Highlights ► Thirty-nine of 215 patients exhibited TFPI2 methylation in their serum DNA. ► TFPI2 methylation was observed more frequently according to the cancer progression. ► Using three serum ...markers including TFPI2 methylation, the detection rate was 42%.
We and others recently isolated a human p53 homologue (p40/p51/p63/p73L) and localized the gene to the distal long arm of chromosome 3. Here we sought to examine the role of p40/p73L, two variants ...lacking the N-terminal transactivation domain, in cancer. Fluorescent in situ hybridization (FISH) analysis revealed frequent amplification of this gene locus in primary squamous cell carcinoma of the lung and head and neck cancer cell lines. (We named this locus AIS for$\underline{a}$mplified$\underline{i}$n$\underline{s}$quamous cell carcinoma). Furthermore, amplification of the AIS locus was accompanied by RNA and protein overexpression of a variant p68AISlacking the terminal transactivation domain. Protein overexpression in primary lung tumors was limited to squamous cell carcinoma and tumors known to harbor a high frequency of p53 mutations. Overexpression of p40AISin Rat 1a cells led to an increase in soft agar growth and tumor size in mice. Our results support the idea that AIS plays an oncogenic role in human cancer.
The Mus81 gene encodes a critical endonuclease involved in DNA repair and tumor suppression. Our previous study has shown reduced expression of Mus81 in hepatocellular carcinoma and its association ...with the metastastic potential and prognosis of hepatocellular carcinoma. However, the role of Mus81 in colorectal carcinoma is currently unknown. We therefore carried out the present study to explore the correlation between Mus81 expression and the progression of colorectal carcinoma. Mus81 expression in 92 cases of colorectal carcinoma and matched normal tissues was determined by quantitative real‐time polymerase chain reaction. Our results showed that Mus81 expression in colorectal carcinoma tissues was significantly reduced compared with the corresponding normal tissues (P < 0.001) and the downregulation of Mus81 (decreased by more than 50%) was found in 60.9% (56/92) of colorectal carcinoma. Moreover, Mus81 downregulation correlated significantly to hepatic metastasis (P = 0.019) and a high TNM stage (P = 0.025) of colorectal carcinoma. In addition, the decrease of Mus81 was also detected in 10 cases of hepatic metastasis tissues compared with the corresponding primary colorectal carcinoma tissues (P = 0.016). More importantly, colorectal carcinoma patients with apparent Mus81 downregulation have shown significantly poorer overall survival than those with little Mus81 downregulation (P = 0.0374). Also, multivariable Cox regression analysis identified Mus81 downregulation as an independent prognostic factor for colorectal carcinoma (hazard ratio, 1.678; P = 0.040). In conclusion, the reduced expression of Mus81 is closely related to hepatic metastasis and poor prognosis of colorectal carcinoma, indicating Mus81 as a novel prognostic marker for colorectal carcinoma. (Cancer Sci 2011; 102: 472–477)
The present study aimed to examine the feasibility of detecting vimentin (VIM) methylation in the serum of patients with colorectal cancer (CRC) and to determine the effectiveness of a relatively ...simple, inexpensive, and non-invasive test performed in combination with the conventional carcinoembryonic antigen analysis.
VIM methylation in the serum DNA of 242 patients with CRC was measured by a quantitative methylation-specific polymerase chain reaction.
A significantly higher positive rate was obtained for VIM methylation than for carcinoembryonic antigen or carbohydrate antigen 19-9 in stage 0, I, and II patients. The combination of all three markers yielded similar sensitivity for patients with disease of stage 0: 57.1%, I: 36.1%, II: 45.2%, and III: 55.4%, whereas the sensitivity reached 85.7% for patients with stage IV disease.
VIM methylation of serum DNA may be a useful marker for the early detection of CRC.
In pancreatic cancers, K-ras mutations have been found frequently (80%-100%), and they could be a good marker to detect tumor DNA in the plasma. Several studies have indicated that polymerase chain ...reaction/restriction fragment length polymorphism (PCR/RFLP) analysis of K-ras mutation was a useful method for the detection of hepatic and lymph node metastasis of pancreatic cancer. However, this method sometimes exhibited false-positive results, and the rate of K-ras mutation might thus be overestimated in these tissues. To diagnose pancreatic cancer correctly at an early stage, we attempted to detect tumor DNA in the plasma of pancreatic cancer patients using a more sensitive and specific method.
We examined 28 pancreatic cancer patients using a sensitive mutation-specific mismatch ligation assay for K-ras gene mutations in primary tumors and paired plasma samples.
K-ras gene mutations were detected in 26 of the 28 (93%) pancreatic cancers. We also found the same mutations in 9 of these 26 (35%) patients in their plasma DNA. This mutation was found even in the plasma of patients with TNM stage II cancer.
Genetic alterations present in the tumors of pancreatic cancer patients can be detected in their plasma, and this approach is potentially applicable for cancer screening and the monitoring of this deadly disease.
