Gains of 12q are the most frequent genomic imbalances in adult fibrosarcoma and are correlated with a poor outcome

Comparative genomic hybridization was used to analyze 41 adult fibrosarcomas from 34 patients. Thirty-one patients showed in their tumors DNA sequence copy number changes (mean 11, range 3-25). The minimal common regions for the most frequent gains were narrowed down to 12q21 (18 cases); 12q14-q15 and 14q22 (16 cases each); 4q22, 7q31, and 14q23-q24 (15 cases each); and 4q21, 4q23-q24, 8q22, and 12q22 (14 cases each). Twenty-five high-level amplifications were observed in 12 samples. 12q21 and 18p were affected three times each; and 1p21, 4q31.3, 7p21, 12q14-q15, Xp22.1-p22.2, and Xq22-q23 two times each. Losses were less frequent than gains. Early stages of adult fibrosarcomas were characterized by frequent gains of chromosomes 2, 4q, and 14q, whereas gains of chromosomes 7 and 8q were associated with progression. Gains of 12q were frequent in all of the developmental steps of this soft-tissue sarcoma. By investigation of several tumors of the same patient, a number of corresponding changes were always detected. Adult fibrosarcomas from patients who died during the observation time showed statistically significant more frequent gains of 8q, 12q, 13q, and 15q compared to the fibrosarcomas of patients who are alive. Gains and high-level amplifications of 12q14-q22, which were the most frequent genomic imbalances, partly reflected an MDM2 amplification, indicating the importance of this region in the tumorigenesis of sarcomas. In adult fibrosarcomas, a gain of 12q22 correlated significantly (P = 0.028) with a poor overall survival rate.     

DNA amplification on chromosome 13q31.1 correlated with poor prognosis in colorectal cancer

Colorectal cancer is a leading cause of cancer deaths worldwide. Genetic markers involved in prognosis of colorectal cancer are still being elucidated. In this study, genetic alterations associated with prognosis of colorectal cancer were determined using arbitrarily primed polymerase chain reaction (AP-PCR) and analyzed quantitatively by real-time PCR. Seven different DNA sequences, mapped on chromosomes 13q31.1, 9q31.1, 1q24, 4q31.3, 10q21, 11q13.4, and 13q13.3, were identified. Among these sequences, seven cases (23%) harbored DNA amplification in chromosome 13q31.1, and 9 (29%) and 7 (23%) presented genetic alterations in chromosome 1q24 and 11q13.4, respectively. Multivariate analysis showed that only DNA amplification in chromosome 13q31.1 was associated with poor survival among patients with colorectal cancer, with median survival time for chromosome 13q31.1 amplification versus no amplification of 64 versus 268 weeks (P = 0.001). This genetic alteration may have a prognostic role in colorectal cancer.     

TRIP13 upregulation is correlated with poor prognosis and tumor progression in esophageal squamous cell carcinoma

Thyroid receptor-interacting protein 13 (TRIP13), a member of the AAA + ATPase super-family, has been proved to be upregulated and identified as a prognostic factor in multiple human cancers, However, the role of TRIP13 in esophageal squamous cell carcinoma (ESCC) and its clinic relevance remains unclear. In the present study, we performed database-mining and detected TRIP13 expression in 158 tissue samples (79 ESCC tissue and 79 matched adjunct non-cancerous tissues). We further investigated the correlation between TRIP13 expression and clinicopathological features and overall survival. Univariate and multivariate Cox regression analyses were applied to evaluate the potential prognostic value of TRIP13 in ESCC patients. In addition, the mechanisms involved in TRIP13 tumor-promoting effect was investigated. Data showed that TRIP13 expression was significantly increased in ESCC tissues, compared with the matched adjunct non-cancerous tissues. Expression of TRIP13 is significantly correlated with T status (P = 0.027), lymphatic metastasis (P = 0.017), and clinical stages of ESCC (P = 0.009). Kaplan-Meier analyses showed that patients with high TRIP13 expression had poor overall survival (P = 0.0022). Multivariate analysis indicated that TRIP13 expression might be an independent prognostic factor in ESCC patients (HR, 1.778, 95% confidence interval = 0.959–3.296, P = 0.028). Furthermore, downregulating TRIP13 in EC109 cell significantly attenuated the cell proliferation and progression, possibly by β-catenin regulated EMT pathway.Conclusions: Our study demonstrated that TRIP13 might be a tumor promoting factor in ESCC and a promising prognostic indicator for ESCC patient.     

