Clinicopathological significance of aberrant methylation of RARβ2 at 3p24, RASSF1A at 3p21.3, and FHIT at 3p14.2 in patients with non-small cell lung cancer

Tomizawa, Yoshio; Iijima, Hironobu; Nomoto, Tomoko; Iwasaki, Yasuki; Otani, Yoshimi; Tsuchiya, Satoshi; Saito, Ryusei; Dobashi, Kunio; Nakajima, Takashi; Mori, Masataka

doi:10.1016/j.lungcan.2004.05.003

Cited by 54 publications

(39 citation statements)

References 26 publications

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“…On the other hand, a statistically significant trend was observed between the RASSF1A methylation and lung adenocarcinoma. Some previous reports are consistent with these findings [13].…”

Section: Discussionsupporting

confidence: 89%

Prognostic significance of DAPK and RASSF1A promoter hypermethylation in non-small cell lung cancer (NSCLC).

Niklińska

Naumnik²,

Sulewska³

et al. 2009

Folia Histochem Cytobiol.

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Abstract. The epigenetic inactivation of tumor suppressor genes may play an important role in the development and progression of many cancer types, including lung cancer. Therefore, we investigated the association between the aberrant promoter methylation of 2 genes: the Death-Associated Protein Kinase (DAPK) and the Ras Association Domain Family 1A (RASSF1A) by using methylation-specific PCR, and the clinicopathological features and prognosis in 70 radically resected non-small cell lung cancers (NSCLCs). Hypermethylation of the DAPK and RASSF1A promoters was found in 24 (34%), and in 18 (26%) tumor DNA samples, respectively. Regarding different clinicopathological features of NSCLCs, the DAPK promoter methylation was more frequently observed in squamous cell carcinoma (46%) than in adenocarcinoma (25%) and large cell carcinoma (22%), but there were no significant statistical differences (p=0.3). On the other hand, a statistically significant trend was observed between the RASSF1A methylation and a histological type of tumor (p=0.06). 45% of adenocarcinoma tumors showed RASSF1A promoter methylation in comparison to 17% of squamous cell carcinomas and 22% of large cell carcinomas. When both markers were analyzed according to the tumor-node-metastasis (TNM) staging system, no statistically significant differences were observed between stage I, II and IIIa, and the DAPK (p=0.2) and RASSF1A methylation (p=0.1). In comparison, when stage I and II were grouped together and considered vs. stage IIIa, a significant association between RASSF1A methylation and the TNM was found (p=0.03). The group of patients with tumors showing DAPK promoter methylation had significantly poorer overall survival rates (p=0.02) than the patients with tumors that did not show DAPK promoter methylation. However, the association between the RASSF1A promoter methylation status and the overall survival rates was not statistically significant (p=0.48). In conclusion, this paper supports the importance of epigenetic gene regulation in lung cancer progression and prognosis.

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“…On the other hand, a statistically significant trend was observed between the RASSF1A methylation and lung adenocarcinoma. Some previous reports are consistent with these findings [13].…”

Section: Discussionsupporting

confidence: 89%

Prognostic significance of DAPK and RASSF1A promoter hypermethylation in non-small cell lung cancer (NSCLC).

Niklińska

Naumnik²,

Sulewska³

et al. 2009

Folia Histochem Cytobiol.

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“…Kim et al (50) recently showed that FHIT methylation was more frequent in older NSCLC patients and was associated with exposure to smoking (P = 0.001). Tomizawa et al (51) showed that FHIT methylation was significantly associated with p16 methylation in smokers with SCC. Our observations with regard to p16 and FHIT were consistent with these reports: our Spearman correlation test showed a significant positive correlation between p16 methylation and FHIT methylation (r = 0.188, P = 0.019); methylation of both genes was more frequent in older and in male patients; methylation of both genes was associated with a significantly worse prognosis only in SCC.…”

Section: Discussionmentioning

confidence: 99%

Aberrant Promoter Methylation Profile and Association with Survival in Patients with Non–Small Cell Lung Cancer

Gu¹,

Berman

Lu³

et al. 2006

Clinical Cancer Research

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Purpose: The aim of this study was to investigate the prognostic value of hypermethylation of tumor suppressor genes in patients with non-small cell lung cancer (NSCLC). Experimental Design: We examined the methylation status of nine genes in 155 tumors from patients with NSCLC using quantitative methylation-specific PCR. We analyzed the associations between gene methylation status and overall patient survival. Results: The methylation index, defined as the ratio between the number of methylated genes and the number of genes tested, was significantly higher in adenocarcinomas (0.38 F 0.20) than in squamous cell carcinomas (0.30 F 0.22; P = 0.027), in tumors from older patients (0.37 F 0.20) than younger patients (0.30 F 0.22; P = 0.040), and in tumors from heavier smokers (0.39 F 0.21) than lighter smokers (0.29 F 0.20; P = 0.042). In the Cox proportional hazards model, p16 methylation was associated with significantly poorer survival [hazard ratio, 1.95; 95% confidence interval (95% CI), 1.21-3.39]. Kaplan-Meier survival curves showed that patients with hypermethylated p16 had significantly shorter survival (median = 21.7 months) than patients without p16 hypermethylation (median = 62.5 months; P = 0.0001, log-rank test). Hypermethylation of CDH1 orTIMP3 gene was associated with significantly better survival with hazard ratios of 0.51 (95% CI, 0.29-0.90) and 0.59 (95% CI, 0.36-0.97), respectively. Joint analysis of these three genes showed a significant trend for poorer survival as the number of unfavorable events increased (P = 0.0007). Conclusion: Hypermethylation of multiple genes exhibited significant differential effect on NSCLC patient survival. Assessment of the effect of each methylated gene on survival is needed to provide optimal prognostic value.Both in the United States and around the world, lung cancer is the leading cause of cancer death in men and women, with a 5-year survival rate of only 15%, a statistic that has changed very little over the past two decades (1). This dismal survival could be improved through earlier detection or through identification of prognostic markers, which could identify subsets of patients with worse prognosis who might benefit from a more aggressive treatment strategy.It is now well established that epigenetic changes (i.e., heritable changes in gene expression without alterations in the primary DNA sequence of a gene; refs. 2, 3) play an important role in cancer development. The major epigenetic aberration in cancer development is inactivation of tumor suppressor genes (TSG) through hypermethylation of CpG islands in their promoter regions. The spectra and frequency of TSG inactivation at the CpG islands vary from cancer to cancer (3 -5). The distinct profile and varying levels of TSG methylations among different cancers, coupled with a sensitive methylation-specific PCR (MSP) technique, have shown promise as a tool for the early detection and diagnosis of cancer and for determining prognosis (5 -9).A number of genes are heavily methylated in non -small cell...