Background: Recently, it was shown that the Vimentin gene, usually activated in mesenchymal cells, was highly methylated in
colorectal carcinoma. Moreover, Vimentin methylation can be applied for the ...screening or as a diagnostic tool of colorectal
carcinomas in the fecal DNA test. Materials and Methods: The methylation status of the Vimentin gene was examined in primary
carcinomas and the corresponding normal tissues derived from 48 patients with colorectal cancer using quantitative methylation-specific
PCR (qMSP) and the correlation between the methylation status and the clinicopathological findings was evaluated. Results.
Aberrant methylation of the Vimentin gene was detected in 31 out of 48 (65%) primary colorectal carcinomas. This result suggested
that the aberrant methylation of the Vimentin gene was frequent in colorectal carcinomas. Subsequently, clinicopathological
data were correlated with the methylation score. A significant difference was observed in age and Dukes' stage (p=0.001 and
p=0.034, respectively). Moreover, a trend was shown toward preferentially developing liver metastasis and peritoneal dissemination
in colorectal carcinomas with Vimentin methylation (p=0.052 and p=0.080, respectively). Conclusion: Vimentin was frequently
methylated in advanced colorectal carcinoma.
Purpose and Experimental Design: Recent evidence shows that the presence of promoter hypermethylation of tumor suppressor genes has been demonstrated in the
serum DNA of patients with various cancers ...such as lung, liver, and head and neck cancer. We have examined promoter hypermethylation
of the p16 gene in esophageal squamous cell carcinoma (SCC) using methylation-specific PCR to detect tumor DNA in the serum.
Results: Aberrant promoter methylation of the p16 gene was detected in 31 of 38 (82%) esophageal SCCs. Subsequently, we tested for promoter methylation in the paired serum
DNA of 31 patients with a p16 alteration in the primary tumor. We found that 7 of these 31 (23%) patients had the same methylation changes in the serum
DNA.
Conclusions: This result indicates that promoter methylation present in the tumors of esophageal SCC patients can be detected in the serum
of the same patient and that this approach can potentially be used for the screening and monitoring of the disease.
To test the hypothesis that plasminogen activator inhibitor‐1 (PAI‐1) may serve as a candidate marker for the malignancy of gastric cancer, we carried out quantitative reverse ...transcription–polymerase chain reaction for the PAI‐1 gene and evaluated the possible relationship between PAI‐1 gene expression levels and clinicopathological findings in gastric cancer. A significant increase in PAI‐1 expression scores was observed in lymph node metastasis‐positive gastric cancers (2.11 ± 0.35) compared to metastasis‐negative cancers (0.33 ± 0.49) (P = 0.0048), as well as in distant metastasis‐positive gastric cancers (3.68 ± 0.58) compared to metastasis‐negative cancers (1.20 ± 0.32). The PAI‐1 expression score markedly increased with tumor stage (P < 0.0001; ANOVA test). Moreover, multivariate analysis revealed the PAI‐1 expression score to be a strong and independent prognostic factor for gastric cancer (P = 0.0450). These results suggested that PAI‐1 might serve as a new and promising parameter for the prediction of prognosis in gastric cancer. (Cancer Sci 2006; 97)
The expression of PGP9.5 was evaluated using immunohistochemistry
in 69 resected ductal carcinomas of the pancreas and in normal
pancreatic tissue. Overexpression did not seem to differ with
...histological type or pathological stage. A significant negative
correlation was found between overexpression of PGP9.5 and
postoperative survival. Multivariate analysis also suggested PGP9.5
along with tumor stage and extrapancreatic plexus invasion as strong
predictors of the outcome. This study suggests that PGP9.5 expression
may be used as a marker for predicting the outcome of resection-treated
pancreatic cancer patients.
It has recently been reported that CDH13 expression is silenced by aberrant methylation of the promoter region in several cancers. We examined the methylation status of the CDH13 gene in pancreatic ...cancer using methylation‐specific PCR (MSP), and detected aberrant methylation of CDH13 in all 6 pancreatic cancer cell lines examined. To confirm the status of the CDH13 gene in relation to the methylation pattern, we next examined CDH13 expression in these cell lines using reverse transcription (RT)‐PCR. As expected, no CDH13 expression was detected in any of the 6 pancreatic cancer cell lines. Moreover, 5‐aza‐2′‐deoxycytidine (5‐aza‐dC) treatment of CDH13‐methylated cell lines led to restoration of CDH13 expression. Among primary pancreatic cancers, 19 of 33 (58%) cases exhibited CDH13 methylation, while no cases exhibited it in corresponding normal pancreatic tissues. CDH13 methylation was detected even in relatively early pancreatic cancers, such as stage II cancers and cancers less than 2 cm in diameter. Our results suggest that the aberrant methylation of CDH13 occurs frequently in pancreatic cancer, even at a relatively early stage.
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