13q deletion is linked to an adverse phenotype and poor prognosis in prostate cancer

Deletions of chromosome arm 13q belong to the most frequent molecular alterations in prostate cancer. To better understand the role of 13q deletion in prostate cancer we took advantage of our large prostate cancer tissue microarray comprising more than 12 000 cancer samples with full pathological and clinical follow‐up data. Fluorescence in situ hybridization with probes for ENOX1 (13q14.11) and the retinoblastoma gene (RB1, 13q14.2) was employed. A 13q deletion was found in 21% of 7375 analyzable cancers. Deletions were always heterozygous and associated with high Gleason grade (P < .0001), advanced tumor stage (P < .0001), high preoperative prostate‐specific antigen (PSA) levels (P = .0125), lymph node metastasis (P = .0377), positive resection margin (P = .0064), and early biochemical recurrence (P < .0001). 13q deletions were marginally more frequent in prostate cancers with negative ERG status (22.9%) than in ERG‐positive tumors (18.7%; P < .0001). Loss of 13q predicted patient prognosis independently from established prognostic parameters that are available at the time of biopsy (P = .0004), including preoperative PSA level, clinical tumor stage, and biopsy Gleason grade. In summary, the results of our study identify 13q deletion as a frequent event in prostate cancer, which is linked to an adverse phenotype and poor prognosis in this disease.     

Cytoplasmic Pin1 expression is correlated with poor prognosis in colorectal cancer

Objective

The aim of this study was to determine the clinicopathological significance and prognostic role of Pin1 expression and subcellular localization in colorectal cancer (CRC).

Gain of 1q is a marker of poor prognosis in Wilms' tumors

Wilms' tumor (WT) trials aim to better tailor treatment intensity to the risk of relapse and death. Currently, stage, histology, age (< or > 24 months), and combined loss of heterozygosity at 1p and 16q in chemotherapy‐naïve WTs are the only risk factors used for treatment stratification. However, they predict only less than one‐third of all relapsing patients, implying that other factors are involved in treatment failure. Previous studies have associated 1q gain with adverse outcome. Therefore, in this study, the role of 1q gain and other common cytogenetic aberrations (CAs) in WTs was investigated and related to follow‐up data from patients with WT treated in the United Kingdom; 19% (64/331) had 1q gain. Gain of 1q was significantly associated with 16q loss (P < 0.001) and 1p loss (P < 0.001). In multivariate analysis taking account of age, tumor stage, anaplasia, and common CA (e.g., 1p loss and 16q loss), 1q gain was independently associated with adverse event‐free survival [EFS; hazard ratio (HR) = 2.45, P = 0.02] and overall survival (HR = 4.28, P = 0.004). Loss of 14q was independently associated with an adverse EFS (HR = 4.0, P = 0.04). Gain of 1q is a marker of poor prognosis in WTs, independent of high tumor stage and anaplasia which remain the overarching adverse prognostic factors. Confirmation in other studies is necessary before future therapeutic studies can incorporate 1q gain into new risk stratification schema. © 2013 Wiley Periodicals, Inc.     

Allelic loss at 1p34, 13q12, 17p13.3, and 17q21.1 correlates with poor postoperative prognosis in breast cancer.

Allelic losses of tumor suppressor genes (TSGs), or the chromosomal regions harboring them, in tumor DNA may become useful postoperative prognostic indicators. To examine whether specific allelic losses might correlate with postoperative survival in a 5-year prospective follow-up, we tested tumors from a cohort of 264 breast cancer patients for allelic losses of 18 microsatellite markers representing either a known TSG or a region where genetic alterations are frequent in breast tumors. Patients whose tumors had lost an allele at 1p34, 13q12, 17p13.3, or 17q21.1 had significantly higher risks of postoperative mortality than those whose tumors retained both alleles at those loci (at 1p34, a 5-year mortality rate of 29% among patients with losses vs. 7% with retentions, P = 0. 0008; at 13q12, 31% vs. 10%, P = 0.0062; at 17p13.3, 24% vs. 13%, P = 0.026; and at 17q21.1, 31% vs. 13%, P = 0.0047). Furthermore, combined losses at 13q12 and 17p13.3 increased the predicted postoperative mortality risks by a factor of 9.6 (5-year mortality rate of 42% vs. 5% with retentions, P = 0.0001), and combined losses at 1p34 and 17p13.3 raised the predicted postoperative mortality risks by a factor of 8.6 (27% vs. 3%, P = 0.0064). We conclude that allelic losses at these loci can serve as negative prognostic indicators to guide postoperative management of patients. Genes Chromosomes Cancer 26:134-141, 1999.     

