Gene Summary

Gene:BUB1; BUB1 mitotic checkpoint serine/threonine kinase
Aliases: BUB1A, BUB1L, hBUB1
Summary:This gene encodes a serine/threonine-protein kinase that play a central role in mitosis. The encoded protein functions in part by phosphorylating members of the mitotic checkpoint complex and activating the spindle checkpoint. This protein also plays a role in inhibiting the activation of the anaphase promoting complex/cyclosome. This protein may also function in the DNA damage response. Mutations in this gene have been associated with aneuploidy and several forms of cancer. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:mitotic checkpoint serine/threonine-protein kinase BUB1
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (22)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Chromosomal Instability
  • Bladder Cancer
  • Chromosome Segregation
  • Gene Expression
  • Cell Cycle Proteins
  • Cell Cycle
  • Mutation
  • Poly-ADP-Ribose Binding Proteins
  • Apoptosis
  • Breast Cancer
  • siRNA
  • Biomarkers, Tumor
  • Cancer DNA
  • Mad2 Proteins
  • Thyroid Cancer
  • Messenger RNA
  • Chromosome 2
  • Aneuploidy
  • Colorectal Cancer
  • Genetic Predisposition
  • Gene Expression Profiling
  • Microtubules
  • M Phase Cell Cycle Checkpoints
  • Calcium-Binding Proteins
  • Ubiquitin-Protein Ligases
  • Mitosis
  • World Health Organization
  • Ribonucleoside Diphosphate Reductase
  • Salivary Gland Cancer
  • DNA Mutational Analysis
  • Wilms Tumour
  • Protein Kinases
  • Ubiquitin-Protein Ligase Complexes
  • Spindle Apparatus
  • Stomach Cancer
  • Neoplasm Proteins
  • Cell Proliferation
  • Treatment Failure
  • Immunohistochemistry
  • Cancer Gene Expression Regulation
  • Tubulin
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: BUB1 (cancer-related)

Piao J, Zhu L, Sun J, et al.
High expression of CDK1 and BUB1 predicts poor prognosis of pancreatic ductal adenocarcinoma.
Gene. 2019; 701:15-22 [PubMed] Related Publications
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common causes of cancer-related death. Increasing evidence suggests that cell cycle dysregulation is one of the hallmarks of cancer. In this study, by using the GEO database, we predicted the cell cycle-related protein CDK1 and BUB1 to be significantly overexpressed in PDAC tissues. Thus, this study aimed to investigate the clinical pathological significance of CDK1 and BUB1 in PDAC.
METHODS: To explore the role of CDK1 and BUB1 in PDAC progression and evaluate their prognostic value, we investigated the expression patterns of CDK1 and BUB1 by using immunohistochemical staining in 99 PDAC and 71 normal pancreatic tissues with complete pathological parameters and survival data.
RESULTS: CDK1 and BUB1 were significantly overexpressed in PDAC tissues. The expression of CDK1 was correlated with tumor size and histological grade, and the expression of BUB1 was correlated with the tumor size of PDAC. With regard to survival, a high expression of either CDK1 or BUB1 was correlated with a short survival of PDAC patients. Additionally, PDAC patients with a concurrent high expression of CDK1 and BUB1 showed the shortest survival.
CONCLUSIONS: Our study demonstrated that CDK1 and BUB1 may play a role in PDAC progression and could be prognostic biomarkers for PDAC patients.

Rahane CS, Kutzner A, Heese K
A cancer tissue-specific FAM72 expression profile defines a novel glioblastoma multiform (GBM) gene-mutation signature.
J Neurooncol. 2019; 141(1):57-70 [PubMed] Related Publications
INTRODUCTION: Glioblastoma multiform (GBM) is a neural stem cell (NSC)-derived malignant brain tumor with complex genetic alterations challenging clinical treatments. FAM72 is a NSC-specific protein comprised of four paralogous genes (FAM72 A-D) in the human genome, but its functional tumorigenic significance is unclear.
METHODS: We conducted an in-depth expression and somatic mutation data analysis of FAM72 (A-D) in GBM using the comprehensive human clinical cancer study database cBioPortal [including The Cancer Genome Atlas (TCGA)].
RESULTS: We established a FAM72 transcription profile across TCGA correlated with the expression of the proliferative marker MKI67 and a tissue-specific gene-mutation signature represented by pivotal genes involved in driving the cell cycle. FAM72 paralogs are overexpressed in cancer cells, specifically correlating with the mitotic cell cycle genes ASPM, KIF14, KIF23, CENPE, CENPE, CEP55, SGO1, and BUB1, thereby contributing to centrosome and mitotic spindle formation. FAM72 expression correlation identifies a novel GBM-specific gene set (SCN9A, MXRA5, ADAM29, KDR, LRP1B, and PIK3C2G) in the de novo pathway of primary GBM predestined as viable targets for therapeutics.
CONCLUSION: Our newly identified primary GBM-specific gene-mutation signature, along with FAM72, could thus provide a new basis for prognostic biomarkers for diagnostics of GBM and could serve as potential therapeutic targets.

