tissue samples. RASSF10 methylation may serve as an early detective marker. The expression of RASSF10 is regulated by promoter region methylation. Since restoration of RASSF10 expression sensitized breast cancer cells to docetaxel, RASSF10 methylation is a potential docetaxel resistant marker. RASSF10 suppresses breast cancer growth by activating P53 signaling.
Li X, Liang Q, Liu W, et al.Ras association domain family member 10 suppresses gastric cancer growth by cooperating with GSTP1 to regulate JNK/c-Jun/AP-1 pathway.
Oncogene. 2016; 35(19):2453-64 [PubMed
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The Ras association domain family (RASSF) encodes several members with tumor-suppressive potentials. We aimed to investigate the biological function and clinical implication of RASSF10 in gastric cancer (GC). We found that RASSF10 was silenced in six of seven GC cell lines and in primary GC tissues, but was highly expressed in normal gastric tissues. The silence of RASSAF10 was mediated by promoter methylation as evaluated by bisulfite genomic sequencing. RASSF10 expression could be restored by demethylation treatment. A negative correlation between methylation and mRNA expression of RASSF10 was observed in 223 gastric samples of The Cancer Genome Atlas study (P<0.0001). Re-expression of RASSF10 in GC cell lines (AGS and MKN45) significantly suppressed cell viability, colony formation, migration and invasion, reduced cells in S phase, accumulated cells in G2 phase and induced cell apoptosis in vitro, and inhibited tumorigenicity in nude mice. These were confirmed by decreased expression of proliferation markers (proliferating cell nuclear antigen, p-CDC2 and p-CDC25) and increased apoptotic cascades (cleaved caspases-9, -8, -3 and cleaved poly (ADP-ribose) polymerase). Conversely, RASSF10 knockdown in normal gastric cell line yielded an opposing effect. Co-immunoprecipitation combined with mass spectrometry analyses were performed to reveal the downstream effectors of RASSF10. The result revealed that glutathione S-transferase Pi 1 (GSTP1) was a direct cooperator of RASSF10. The tumor-suppressive effect of RASSF10 was partially mediated by cooperating with GSTP1 to deregulate Jun N-terminal kinase (JNK)/c-Jun/AP-1 pathway. Importantly, RASSF10 methylation was detected in 56.6% (98/173) of primary GCs and is an independent risk factor for poor survival of GC patients (P=0.001). In conclusions, RASSF10 functions as a tumor suppressor by cooperating with GSTP1 to deregulate JNK/c-Jun/AP-1 pathway in GC. Promoter methylation of RASSF10 is associated with poor survival of GC patients.
RASSF10 has previously been reported to be frequently methylated in a number of malignancies. To understand the importance of RASSF10 inactivation in colorectal carcinogenesis, eight colorectal cancer cell lines, 89 cases of primary colorectal cancer and 5 cases of normal colorectal mucosa were examined. Methylation specific PCR, western blot, siRNA, gene expression array and xenograft mice were employed. The expression of RASSF10 was regulated by promoter regional methylation in colorectal cancer cells. RASSF10 was methylated in 60.7% (54/89) of primary colorectal cancers and was positively associated with tumor stage (p < 0.05) and metastasis (p < 0.05). Restoration of RASSF10 led to inhibition of colorectal cancer cell proliferation in vitro and in vivo and increased apoptosis. Gene expression arrays discovered RASSF10 inhibition of MDM2 expression as a mediator of these effects, which was confirmed with RT-PCR and western blot. RASSF10 was shown to activate P53 signaling in RKO and HCT116 cells after UV exposure, and sensitized these cells to docetaxel. In conclusion, our study demonstrates RASSF10 is frequently methylated in human colorectal cancer leading to loss of expression. RASSF10 normally suppresses human colorectal cancer growth by activating P53 signaling in colorectal cancer, and restored expression sensitizes colorectal cancer to docetaxel.
Lu D, Ma J, Zhan Q, et al.Epigenetic silencing of RASSF10 promotes tumor growth in esophageal squamous cell carcinoma.