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“…6,[18][19][20][21] The RASSF1A and CDKN2A genes at chromosome regions 3p21 and 9p21, respectively, encode the tumor suppressors, Rassf1a and p16, that are also frequently silenced in lung cancers. 22,23 Because promoter hypermethylation is responsible for silencing FHIT in >30%, WWOX in >40%, RASSF1A in >32% and CDKN2A in >66% of NSCLCs, 6,22,23 pharmacologic therapy to restore expression of Fhit, Wwox and other tumor suppressors, for treatment of NSCLC offers a potentially efficacious approach.…”

mentioning

confidence: 99%

Epigenetic modulation of endogenous tumor suppressor expression in lung cancer xenografts suppresses tumorigenicity

Cantor

Iliopoulos

Rao

et al. 2006

Intl Journal of Cancer

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Epigenetic changes involved in cancer development, unlike genetic changes, are reversible. DNA methyltransferase and histone deacetylase inhibitors show antiproliferative effects in vitro, through tumor suppressor reactivation and induction of apoptosis. Such inhibitors have shown activity in the treatment of hematologic disorders but there is little data concerning their effectiveness in treatment of solid tumors. FHIT, WWOX and other tumor suppressor genes are frequently epigenetically inactivated in lung cancers. Lung cancer cell clones carrying conditional FHIT or WWOX transgenes showed significant suppression of xenograft tumor growth after induction of expression of the FHIT or WWOX transgene, suggesting that treatments to restore endogenous Fhit and Wwox expression in lung cancers would result in decreased tumorigenicity. H1299 lung cancer cells, lacking Fhit, Wwox, p16 INK4a and Rassf1a expression due to epigenetic modifications, were used to assess efficacy of epigenetically targeted protocols in suppressing growth of lung tumors, by injection of 5-aza-2-deoxycytidine (AZA) and trichostatin A (TSA) in nude mice with established H1299 tumors. High doses of intraperitoneal AZA/TSA suppressed growth of small tumors but did not affect large tumors (200 mm 3 ); lower AZA doses, administered intraperitoneally or intratumorally, suppressed growth of small tumors without apparent toxicity. Responding tumors showed restoration of Fhit, Wwox, p16 INKa , Rassf1a expression, low mitotic activity, high apoptotic fraction and activation of caspase 3. These preclinical studies show the therapeutic potential of restoration of tumor suppressor expression through epigenetic modulation and the promise of re-expressed tumor suppressors as markers and effectors of the responses. ' 2006 Wiley-Liss, Inc.Key words: DNA methylation; tumor suppressor genes; 5-aza-2-deoxycytidine Lung cancer is the leading cause of cancer death in the western hemisphere for men and women, eclipsing the combined mortalities from breast, colon and prostate cancers. Genomic aberrations involving chromosome 3p are the most frequent and earliest genetic events in lung carcinogenesis. 1,2 In particular, the FHIT gene, spanning the human common fragile site, FRA3B, at chromosome 3p14.2, and the RASSF1A gene at 3p21 are frequently silenced in lung cancer and show hallmarks of tumor suppressor genes. 3 FHIT is altered in many other types of cancers, including breast, head and neck, cervical, bladder, esophageal, gastric, pancreatic and renal cancer and alterations occur in very early stages of preneoplasia in some organs. Fhit loss is associated with progression and outcome in cancers of various organs. 4 Similarly, the WWOX gene at FRA16D is frequently silenced in lung cancers, and has recently been shown to suppress growth of lung cancer cells in nude mice. [5][6][7] The RASSF1A promoter region is hypermethylated in a large fraction of lung and other cancers 8,9 and methylation of the RASSF1A regulatory region has been proposed as a biomarker of lung ca...

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Clinicopathological significance of aberrant methylation of RARβ2 at 3p24, RASSF1A at 3p21.3, and FHIT at 3p14.2 in patients with non-small cell lung cancer

Cited by 54 publications

References 26 publications

Prognostic significance of DAPK and RASSF1A promoter hypermethylation in non-small cell lung cancer (NSCLC).

Prognostic significance of DAPK and RASSF1A promoter hypermethylation in non-small cell lung cancer (NSCLC).

Aberrant Promoter Methylation Profile and Association with Survival in Patients with Non–Small Cell Lung Cancer

Epigenetic modulation of endogenous tumor suppressor expression in lung cancer xenografts suppresses tumorigenicity

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