Guo X, Dai X, Ni J, et al.
Geraniin Differentially Modulates Chromosome Stability of Colon Cancer and Noncancerous Cells by Oppositely Regulating their Spindle Assembly Checkpoint.
Environ Mol Mutagen. 2019; 60(3):254-268 [PubMed] Related Publications
Geraniin has been reported to specifically induce apoptosis in multiple human cancers, but the underlying mechanism is poorly defined. The spindle assembly checkpoint (SAC) is a surveillance system to ensure high-fidelity chromosome segregation during mitosis. Weakening of SAC to enhance chromosome instability (CIN) can be therapeutic because very high levels of CIN are lethal. In this study, we have investigated the effects of geraniin on the SAC of colorectal cancer HCT116 cells and noncancerous colon epithelial CCD841 cells. We find that treatment of HCT116 cells with geraniin leads to dose-dependent decrease of cell proliferation, colony formation, and anchorage-independent growth. Geraniin is found to induce apoptosis in mitotic and postmitotic HCT116 cells. Furthermore, geraniin weakens the SAC function of HCT116 cells by decreasing the transcriptional expression of several SAC kinases (particularly Mad2 and Bub1), which in turn leads to premature anaphase entry, mitotic aberrations, and CIN in HCT116 cells. In contrast, the proliferation of CCD841 cells is slightly inhibited by geraniin. Even more interestingly, geraniin increases the transcriptional expression of several SAC kinases (e.g., Mad1 and BubR1) to strengthen SAC efficiency, which contributes to the reduction of mitotic aberrations and CIN in CCD841 cells. Altogether, our findings reveal that the SAC pathway in human colon cancer and noncancerous cell lineages responses oppositely to geraniin treatment, resulting CIN promotion and suppression, respectively. Specific abrogation of SAC to induce catastrophic CIN in HCT116 cells may account for the selective anticancer action of geraniin.. Environ. Mol. Mutagen. 60:254-268, 2019. © 2018 Wiley Periodicals, Inc.

Chen QF, Xia JG, Li W, et al.
Examining the key genes and pathways in hepatocellular carcinoma development from hepatitis B virus‑positive cirrhosis.
Mol Med Rep. 2018; 18(6):4940-4950 [PubMed] Free Access to Full Article Related Publications
To identify the key genes and pathways in the development of hepatocellular carcinoma (HCC) from hepatitis B virus (HBV)‑positive liver cirrhosis, differentially expressed genes (DEGs) between HCC and liver cirrhosis tissue samples from the GSE17548 gene expression profile dataset were screened. A total of 1,845 DEGs were identified, including 1,803 upregulated and 42 downregulated genes. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein‑protein interaction (PPI) network analyses were performed. It was identified that the 'cell cycle' and 'progesterone‑mediated oocyte maturation' KEGG pathways were significantly enriched in the DEGs. In addition, the high expression of the hub genes from the PPI network (including cyclin dependent kinase 1, cyclin B1, cyclin B2, mitotic arrest deficient 2 like 1, BUB1 mitotic checkpoint serine/threonine kinase and cyclin A2; P=0.00116, 0.00021, 0.04889, 0.00222, 0.00015 and 0.00647, respectively) was associated with a decrease in overall survival for patients with HCC as identified using survival and expression data from The Cancer Genome Atlas. The identified hub genes and pathways may help to elucidate the molecular mechanisms of HCC progression from HBV‑positive liver cirrhosis. Additionally, they may be useful as therapeutic targets or serve as novel biomarkers for HCC prognosis prediction.