Discov Med. 2014; 17(94):169-78 [PubMed
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UNLABELLED: Esophageal squamous cell carcinoma (ESCC) is one of the most malignant diseases and the five year survival rate remains less than 10%. RASSF10 is a newly identified member of the Ras-association family, but the regulation and the function of RASSF10 in ESCC remain unclear. Research methodologies such as methylation specific PCR (MSP), semi-quantitative RT-PCR, immunohistochemistry, Sodium bisulfite sequencing, and colony formation assay were utilized in this investigation. Loss of RASSF10 expression was found in KYSE150 cells and reduced expression was found in KYSE70 and KYSE180 cells. Expression of RASSF10 was found in KYSE140, KYSE450, KYSE510, TE1, TE3, and TE8 cell lines. Complete methylation was found in KYSE30 and KYSE150 cells, partial methylation was found in KYSE70, KYSE180, KYSE510, and TE1, and unmethylation was found in KYSE140, KYSE450, TE3, and TE8. Re-expression or increased expression was induced by 5-Aza-dC treatment. RASSF10 was methylated in 44.3% primary esophageal squamous cell carcinoma. RASSF10 inhibits cell proliferation and induces G2/M phase arrest in esophageal cancer cells.
IN CONCLUSION: RASSF10 was frequently methylated in human esophageal squamous cell carcinoma and expression of RASSF10 was regulated by promoter region hypermethylation. RASSF10 may serve as a tumor suppressor of esophageal cancer.
Li Z, Chang X, Dai D, et al.RASSF10 is an epigenetically silenced tumor suppressor in gastric cancer.
Oncol Rep. 2014; 31(4):1661-8 [PubMed
] Related Publications
To better understand the role of the N-Terminal Ras association domain family (RASSF) genes in the development of gastric cancer, we examined the expression of RASSF7 and RASSF10 and RASSF10 methylation in gastric cancer. We found that RASSF10 expression was lost in six gastric cancer cell lines, and was rescued by a DNA demethylating agent and a histone deacetylase inhibitor. However, RASSF7 expression was strong in four cancer cell lines as well as in 87% of primary gastric cancer tissues. In contrast, RASSF7 expression was moderate in the GES-1 cell line and negative in 33.3% of the corresponding non-cancerous tissues. Analysis of RASSF10 methylation by methylation-specific PCR (MSP) and sequencing revealed that the methylation frequency in primary gastric carcinoma tissues was significantly higher compared to that in adjacent non-carcinoma tissues (61.6 vs. 38.4%; p<0.01). The methylation frequency in the tumor with invasion depth at T3 and T4 was significantly higher compared to that with invasion depth at T1 and T2 (67.1 vs. 37.5%; p<0.05). Hypermethylation of RASSF10 was found in the patients with lymph node metastasis, compared to those with unaffected lymph nodes (68.8 vs. 40.9%; p<0.05). Among the 4 gross types of the Borrmann classification, i.e. EGC, Borrmann Ⅰ, Borrmann Ⅱ, Borrmann Ⅲ and Borrmann Ⅳ, the last one was more frequently methylated (85.7 vs. 56.9%; p<0.05). The present study revealed that RASSF10 is an epigenetically silenced gene involved in tumor invasion and metastasis in gastric cancer, suggesting that the methylation status of RASSF10 may be a useful indicator to predict the malignant degree of gastric cancer.
Wang Y, Ma T, Bi J, et al.RASSF10 is epigenetically inactivated and induces apoptosis in lung cancer cell lines.
Biomed Pharmacother. 2014; 68(3):321-6 [PubMed
] Related Publications
Ras-association domain family 10 (RASSF10), the latest member of the RASSF family with Ras effector function, has been frequently inactivated by aberrant promoter hypermethylation in several human cancers. However, its role in lung cancer has remained unclear. In this study, we investigated the methylation status of RASSF10 by combined bisulfate restriction analysis (COBRA) and examined its preliminary function in lung cancer cell lines. RASSF10 was methylated in four out of six lung cancer cell lines, including NCI-H157, NCI-460, SPCA-1 and NCI-H446. Treatment with a DNA methylation inhibitor, 5-aza-2'-deoxycytiding (5-aza-DC), restored RASSF10 mRNA expression and the restoration of RASSF10 increased cell apoptosis in a dose dependent manner, whereas knockdown of RASSF10 improved cell proliferation ability and inhibited cell apoptosis rate significantly. Immunofluorescence revealed that RASSF10 protein was located in the cell membrane. Taken together, our data for the first time demonstrates the frequent epigenetic inactivation of RASSF10 in lung cancer cell lines. RASSF10 induces cell apoptosis and might function as a tumor suppressor gene in lung cancer.
