Identification and characterization of survival-related gene, a novel cell survival gene controlling apoptosis and tumorigenesis

Apoptosis plays a critical role in cellular homeostasis during development, immune responses, and tumorigenesis. Recent studies have identified a number of genes that control this process. We report here our identification of a novel cell survival-related gene (SRG) from a human expression cDNA library by functional cloning. SRG shows no significant nucleotide sequence homology to any known genes in the Genbank. Our fluorescence in situ hybridization analysis has estimated that SRG is located at 1p36, agreeing with the location at 1p36.22 in the human genome sequence. SRG encodes a putative protein of 172 amino acids, which is mainly located in the perinuclear region. Northern blotting analysis indicates that SRG is highly expressed in many human cancer cell lines although it is low in most tissues except liver and placenta. To investigate the function of SRG in apoptosis, we transfected SRG cDNA into BAF/BO3 and B16/F0 cells and induced apoptosis by cytokine/serum deprivation. We found that SRG-transfected cells are resistant to apoptosis induced by cytokine/serum deprivation. In addition, mice bearing SRG-transfected melanoma had more tumor formation and larger tumor growth. Melanoma transfected with antisense SRG showed significantly less tumor formation and smaller tumor growth. Interestingly, mouse SRG gene was also identified on chromosome 4 and blocking SRG expression with small interfering RNA promoted serum deprivation-induced apoptosis of NIH3T3 cells. Our results show that SRG is a novel cell survival gene that critically controls apoptosis and tumor formation.     

Response, survival, and prognostic factors after hepatic arterial chemoembolization in patients with liver metastases from cutaneous melanoma

We reviewed the medical records of 42 patients with cutaneous melanoma metastatic to the liver who underwent hepatic artery chemoembolization (HACE) at our institution. HACE resulted in radiologic response (38.9%) or disease stabilization (47.2%) in most patients. The median overall survival (OS) and time to progression (TTP) of liver disease were 7.7 and 6 months, respectively. Patient's age, lactate dehydrogenase (LDH) levels, type of treatment, number of extrahepatic metastatic sites, and response to therapy were found to be significant predictors of OS after HACE. Prolonged survival was seen in patients who responded to HACE (p = .034).     

Establishment and validation of an autophagy-related prognostic signature for survival predicting in cutaneous melanoma

Existing staging system for prognosis evaluating for Skin Cutaneous Melanoma (SKCM) patients had defects of subjective, inaccuracy and inconsistently, therefore, to identify specific and applicable prognostic markers and promote personalized therapeutic interventions is urgently required. This study aims to build a robust autophagy-related genes (ARGs) signature for prognosis monitoring of SKCM patients. We determined 26 ARGs as differentially expressed autophagy-related genes (DEARGs) from 103 SKCM and 23 normal skin samples in {"type":"entrez-geo","attrs":{"text":"GSE15605","term_id":"15605"}}GSE15605 and {"type":"entrez-geo","attrs":{"text":"GSE3189","term_id":"3189"}}GSE3189 datasets. Optimal prognostic DEARGs composed the risk model were screened and verified in 458 SKCM patients in TCGA cohort as the training cohort and 209 patients in {"type":"entrez-geo","attrs":{"text":"GSE65904","term_id":"65904"}}GSE65904 as the test cohort. Finally, 4 optimal independent prognostic DEARGs (CAPNS1, DAPK2, PARP1 and PTK6) were filtered out in the training cohort to establish the risk model. A prognostic nomogram was established for quantitative survival prediction. The risk model grouped high-risk SKCM cancer patients exhibited significantly shorter survival times in both training and test cohorts. The area under the ROC curve for risk score model was 0.788 and 0.627 in the training and test cohorts indicated the risk model was relatively accurate for prognosis monitoring. Clinical correlation analysis exhibited that risk score was an independent predictor for prognosis significantly associated with T/N classification. The prognostic value of the 4 risk genes formed the risk model was also validated respectively. We identified a novel autophagy-related signature for prognosis monitoring. It has the potential to be an independent prognostic indicator and can benefit targeted therapy.     

