Reduced expression of MYO18B, a candidate tumor‐suppressor gene on chromosome arm 22q, in ovarian cancer

Abstract

Allelic imbalance on chromosome arm 22q has been detected in 50 -70% of ovarian cancers, suggesting the presence of a tumor-suppressor gene on this chromosome arm that is involved in ovarian carcinogenesis. Recently, we isolated a candidate tumor-suppressor gene, MYO18B, at 22q12.1, which is deleted, mutated and hypermethylated in approximately 50% of lung cancers. In our study, we analyzed genetic and epigenetic alterations of the MYO18B gene in ovarian cancers. Missense MYO18B mutations were detected in 1 of 4 (25%) ovarian cancer cell lines and in 1 of 17 (5.9%) primary ovarian cancers. MYO18B expression was reduced in all 4 ovarian cancer cell lines and in 12 of 17 (71%) of primary ovarian cancers. MYO18B expression was restored by treatment with 5-aza-2-deoxycytidine and/or trichostatin A in 3 of 4 cell lines with reduced MYO18B expression, and hypermethylation of the promoter CpG island for MYO18B was observed in 2 of these 3 cell lines. Its hypermethylation was also observed in 2 of 15 (13%) primary ovarian cancers. Thus, it was indicated that MYO18B expression is reduced in a considerable fraction of ovarian cancers by several mechanisms, including hypermethylation, while the MYO18B gene is mutated in a small subset of ovarian cancers. The present results suggest that MYO18B alterations, including both epigenetic and genetic alterations, play an important role in ovarian carcinogenesis. © 2004 Wiley-Liss, Inc. Key words: tumor-suppressor gene; ovarian cancer; 22qOvarian cancer is the leading cause of death from gynecologic malignancies due to its aggressive nature and the fact that the majority of patients are diagnosed in advanced stages of the disease. To date, several types of genetic studies have been performed to understand the molecular pathways of ovarian carcinogenesis. [1][2][3][4][5] Approximately 5-10% of ovarian cancers are hereditary, and the remaining 90 -95% are sporadic. The majority of hereditary cancers occur in women with germline mutations of the BRCA1 or BRCA2 gene, whereas, in sporadic ovarian cancers, somatic mutations of the c-erbB-2, c-myc and K-ras oncogenes and of the p53 tumor-suppressor gene (TSG) have been frequently observed. However, genetic studies have further indicated that a number of other tumor-suppressor genes are also involved in ovarian carcinogenesis, since various chromosomal regions show high frequencies of allelic imbalance (AI) and, except for the p53 gene, there have been no known genes showing high frequencies of somatic mutations in ovarian cancers. Therefore, further efforts for the identification of target tumor-suppressor genes are needed to fully understand the molecular pathways of ovarian carcinogenesis.Deletions of chromosome arm 22q have been detected in 50 -70% of ovarian cancers by AI analyses. 6 -8 Deletions of chromosome 22 have also been observed by cytogenetic and comparative genomic hybridization analyses. 9 -11 Therefore, it has been indicated that chromosome arm 22q contains a TSG(s) playing a role in ovarian carcinogenesis. This chromosom...

Chromosomal aberrations of malignant pleural effusions of lung adenocarcinoma: Different cytogenetic changes are correlated with genders and smoking habits

“…tion of 22q was frequently found in colon [22] and ovarian cancer [23]. MYO18B, a gene encoding a novel unconventional myosin heavy chain expressed in striated muscles [24], is located on 22q11.2-q12.1 and has been shown downregulated in colon [25], ovarian [26] and lung cancer [27] through genetic or epigenetic mechanisms. Contributions of these chromosomal aberrations and genes to the pathogenesis of lung adenocarcinoma associated pleural effusion are worth studying.…”

How myosin organization of the actin cytoskeleton contributes to the cancer phenotype

“…However, MYO18A was not overexpressed in prostate cancer tissues, and so far has not been associated with other cancers. In contrast, MYO18B, has been identified as a tumour suppressor gene, with loss of expression, deletions and/or mutations reported for a lung cancer cell line, and malignant pleural mesothelioma [64] as well as ovarian [65] and other lung cancers [57,66], melanoma and pancreatic carcinoma [67]. Restoration of MYO18B expression in the lung cancer cell line H1299 inhibited anchorage independent growth and motility through an interaction with HOMER2 [58].…”

Myosins: Tails (and Heads) of Functional Diversity

“…Myo18b has recently been implicated as a potential tumor suppressor based on the observations that it exhibits reduced expression in a large number of ovarian tumors; mutations in Myo18b were observed in a subset of these tumors (155).…”