Chan JJ, Katan MPLCɛ and the RASSF family in tumour suppression and other functions.
Adv Biol Regul. 2013; 53(3):258-79 [PubMed
] Related Publications
Not all proteins implicated in direct binding to Ras appear to have a positive role in the generation and progression of tumours; examples include Phospholipase C epsilon (PLCɛ) and some members of the Ras-association domain family (RASSF). The RASSF family comprises of ten members, known as RASSF1 to RASSF10. PLCɛ and RASSF members carry a common Ras-association domain (RA) that can potentially bind Ras oncoproteins and mediate Ras-regulated functions. RASSF1 to RASSF6 also share a common SARAH domain that facilitates protein-protein interactions with other SARAH domain proteins. The majority of the family are frequently downregulated by epigenetic silencing in cancers. They are implicated in various important biological processes including apoptosis, microtubule stabilisation and cell cycle regulation. Recent studies have reinforced the tumour suppressive properties of the RASSF family, with new evidence of emerging pathways and novel functions that suggest a wider role for these proteins. This review will first describe an emerging role of PLCɛ in tumour suppression and then focus on and summarise the new findings on the RASSF family in the last five years to consolidate their well-established functions, and highlight the new regulatory roles of specific RASSF members.
Ras-association domain family of genes consist of 10 members (RASSF1-RASSF10), all containing a Ras-association (RA) domain in either the C- or the N-terminus. Several members of this gene family are frequently methylated in common sporadic cancers; however, the role of the RASSF gene family in rare types of cancers, such as bone cancer, has remained largely uninvestigated. In this report, we investigated the methylation status of RASSF1A and RASSF2 in Ewing sarcoma (ES). Quantitative real-time methylation analysis (MethyLight) demonstrated that both genes were frequently methylated in Ewing sarcoma tumors (52.5% and 42.5%, respectively) as well as in ES cell lines and gene expression was upregulated in methylated cell lines after treatment with 5-aza-2'-deoxcytidine. Overexpression of either RASSF1A or RASSF2 reduced colony formation ability of ES cells. RASSF2 methylation correlated with poor overall survival (p = 0.028) and this association was more pronounced in patients under the age of 18 y (p = 0.002). These results suggest that both RASSF1A and RASSF2 are novel epigenetically inactivated tumor suppressor genes in Ewing sarcoma and RASSF2 methylation may have prognostic implications for ES patients.
Wei Z, Chen X, Chen J, et al.RASSF10 is epigenetically silenced and functions as a tumor suppressor in gastric cancer.
Biochem Biophys Res Commun. 2013; 432(4):632-7 [PubMed
] Related Publications
Ras association domain family (RASSF) proteins are encoded by several tumor suppressor genes that are frequently silenced in human cancers. In this study, we investigated RASSF10 as a target of epigenetic inactivation and examined its functions as a tumor suppressor in gastric cancer. RASSF10 was silenced in six out of eight gastric cancer cell lines. Loss or downregulation of RASSF10 expression was associated with promoter hypermethylation, and could be restored by a demethylating agent. Overexpression of RASSF10 in gastric cancer cell lines (JRST, BGC823) suppressed cell growth and colony formation, and induced apoptosis, whereas RASSF10 depletion promoted cell growth. In xenograft animal experiments, RASSF10 overexpression effectively repressed tumor growth. Mechanistic investigations revealed that RASSF10 inhibited tumor growth by blocking activation of β-catenin and its downstream targets including c-Myc, cyclinD1, cyclinE1, peroxisome proliferator-activated receptor δ, transcription factor 4, transcription factor 1 and CD44. In conclusion, the results of this study provide insight into the role of RASSF10 as a novel functional tumor suppressor in gastric cancer through inhibition of the Wnt/β-catenin signaling pathway.