Mage-b4, a novel melanoma antigen (MAGE) gene specifically expressed during germ cell differentiation

The MAGE genes were initially isolated from different kinds of tumors, and based on their virtually exclusive tumor-specific expression in adult tissues, they have been used as targets for cancer immunotherapy. However, although a large number of MAGE genes have now been identified and extensively studied in tumors of various origin, their functions in normal cells remain unknown. Here we describe the isolation and characterization of a novel murine MAGE homologue, Mage-b4. mRNA expression studies in a wide variety of adult and embryonic tissues revealed that Mage-b4 is specifically expressed in fetal and adult gonads. An antibody specific to Mage-b4 was developed, and using this antibody, we found that the Mage-b4 protein was confined to the cytoplasm of germ cells. Double-labeling experiments using antibodies against the meiosis-specific SCP3 protein and the Mage-b4 protein showed that Mage-b4 is down-regulated as the germ cells enter meiosis in adult testis. In contrast, Mage-b4 was expressed in female germ cells throughout meiosis, and the protein was also found in dormant primary oocytes.     

Identification of a novel gene, LDOC1, down-regulated in cancer cell lines

By screening for differentially expressed genes in cancer cells, using the RNA differential display (DD) technique, we identified a novel cDNA, LDOC1, that is down-regulated in some cancer cell lines. A Northern blot analysis revealed no expression in pancreatic and gastric cancer cell lines but ubiquitous expression in normal human tissues. This new gene was mapped on chromosome Xq27 and the predicted protein sequence showed no similarity to known sequences in the database except for a leucine zipper-like motif at the N-terminal region and a proline-rich region that shares marked similarity to an SH3-binding domain. In an enhanced green fluorescent protein (EGFP) assay, the EGFP-LDOC1 fusion protein was localized in the nucleus. Although the function of LDOC1 is still unknown, our results suggest that this novel gene codes for a nuclear protein, and down-regulation of LDOC1 may have an important role in the development and/or progression of some cancers.     

皮肤梭形细胞黑色素瘤患者生存预测模型的构建及验证

背景与目的：梭形细胞黑色素瘤（spindle cell melanoma,SCM）是一种罕见的黑色素瘤类型,有关SCM患者生存预后的研究较少。通过提取公共数据库中的SCM临床信息,构建并验证皮肤SCM患者5和10年癌症特异性生存率（cancer-specific survival,CSS）和总生存率（overall survival,OS）的生存预测模型。方法：从美国国立癌症研究所监测、流行病学和最终结果（Surveillance, Epidemiology, and End Results,SEER）数据库筛选出共1 445例患者,分成建模组（n=1 011）和验证组（n=434）。通过单因素和多因素COX回归分析确定独立预后影响因素,建立列线图预测模型。利用一致性指数（concordance index,C-index）、受试者工作特征（receiver operating characteristic,ROC）曲线和校准曲线评估模型的区分度和准确性,利用决策曲线分析（decision curve analysis,DCA）评估模型的临床实用性。结果：年龄、肿瘤部位、肿瘤厚度、溃疡...     

Biallelic deletions in INK4 in cutaneous melanoma are common and associated with decreased survival.