Matrix metalloproteinase 13 activity is associated with poor prognosis in colorectal cancer

AIMS: The matrix metalloproteinases (MMPs) are a family of proteolytic enzymes collectively capable of degrading all extracellular matrix components, in particular fibrillar collagen. The importance of this group of proteins in the processes of tumour invasion and metastasis is now widely acknowledged. MMP-13 (collagenase 3) has a central role in the MMP activation cascade. The purpose of this study was to investigate the presence and activity of MMP-13 in colorectal cancer and relate these to clinicopathological features. METHODS: Immunohistochemistry for MMP-13 was performed on formalin fixed, paraffin wax embedded sections of a large series of colorectal cancers (n = 249), all of which had uniform clinical and pathological information available. Immunoreactivity to MMP-13 was detected with a monoclonal antibody to MMP-13 using a Dako TechMate 500 automated immunostaining system. The presence and cellular localisation of MMP-13 was assessed using a semiquantitative scoring system. Gelatin zymography was used to detect and measure MMP-13 activity. The zymography was performed on a subset of the cases studied by immunohistochemistry using two groups of 10 paired Dukes's C tumours and normal samples, selected by either having "good" or "poor" survival. RESULTS: Immunoreactivity to MMP-13 was identified in 91% of cases and immunoreactivity was localised to the cytoplasm of tumour cells. A high MMP-13 staining score showed a trend towards poorer survival. Tumours had significantly greater MMP-13 activity compared with normal colonic mucosa (p < 0.001). Furthermore, the tumour to normal tissue ratio was significantly higher in the poor survival group (p = 0.02). CONCLUSIONS: These results show that MMP-13 is frequently present and active in colorectal cancer and suggest that the activity of MMP-13 is associated with poorer survival in colorectal cancer.     

Overexpression of UQCRC2 is correlated with tumor progression and poor prognosis in colorectal cancer

Ubiquinol-cytochrome c reductase complex core protein 2 (UQCRC2) is an important subunit of mitochondrial respiratory complex III. However, its role in tumorigenesis and tumor progression remains unknown, especially with regards to colorectal cancer (CRC). In this research, we measured the expression of UQCRC2 protein by immunohistochemistry assay in 89 paired paraffin-embedded tumor tissues and corresponding adjacent normal tissues from patients with colorectal adenocarcinoma and investigated possible correlations of UQCRC2 expression with clinicopathological parameters and prognosis. We found that UQCRC2 was significantly upregulated in CRC tissues compared with adjacent normal tissues, and immunohistochemical UQCRC2 status was correlated to the depth of invasion (T), lymph node metastasis (N), advanced TNM stage. Multivariate analysis indicated that UQCRC2 remained an independent prognostic factor for poorer overall survival. Furthermore, we determined the role of UQCRC2-knockdown in CRC cells (RKO and HCT116) using lentivirus-mediated small hairpin RNAs (shRNAs). The effects of UQCRC2 knockdown on CRC cells (RKO and HCT116) proliferation were analyzed by cell proliferation and colony formation assay, and cell cycle and apoptosis were assessed by flow cytometry. We found that silencing UQCRC2 suppressed cell proliferation and colony formation in RKO and HCT116 cells, led to a cell cycle arrest and induced cell apoptosis in vitro. These results provided novel insights into the potential role of UQCRC2 in the tumorigenesis and progression of CRC, and revealed that UQCRC2 may serve as a new prognostic and therapeutic target in CRC.     

Decreased CDKL2 expression is correlated with the progression and poor prognosis of glioma

Glioma is the most common form of malignant intracranial tumors. Cyclin-dependent kinase-like 2 (CDKL2) was observed in various regions of the brain, but the specific role of CDKL2 in glioma has not been reported yet. In the present study, the expression of CDKL2 mRNA was detected by real-time QPCR in freshly collected glioma and para-carcinoma tissues, and we collected genomic and clinical data from The Cancer Genome Atlas to determine mRNA expression levels of CDKL2 in the normal brain and glioma samples. Moreover, western blot assay and immunohistochemistry experiments were implemented to identify CDKL2 protein expression, and clinical pathology characteristics from 151 glioma cases and thirty-four para-carcinoma tissues were also examined. The relationship between the levels of CDKL2 expression and clinical data was analyzed. Low mRNA and protein expression of CDKL2 was observed in glioma tissues compared to non-cancerous tissues. In addition, low levels of CDKL2 correlated with Astrocytic type, higher clinical WHO grade, and higher Ki-67 expression in glioma. Low mRNA and protein expression of CDKL2 in glioma predicted an observably shorter overall survival time than high expression. However, as revealed by multivariate analysis, CDKL2 protein expression was not an independent prognostic biomarker for the survival of patients with glioma. Our study firstly determined that low levels of CDKL2 expression are associated with poor clinical diagnosis. Thus, CDKL2 may serve as a prognostic factor of glioma.     