We quantitated the methylated fraction of CpG sites in the promoter regions of O6-MGMT, p14ARF, p16INK4a, RASSF1A and APC1A in tumor tissue from patients with colorectal cancer (CRC) in order to determine if promoter hypermethylation of any of these genes predicts survival. DNA was isolated from 111 primary CRC and 46 matched normal colorectal mucosa samples from the same patients, obtained at primary surgery and DNA methylation was examined by Pyrosequencing®. Follow-up time was up to 20 years. Patients showed partial promoter methylation in the following frequencies: O6-MGMT, 34%; p14ARF, 29%; p16INK4a, 28%; RASSF1A, 14%; and APC1A, 27%. Normal mucosa was always unmethylated. CRC patients with methylated p14ARF gene promoter had significantly worse prognosis (p=0.036), whereas those with methylated O6-MGMT had significantly better prognosis through the first 60 months post-treatment (RR 0.36; p=0.023). Methylation of one or more of the genes from the set p14ARF, RASSF1A and APC1A, was significantly (p=0.021) associated with worse prognosis even adjusting for tumor stage and differentiation (RR 2.2, p=0.037). Thus, DNA methylation of the p14ARF, RASSF1A and APC1A genes, diagnosed by Pyrosequencing, defines a poor prognosis subset of CRC patients independently of both tumor stage and differentiation. O6-MGMT methylation may play a protective role.
BACKGROUND: 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.
RESULTS: 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.
Shinawi T, Hill V, Dagklis A, et al.KIBRA gene methylation is associated with unfavorable biological prognostic parameters in chronic lymphocytic leukemia.
Epigenetics. 2012; 7(3):211-5 [PubMed
] Related Publications
Ras-association domain family (RASSF) members are a family of genes containing an RA domain in either the C-terminus (RASSF1-RASSF6) or in the N-terminus (RASSF7-RASSF10). Members of this gene family are core members of the Salvador/Warts/Hippo (SWH) tumor suppressor network and have been shown to be involved in human tumorigenesis. Among the RASSF genes, RASSF1A is one of the most frequently methylated genes in a wide range of epithelial cancers, and we previously demonstrated that RASSF6 and RASSF10 genes are frequently epigenetically inactivated in acute leukemias, particularly in those of the B cell type. We here determined the methylation profiles of all members of the RASSF gene family as well as two recently identified (KIBRA, CRB3) upstream members of the SWH pathway in the leukemic B cells obtained from a well-characterized cohort of 95 patients with chronic lymphocytic leukemia (CLL). Among the RASSF genes, RASSF10 (50%) was the most frequently methylated gene, followed by RASSF6 (16%). The remaining RASSF genes were either unmethylated or showed a frequency of methylation < 10%. The upstream SWH member KIBRA was also frequently methylated in CLL (35%) in contrast to CRB3. Interestingly, the analysis of clinical-pathological parameters showed that KIBRA methylation was associated with unfavorable biological prognostic parameters, including unmutated IGHV genes (p = 0.007) and high CD38 expression (p < 0.05).
Dansranjavin T, Wagenlehner F, Gattenloehner S, et al.Epigenetic down regulation of RASSF10 and its possible clinical implication in prostate carcinoma.
Prostate. 2012; 72(14):1550-8 [PubMed
] Related Publications
BACKGROUND: Ras association domain family (RASSF) comprises several tumor suppressor genes, which are often epigenetically inactivated in human tumors. Here, we aim to analyze the relevance of the recently identified member RASSF10 in prostate carcinogenesis.
METHODS: RASSF10 promoter methylation and mRNA expression were investigated by bisulfite-pyrosequencing and qRT-PCR, respectively, in prostate carcinoma (PCa) cell lines (LNCaP, 22Rv1, DU-145) and in 83 primary PCa and 53 primary benign prostatic hyperplasia (BPH) tissues obtained after radical prostatectomy. Histological localization of RASSF10 was done by in situ hybridization. To prove the epigenetic nature of RASSF10 down regulation, PCa cell lines were treated with 5-aza-2-deoxycytidine and trichostatin A. Potential function of RASSF10 was analyzed in LNCaP by colony formation and apoptosis assays.