PURPOSE: Both the retinoblastoma and p53 pathways are often genetically altered in human cancers and their complex regulation is in part mediated by the three gene products p16, p14(ARF), and p15 of the INK4 locus on chromosome 9p21. Partial or complete biallelic deletions of the INK4 locus have been recognized in a variety of malignant tumors, including malignant melanoma. We have in the present study measured the frequency of INK4 deletions in a large number of melanoma metastases and determined their association with clinicopathologic variables and survival data. EXPERIMENTAL DESIGN: Quantitative real-time PCR, as well as fluorescence-based fragment analysis, has been used to perform measurements of the relative allelic concentrations of the INK4 genes in 112 human melanoma tumor samples from 86 patients. RESULTS: Thirty-eight of 86 melanoma patients (44%) had metastases with biallelic losses in INK4. Ten of 20 patients with multiple metastases showed similar deletion patterns in all analyzed tumors. There was no significant association between any of the clinicopathologic variables and loss of INK4. However, loss of INK4 had an adverse effect on median survival from time of diagnosis. Patients with tumors with diploid INK4 had a median survival of 142 months, whereas those with monoallelic or biallelic loss in INK4 had a median survival of only 47 months (P = 0.006). CONCLUSIONS: Our results point to homozygous deletions in the INK4 region as being one of the most common genetic alterations in malignant cutaneous melanoma. INK4 deletions are associated with an adverse prognosis.     

EGF +61 gene polymorphism and susceptibility to and prognostic markers in cutaneous malignant melanoma

CMM is the most serious cutaneous malignancy and is increasing in frequency among most Caucasian populations, where the most important risk factor is exposure to UV light. Relatively little is known of the genetic factors that mediate susceptibility to and prognosis in sporadic CMM, although a number of genes have been implicated. A striking association between EGF polymorphism and Breslow thickness of invasive CMM has been reported. We have sought confirmation of this finding in an independent study of 159 patients and 310 controls using TaqMan fluorescence-based genotyping for EGF +61. In our study group, there were no significant differences in EGF genotype frequencies between patients and controls nor was EGF genotype associated with tumour growth phase, stage or mitotic count. However, correlation between EGF genotype and Breslow thickness showed a modestly significant increase in frequency of the EGF (G/G) genotype among tumours >3.5 mm thick (30.0% vs. 9.8%, p = 0.03). In summary, in our group, the EGF +61 polymorphism was not a risk factor for CMM susceptibility, but this polymorphism may play a role in disease progression.     

Expression of Melan-A/MART-1 antigen as a prognostic factor in primary cutaneous melanoma

In this study we assessed the expression of the Melan-A/MART-1 antigen by immunohistochemistry using monoclonal antibody A103 in 73 primary cutaneous melanomas and its correlation with tumor staging and patient survival. Melan-A/MART-1 was expressed in 90% of primary tumors, with loss of expression increasing with Breslow thickness. Kaplan-Meier analysis demonstrated a significantly reduced disease-free interval and overall survival rate for patients not expressing this antigen. The poor prognosis of such patients was even worse for those presenting with a primary melanoma and a Breslow thickness of > or = 1 mm. Thus, Melan-A/MART-1 is not only a useful and specific additional marker for the diagnosis of primary cutaneous melanoma, but it may also help refine the prognosis of patients with malignant melanoma.     

Clinical, histological and quantitative prognostic factors in cutaneous malignant melanoma.

A retrospective study including 55 cutaneous melanoma patients with 9.5 years follow-up was carried out to assess the significance of various prognostic factors. The histological samples were evaluated according to Clark's and Breslow's classifications and six nuclear features were measured by interactive morphometry. Mitotic activity was assessed by two different methods: mitotic activity index (MAI) and volume corrected mitotic index (M/V index). The overall disease-related five-year survival of patients was 76.4%. TNM stage (p = 0.0001), sex (p = 0.0024), M/V index (p = 0.003), standard deviation of nuclear form factor (p = 0.023), MAI (p = 0.02), shortest nuclear axis (p = 0.023) and Breslow's classification (p = 0.044) predicted survival in univariate analysis. A multivariate analysis including clinical, histological and morphometric features pointed the Clark's classification as the most important predictor of survival (p = 0.002), while the other variables included had no independent prognostic value. The prognostic importance of mitotic indices and morphometric features is clearly a subject for further studies in superficial melanomas.     