Overexpression of eIF3e is correlated with colon tumor development and poor prognosis

EIF3e is a component of the eukaryotic translation initiation factor 3 (eIF-3) complexes, which is an essential factor for initiation of protein synthesis in mammalian cells. Translational control plays key roles in the complex mechanism of cancer development and progression. However, the clinical significance of eIF3e in colon cancer remains to be elucidated. We analyzed the eIF3e expression in a tissue microarray (TMA), which contained 173 colon cancer tissues paired with adjacent normal mucosa and lymph node metastasis. The expression of eIF3e was significantly elevated in colon cancer tissues in comparison with those in adjacent normal mucosa (P < 0.001) and lymph node metastasis (P < 0.001). The high expression of eIF3e in colon cancer was significantly correlated with tumor size (P < 0.001), lymph node involvement (P < 0.001), distant metastasis (P < 0.001), clinical stage (P < 0.001), histopathologic classification (P < 0.001), and vessel invasion (P = 0.036). Univariate and multivariate analysis revealed that eIF3e is an independent prognosis factor for overall survival and disease-free survival in colon cancer. Down-regulation of eIF3e in vitro inhibited colon cancer cell proliferation, clonality and promoted cell apoptosis. Taken together, high eIF3e expression may contribute to tumor progression and predict poor prognosis in colon cancer.     

Down-regulation of microRNA-124 is correlated with tumor metastasis and poor prognosis in patients with lung cancer

Introduction: MicroRNA-124 (miR-124) has been proven dysregulated in several human malignancies and correlated with tumor progression. However, its expression and clinical significance in non-small cell lung cancer (NSCLC) is still unclear. Thus, the aim of this study was to investigate the clinical significance of miR-124 expression in NSCLC. Methods: Expression levels of miR-124 in 92 pairs of NSCLC and adjacent non-tumor tissues were detected by quantitative real-time PCR (qRT-PCR). In order to determine its prognostic value, overall survival (OS) and disease-free survival (DFS) were evaluated using the Kaplan-Meier method, and multivariate analysis was performed using the Cox proportional hazard analysis. Results: miR-124 expression level was significantly lower in NSCLC tissues compared with adjacent non-tumor tissues (P < 0.05). The 5-year OS of low miR-124 expression group was significantly shorter than that of high miR-124 expression group (P < 0.05). Moreover, the 5-year DFS of low miR-124 expression group was also significantly shorter than that of high miR-124 expression group (P < 0.05). In a multivariate Cox model, we found that miR-124 expression was an independent prognostic factor for both 5-year OS and 5-year DFS in NSCLC (P < 0.05). Conclusions: Our results offer the convincing evidence that miR-124 may play key roles in the progression of lung cancer and that the down-regulated expression of miR-124 may be independently associated with shorter OS and DFS of patients, suggesting that miR-124 might be a potential marker for further risk stratification in the treatment of lung cancer.     

High expression of TROP2 is correlated with poor prognosis of oral squamous cell carcinoma

Human trophoblastic cell-surface antigen 2 (TROP2) is a cell surface glycoprotein that exhibits high expression in various carcinomas but low or no expression in normal tissues. High TROP2 expression plays an important role in promoting tumor development and aggressiveness, which is correlated with reduced patient survival. However, there are few studies regarding TROP2 in relation to both oral squamous cell carcinoma (OSCC) and oral potentially malignant lesions. The expression of TROP2 protein and mRNA was investigated in OSCC tissues, oral potentially malignant lesion tissues, and normal oral tissues using immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). The association between TROP2 expression and clinicopathological characteristics of OSCC was also analyzed, and the prognostic value of TROP2 was evaluated. The expression of TROP2 protein and mRNA were both higher in OSCC tissues than in oral potentially malignant lesion tissues or normal oral tissues. Positive TROP2 expression was related to differentiation, lymph node metastases, TNM stage, perineural infiltration, and vascular invasion. Poor overall survival was associated with high TROP2 expression and other factors associated with poor overall survival including poor differentiation, lymph node metastasis, TNM stage, vascular invasion, and perineural invasion in univariate analyses. TROP2 expression as well as TNM stage and vascular invasion were independent prognostic factors associated with the overall survival of OSCC patients in multivariate analyses. In summary, High TROP2 expression is associated with poor overall survival and serves as an independent prognostic factor in OSCC. The results suggest that TROP2 expression could be an effective prognostic biomarker for OSCC.     