RESULTS: RASSF10 mRNA was localized to cells of the basal layer of the prostatic gland. Absence (LNCaP) and decrease (22Rv1, DU-145) of RASSF10 expression was associated with promoter methylation and could be restored by demethylating agents. A link between RASSF10 mRNA reduction and promoter methylation was also detected in primary prostate tissues (P = 0.006), where PCa showed more frequently reduced RASSF10 levels when compared with BPH (33.7% vs. 13.2%, P = 0.009). RASSF10 methylation could be further associated with advanced tumor stage and advanced age (P-values < 0.05). Our preliminary functional assays revealed the ability of RASSF10 to inhibit colony formation (P = 0.018) and to increase apoptosis (P = 0.035).
CONCLUSIONS: This is the first study, which demonstrates the frequent epigenetic inactivation of RASSF10 in PCa and its implication in clinical symptoms of PCa.
Helmbold P, Richter AM, Walesch S, et al.RASSF10 promoter hypermethylation is frequent in malignant melanoma of the skin but uncommon in nevus cell nevi.
J Invest Dermatol. 2012; 132(3 Pt 1):687-94 [PubMed
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The Ras association domain family (RASSF) consists of several tumor suppressor genes, which are frequently silenced in human cancers. We analyzed the epigenetic inactivation of RASSF2 and RASSF10 in malignant melanoma (MM) of the skin, including 5 MM cell lines, 28 primary MM, 33 metastases of MM, 47 nevus cell nevi (NCN), and 22 control tissues. The RASSF2 promoter was epigenetically downregulated in two MM cell lines only, but not in any of the investigated tumor samples. In contrast, hypermethylation of the RASSF10 promoter was found in all investigated cell lines, 19/28 (68%) of the primary MM and 30/33 (91%) of the MM metastases, 2/18 (11%) of the dysplastic NCN, and 0/29 (0%) of the non-dysplastic NCN (difference between MM and all nevi, P<0.001). RASSF10 promoter hypermethylation correlated with a reduced RASSF10 mRNA expression in 3/4 MM cell lines, and treatment with a DNA methylation inhibitor reactivated RASSF10 transcription. Furthermore, immunohistological RASSF10 expression corresponds negatively to its promoter methylation state. In summary, RASSF10 proved to be a characteristically epigenetically silenced tumor suppressor in melanomagenesis, and analysis of RASSF10 methylation status represents a new candidate tool to assist in discrimination between MM and NCN.
Epigenetic inactivation of tumor suppressor genes is a hallmark of cancer development. RASSF1A (Ras Association Domain Family 1 isoform A) tumor suppressor gene is one of the most frequently epigenetically inactivated genes in a wide range of adult and children's cancers and could be a useful molecular marker for cancer diagnosis and prognosis. RASSF1A has been shown to play a role in several biological pathways, including cell cycle control, apoptosis and microtubule dynamics. RASSF2, RASSF4, RASSF5 and RASSF6 are also epigenetically inactivated in cancer but have not been analysed in as wide a range of malignancies as RASSF1A. Recently four new members of the RASSF family were identified these are termed N-Terminal RASSF genes (RASSF7-RASSF10). Molecular and biological analysis of these newer members has just begun. This review highlights what we currently know in respects to structural, functional and molecular properties of the N-Terminal RASSFs.
Hill VK, Underhill-Day N, Krex D, et al.Epigenetic inactivation of the RASSF10 candidate tumor suppressor gene is a frequent and an early event in gliomagenesis.
