Atsushi Shirahata

Aberrant Methylation of the Netrin-1 Receptor Genes UNC5C and DCC Detected in Advanced Colorectal Cancer

BackgroundUNC5C and DCC, the netrin-1 receptors, belong to the functional dependence receptors family, which shares the ability to induce apoptosis in the absence of their ligands. Recently, two reports indicated that UNC5C and DCC methylation was closely associated with loss of gene expression in colorectal cancer. These results prompted us to examine the methylation status of the UNC5C and DCC genes in the colorectal carcinomas we surgically removed.MethodsThe methylation status of the UNC5C and DCC genes were examined in primary carcinomas and the corresponding normal tissues derived from 50 patients with colorectal cancer using quantitative methylation-specific polymerase chain reaction (qMSP). The correlation between the methylation status and the clinicopathologic findings was then evaluated.ResultsAberrant methylation of the netrin-1 receptor genes were detected in 41 of the 50 (82%) primary colon cancers, suggesting that the aberrant methylation of netrin-1 receptors was frequently observed in colorectal cancer. The clinicopathologic data were then correlated with this result.ConclusionsA significant difference was observed in the Dukes stage (p = 0.0438). Netrin-1 receptors might act as a tumor suppressor in colorectal cancers, and thus methylation might present a malignant potential in colorectal cancer.

Downregulation of Mus81 as a novel prognostic biomarker for patients with colorectal carcinoma

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)

Heterozygous loss of NF2 is an early molecular alteration in well-differentiated papillary mesothelioma of the peritoneum

Well-differentiated papillary mesothelioma of the peritoneum (WDPMP) is a rare disease, and many cases are either benign neoplasms or low-graded malignancies; however, a few cases show rapid progressive clinical courses. No effective therapy has yet been established for WDPMP, and the molecular basis of WDPMP tumorigenesis has never been reported. This study shows the malignant transformation of WDPMP in a Japanese female patient, who was alive for 54 months after the initial diagnosis by a laparoscopic biopsy. A molecular analysis of single nucleotide polymorphisms (SNPs), which were located in the neurofibromatosis type 2 (NF2) gene, a tumor suppressor gene assigned to chromosome 22q12.3, revealed the loss of heterozygosity (LOH) of the NF2 gene. Furthermore, SNP analyses determined that LOH was observed in the IL17RA (22q11.1), CHECK2 (22q12.1), and SHANK3 (22q13.3) genes, thus suggesting that NF2 loss occurred through 22q deletions or monosomy 22. The LOH of the NF2 gene was observed in an early stage of WDPMP, thus indicating that LOH of the NF2 gene is an early molecular alteration, and NF2 loss is a molecular mechanism associated not only with malignant pleural mesothelioma, but also with WDPMP.

A Long Survival Case of Metachronous Cerebellar Metastasis that was caused by Gastric Cancer

症例は72歳の男性で, 平成14年8月, MU領域の3型胃癌に対し胃全摘術, 脾合併切除が行われた. 最終診断はMU type3, 98×90mm, tub1, T2 (SS) N0 H0 P0 CY0 M0 stage IB根治度Aであった. 平成15年4月上旬より,「喋りにくい」,「小さい文字が書きづらい」といった症状を自覚するようになり, 同年5月初旬に来院された. 頭部MRI上, 右小脳半球に約35mmのringed enhancementを伴う腫瘤が認められた. 単発であることから腫瘍摘出術が行われた. 病理組織像は高分化型腺癌であり, H.E.染色像, 免疫染色像ともに原発巣とよく一致し胃癌異時性小脳転移と診断された. 術後はTS-1による補助化学療法が行われた. 平成19年2月現在, 再発なく生存中である. 胃癌脳転移はまれな疾患であり, その予後は不良である. 本症例は脳転移診断から3年9か月以上の長期にわたり, 再発なく生存中である極めてまれな症例である.