Invasive cutaneous malignant melanoma in Sweden, 1990-1999. A prospective, population-based study of survival and prognostic factors

BACKGROUND: The objective of the current study was to compile prospective, population-based data on cutaneous invasive melanomas in Sweden during the period from 1990 to 1999, to describe and analyze survival data and prognostic factors, and to make comparisons with previously published Swedish and international data. METHODS: Twelve thousand five hundred thirty-three patients, which included 97% of all registered melanomas in Sweden, were included and described. Among these, 9515 patients with clinical Stage I and II melanoma were included in an analysis of survival and in a univariate analysis, and 6191 patients were included in a multivariate analysis of prognostic factors. RESULTS: There was no significant change in melanoma incidence during 1990-1999. Favorable prognostic factors were found, especially in younger and female patients, resulting in a relative 5-year survival rate of 91.5%. In the multivariate analysis, significant factors that had a negative effect on survival were Clark level of invasion, Breslow thickness, ulceration, older patient age, trunk location, greatest tumor dimension, nodular histogenetic type, and male gender. CONCLUSIONS: During the period from 1990 to 1999, the 5-year survival of patients with malignant melanoma in Sweden was better compared with the previously reported rates in published, population-based studies from Sweden, probably as a result of better secondary prevention due to better knowledge and awareness by both patients and the medical profession. The more favorable prognostic factors and the change in melanoma location found in younger patients, compared with earlier reports, may reflect changes in clothing as well as tanning habits; however, a decrease also was found in Clark Level II and thin melanomas for the same patient group. The authors concluded that further improvements can be achieved with better access to health care and with the use of early melanoma detection campaigns.     

nmb,a novel gene,is expressed in low-metastatic human melanoma cell lines and xenografts

From a subtractive cDNA library, we isolated several cDNA clones which showed differential expression between highly and lowly metastatic human melanoma cell lines. One clone, designated nmb, showed preferential expression in the low-meta-static cell lines and was chosen for further characterization. Sequence analysis revealed that this clone represents a novel gene, encoding a putative transmembrane glycoprotein which showed the highest homology to the precursor of pMEL17, a melanocyte-specific protein. nmb RNA expression was absent in most tumor-cell lines tested and not restricted to the melanocytic lineage. Transfection of a partial nmb cDNA into a highly metastatic melanoma cell line (BLM) resulted, in 2 of 3 transfectants, in slower subcutaneous tumor growth and, in 1 of 3 transfectants, in reduction of the potential for spontaneous metastasis in nude mice. © 1995 Wiley-Liss, Inc.     

Ki-67 expression is superior to mitotic count and novel proliferation markers PHH3, MCM4 and mitosin as a prognostic factor in thick cutaneous melanoma

Background  

Tumor cell proliferation is a predictor of survival in cutaneous melanoma. The aim of the present study was to evaluate the prognostic impact of mitotic count, Ki-67 expression and novel proliferation markers phosphohistone H3 (PHH3), minichromosome maintenance protein 4 (MCM4) and mitosin, and to compare the results with histopathological variables.     

Trends in prognostic factors and survival from cutaneous melanoma in Yorkshire, UK and New South Wales, Australia between 1993 and 2003

The aim of this study was to compare trends in prognostic factors and survival from cutaneous melanoma between 1993 and 2003 in 2 populations with dramatically different underlying incidence rates [Yorkshire, UK, and New South Wales (NSW), Australia] and to look at whether the greater investment in melanoma prevention and early detection in Australia has resulted in any relative differences in survival. Patients diagnosed with invasive melanoma between 1993 and 2003 in Yorkshire (n = 4,170) and NSW (n = 30,520) were identified from cancer registry databases and prognostic information (age, sex, socioeconomic background, tumour site and Breslow thickness) was extracted. Age-standardised incidence rates, 5-year relative survival and relative excess risk of death were calculated. Between 1993-1995 and 2001-2003, the incidence of melanoma increased in both areas. These increases were mainly seen in tumours with thickness 相似文献