Oncogene. 2011; 30(8):978-89 [PubMed
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We have recently described the N-terminal RAS association domain family of genes, RASSF7-10. Previously, we cloned the N-terminal RASSF10 gene and demonstrated frequent methylation of the associated 5'-CpG island in acute lymphoblastic leukemia. To characterize RASSF10 gene expression, we demonstrate that in developing Xenopus embryos, RASSF10 shows a very striking pattern in the rhombencephalon (hind brain). It is also expressed in other parts of the brain and other organs. Due to the well-defined expression pattern in the brain of Xenopus embryos, we analyzed the methylation status of the RASSF10-associated 5'-CpG island in astrocytic gliomas. RASSF10 was frequently methylated in WHO grade II-III astrocytomas and WHO grade IV primary glioblastomas (67.5%), but was unmethylated in grade I astrocytomas and in DNA from age matched control brain samples. RASSF10 gene expression both at the mRNA and protein levels could be switched back on in methylated glioma cell lines after treatment with 5-aza-2'-deoxycytidine. In secondary glioblastomas (sGBM), RASSF10 methylation was an independent prognostic factor associated with worst progression-free survival and overall survival and occurred at an early stage in their development. In cell culture experiments, overexpression of RASSF10 mediated a reduction in the colony forming ability of two RASSF10-methylated glioma cell lines. Conversely, RNAi-mediated knockdown of RASSF10-stimulated anchorage-independent growth of U87 glioma cells, increased their viability and caused an increase in the cells' proliferative ability. We generated and characterized a RASSF10-specific antibody and demonstrated for the first time that RASSF10 subcellular localization is cell-cycle dependent with RASSF10 colocalizing to centrosomes and associated microtubules during mitosis. This is the first report demonstrating that RASSF10 can act as a tumor suppressor gene and is frequently methylated in gliomas and can potentially be developed into a prognostic marker for sGBM.
Schagdarsurengin U, Richter AM, Wöhler C, Dammann RHFrequent epigenetic inactivation of RASSF10 in thyroid cancer.
Epigenetics. 2009; 4(8):571-6 [PubMed
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The Ras association domain family (RASSF) encodes for distinct tumor suppressors and several members are frequently silenced in human cancer. In our study, we analyzed the role of a novel RASSF member termed RASSF10 in thyroid carcinogenesis. The RASSF10 CpG island promoter was intensively methylated in nine thyroid cancer cell lines and in 66% of primary thyroid carcinomas. RASSF10 methylation was significantly increased in primary thyroid carcinoma compared to normal thyroid and follicular adenoma (0 and 10%, respectively; p < 0.004). Patients with cancerous lymph nodes were significantly hypermethylated for RASSF10 in primary thyroid tumors compared to those with non-affected lymph nodes (79 vs. 36%; p = 0.047). RASSF10 promoter hypermethylation correlated with a reduced expression and treatment with a DNA methylation inhibitor reactivated RASSF10 transcription. In summary, our data show frequent epigenetic inactivation of RASSF10 in thyroid cancer. These results suggest that RASSF10 may encode a novel epigenetically inactivated candidate tumor suppressor gene in thyroid carcinogenesis.
BACKGROUND: The Ras-association family (RASSF) of tumour suppressor genes (TSGs) contains 10 members that encode proteins containing Ras-association (RA) domains. Several members of the RASSF family are frequently epigenetically inactivated in cancer, however, their role in leukaemia has remained largely uninvestigated. Also, RASSF10 is a predicted gene yet to be experimentally verified. Here we cloned, characterised and demonstrated expression of RASSF10 in normal human bone marrow. We also determined the methylation status of CpG islands associated with RASSF1-10 in a series of childhood acute lymphocytic leukaemias (ALL) and normal blood and bone marrow samples.
RESULTS: COBRA and bisulphite sequencing revealed RASSF6 and RASSF10 were the only RASSF members with a high frequency of leukaemia-specific methylation. RASSF6 was methylated in 94% (48/51) B-ALL and 41% (12/29) T-ALL, whilst RASSF10 was methylated in 16% (8/51) B-ALL and 88% (23/26) T-ALL. RASSF6 and RASSF10 expression inversely correlated with methylation which was restored by treatment with 5-aza-2'deoxycytidine (5azaDC).
CONCLUSION: This study shows the hypermethylation profile of RASSF genes in leukaemias is distinct from that of solid tumours and represents the first report of inactivation of RASSF6 or RASSF10 in cancer. These data show epigenetic inactivation of the candidate TSGs RASSF6 and RASSF10 is an extremely frequent event in the pathogenesis of childhood leukaemia. This study also warrants further investigation of the newly identified RASSF member RASSF10 and its potential role in leukaemia.