Hu S, Liao Y, Chen L
Identification of Key Pathways and Genes in Anaplastic Thyroid Carcinoma via Integrated Bioinformatics Analysis.
Med Sci Monit. 2018; 24:6438-6448 [PubMed] Free Access to Full Article Related Publications
BACKGROUND To provide a better understanding of anaplastic thyroid carcinoma (ATC) at the molecular level, this study aimed to identify the genes and key pathways associated with ATC by using integrated bioinformatics analysis. MATERIAL AND METHODS Based on the microarray data GSE9115, GSE65144, and GSE53072 derived from the Gene Expression Omnibus, the differentially expressed genes (DEGs) between ATC samples and normal controls were identified. With DEGs, we performed a series of functional enrichment analyses. Then, a protein-protein interaction (PPI) network was constructed and visualized, with which the hub gene nodes were screened out. Finally, modules analysis for the PPI network was performed to further investigate the potential relationships between DEGs and ATC. RESULTS A total of 537 common DEGs were screened out from all 3 datasets, among which 247 genes were upregulated and 275 genes were downregulated. GO analysis indicated that upregulated DEGs were mainly involved in cell division and mitotic nuclear division and the downregulated DEGs were significantly enriched in ventricular cardiac muscle cell action potential. KEGG pathway analysis showed that the upregulated DEGs were mainly enriched in cell cycle and ECM-receptor interaction and the downregulated DEGs were mainly enriched in thyroid hormone synthesis, insulin resistance, and pathways in cancer. The top 10 hub genes in the constructed PPI network were CDK1, CCNB1, TOP2A, AURKB, CCNA2, BUB1, AURKA, CDC20, MAD2L1, and BUB1B. The modules analysis showed that genes in the top 2 significant modules of PPI network were mainly associated with mitotic cell cycle and positive regulation of mitosis, respectively. CONCLUSIONS We identified a series of key genes along with the pathways that were most closely related with ATC initiation and progression. Our results provide a more detailed molecular mechanism for the development of ATC, shedding light on the potential biomarkers and therapeutic targets.

Zhang L, Huang Y, Ling J, et al.
Screening and function analysis of hub genes and pathways in hepatocellular carcinoma via bioinformatics approaches.
Cancer Biomark. 2018; 22(3):511-521 [PubMed] Related Publications
BACKGROUND: Liver carcinoma is a major cause of cancer-related death worldwide. Up to date, the mechanisms of liver cancerigenesis and development have not been fully understood. Multi-genes and pathways were involved in the tumorigenesis of liver cancer.
OBJECTIVE: The aim of the present study was to screen key genes and pathways in liver cancerigenesis and development by using bioinformatics methods.
METHODS: A dataset GSE64041 were retrieved from GEO database and the differentially expressed genes (DEGs) were screened out. Then the DEG functions were annotated by gene ontology (GO) and pathway enrichment analysis, respectively. The hub genes were further selected by protein-protein interaction (PPI) analysis. Afterwards, the mRNA and protein expressions as well as the prognostic values of the hub genes were assessed.
RESULTS: As a result, 208 up-regulated and 82 down-regulated genes were screened out. These DEGs were mainly enriched in cell cycle and metabolism-related pathways. Through PPI analysis, TOP2A, PRDM10, CDK1, AURKA, BUB1, PLK1, CDKN3, NCAPG, BUB1B and CCNA2 were selected as hub genes, which were all over-expressed in liver cancers relative to those in normal tissues, respectively. Among them, PLK1 and CCNA2 were suggested to be prognostic factors for liver carcinoma.
CONCLUSION: In conclusion, the present study identified several hub genes, and cell cycle and metabolism-related pathways that may play critical roles in the tumorigenesis of liver cancer. Future validation laboratory experiments are required to confirm the results.