Thymidine phosphorylase expression in tumor-infiltrating macrophages may be correlated with poor prognosis in uterine endometrial cancer

Expression of thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor, in several types of malignant tumors has been associated with angiogenesis and an unfavorable prognosis. We performed a retrospective study on the immunohistochemical expression of TP in patients with uterine endometrial cancer to investigate correlations between the expression of TP and the clinicopathologic features and the prognosis. The immunohistochemical staining for TP, CD68 (macrophage/monocyte-specific antibody), and von Willebrand factor was performed in surgically resected specimens from 101 patients with operable endometrial cancer. A semiquantitative grading system was used to examine the staining pattern for TP. Positive staining for both cancer cell and tumor stromal cell TP was noted in 41% of the cases. Most of tumor stromal cells expressing TP were shown to coexpress CD68. High angiogenesis was also associated with TP overexpression in either cancer cells or tumor stromal cells. When stromal macrophages/fibroblasts exhibited high TP expression, independent of whether cancer cells showed the positive TP expression, a significant decrease in disease-free survival and overall survival was observed, which was found to be an independent prognostic factor. Stromal macrophage/fibroblast TP expression remained significant on multivariate analysis. We conclude that (1) TP is present in both cancer cells and stromal macrophages/fibroblasts, (2) high angiogenesis correlated with TP overexpression, (3) TP produced by neighboring tumor-infiltrating macrophages may play a part in the regulation of the local invasion and distant metastatic behavior, and (4) TP overexpression in stromal macrophages/fibroblasts may be associated with a poor prognosis.     

FRZB up-regulation is correlated with hepatic metastasis and poor prognosis in colon carcinoma patients with hepatic metastasis

Frizzled-related protein (FRZB) was up-regulated in hepatic metastasis samples compared with primary colon cancer samples in our previous work. However, the clinical relevance of FRZB in colon cancer hepatic metastasis remains uncertain. The aim of this study was to assess the prognostic value of FRZB in patients with colon carcinoma hepatic metastasis after hepatic resection. FRZB expression was evaluated by immunohistochemistry in formalin-fixed paraffin embedded (FFPE) primary colon carcinoma and paired hepatic metastasis tissues from 136 patients with liver metastasis from colon carcinoma that underwent hepatic resection. The relation between FRZB expression and clinicopathologic factors and long-term prognosis in these 136 patients was retrospectively examined. The prognostic significance of negative or positive FRZB exspression in colon carcinoma hepatic metastasis was assessed using Kaplan-Meier survival analysis and log-rank tests. Positive expression of FRZB was correlated with liver metastasis of colon cancer. Univariate analysis indicated significantly worse overall survival (OS) for patients with a positive FRZB expression in colon carcinoma hepatic metastasis than for patients with a negative FRZB expression. Multivariate analysis showed positive-FRZB in colon carcinoma hepatic metastasis to be an independent prognostic factor for OS after hepatic resection (P = 0.001). Positive expression of FRZB was statistically significantly associated with poor prognosis of patients with colon carcinoma hepatic metastasis. FRZB could be a novel predictor for poor prognosis of patients with colon carcinoma hepatic metastasis after hepatic resection.     

A recognizable phenotype in a child with partial duplication 13q in a family with t(10q;13q)

A case of partial duplication 13q14 → qter is reported in a 9-year-old male with clinical symptoms which include trigonocephaly and synophrys, producing an easily identifiable phenotype. The chromosome duplication resulted from a familial t(10;13)(qter;q14). Subsequently, a normal balanced carrier sibling was diagnosed prenatally.     

Deletion (13)(q13q14.3) with retinoblastoma: confirmation and extension of a recognisable pattern of clinical features in retinoblastoma patients with 13q deletion.

A girl with retinoblastoma and a del(13)(q13q14.3) is presented. This case helps to confirm and extend our previous observations regarding a recognisable facial pattern in retinoblastoma patients with 13q deletion involving 13q14 and its adjacent segments.     

Angelman syndrome with a chromosomal inversion 15 inv(p11q13) accompanied by a deletion in 15q11q13.

A family is described in which an inversion of chromosome 15, 15 inv(p11q13), is segregating. All family members are healthy except the proband who is a 10 year old boy with Angelman syndrome. Although the chromosomal inversion has been passed from the grandfather to both his son and his daughter with no ill effect, passage from daughter to grandson has resulted in a deletion of chromosome 15 material which is presumed to be the cause of Angelman syndrome in this boy. The probabilities of an inversion of this type being instrumental in causing the syndrome are discussed.