Zang Y, Dong M, Zhang K, et al.
Bioinformatics analysis of key differentially expressed genes in well and poorly differentiated endometrial carcinoma.
Mol Med Rep. 2018; 18(1):467-476 [PubMed] Related Publications
Endometrial carcinoma (EC) is one of the most common gynecological malignancies. The malignant degree increases between grade (G)1 and G3, and EC of G3 usually presents a high recurrence rate and poor prognosis. Therefore, the present study aimed to examine the principal genes associated with the degree of differentiation in EC. The microarrays GSE17025, GSE24537 and GSE35784, representing data of Type I EC samples of G1 and G3, were downloaded from the Gene Expression Omnibus. The differentially expressed genes (DEGs) and differentially expressed micro (mi)RNAs (DEMs) were identified, followed by functional enrichment analyses and interaction network construction. In total, 83 upregulated and 130 downregulated DEGs with the same expression trends in two mRNA datasets were screened. The upregulated DEGs were primarily enriched in 'mitotic cell cycle process', 'cell cycle process' and 'mitotic cell cycle'; while the downregulated DEGs were enriched in 'cellular component assembly involved in morphogenesis', 'cell projection organization' and 'microtubule‑based movement'. From the protein‑protein interaction network, DNA topoisomerase IIα, kinesin family member 11, cyclin B1 and BUB1 mitotic checkpoint serine/threonine were identified as foremost hub genes. One module was extracted and involved in 'mitotic cell cycle process' and 'cell cycle process'. Based on the analysis of DEMs and the miRNA‑target regulatory network, miRNA‑9 may be the most important upregulated DEM, and the DEGs forkhead box P1 and cyclin E1 may serve vital roles in the differentiation of EC. In conclusion, principal genes were identified that may be determinants of the carcinogenesis of poorly differentiated EC, which may facilitate the examination of potential molecular mechanisms. These genes may additionally help identify candidate biomarkers and novel therapeutic targets for poorly differentiated EC.

Wen DY, Lin P, Pang YY, et al.
Expression of the Long Intergenic Non-Protein Coding RNA 665 (LINC00665) Gene and the Cell Cycle in Hepatocellular Carcinoma Using The Cancer Genome Atlas, the Gene Expression Omnibus, and Quantitative Real-Time Polymerase Chain Reaction.
Med Sci Monit. 2018; 24:2786-2808 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Long non-coding RNAs (lncRNAs) have a role in physiological and pathological processes, including cancer. The aim of this study was to investigate the expression of the long intergenic non-protein coding RNA 665 (LINC00665) gene and the cell cycle in hepatocellular carcinoma (HCC) using database analysis including The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and quantitative real-time polymerase chain reaction (qPCR). MATERIAL AND METHODS Expression levels of LINC00665 were compared between human tissue samples of HCC and adjacent normal liver, clinicopathological correlations were made using TCGA and the GEO, and qPCR was performed to validate the findings. Other public databases were searched for other genes associated with LINC00665 expression, including The Atlas of Noncoding RNAs in Cancer (TANRIC), the Multi Experiment Matrix (MEM), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) networks. RESULTS Overexpression of LINC00665 in patients with HCC was significantly associated with gender, tumor grade, stage, and tumor cell type. Overexpression of LINC00665 in patients with HCC was significantly associated with overall survival (OS) (HR=1.47795%; CI: 1.046-2.086). Bioinformatics analysis identified 469 related genes and further analysis supported a hypothesis that LINC00665 regulates pathways in the cell cycle to facilitate the development and progression of HCC through ten identified core genes: CDK1, BUB1B, BUB1, PLK1, CCNB2, CCNB1, CDC20, ESPL1, MAD2L1, and CCNA2. CONCLUSIONS Overexpression of the lncRNA, LINC00665 may be involved in the regulation of cell cycle pathways in HCC through ten identified hub genes.

Chong T, Sarac A, Yao CQ, et al.
Deregulation of the spindle assembly checkpoint is associated with paclitaxel resistance in ovarian cancer.
J Ovarian Res. 2018; 11(1):27 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ovarian cancer is the leading gynecologic cancer diagnosed in North America and because related symptoms are not disease specific, this often leads to late detection, an advanced disease state, and the need for chemotherapy. Ovarian cancer is frequently sensitive to chemotherapy at diagnosis but rapid development of drug resistance leads to disease progression and ultimately death in the majority of patients.
RESULTS: We have generated paclitaxel resistant ovarian cell lines from their corresponding native cell lines to determine driver mechanisms of drug resistance using gene expression arrays. These paclitaxel resistant ovarian cells demonstrate: (1) Increased IC
CONCLUSIONS: We have generated model systems to explore drug resistance in ovarian cancer, which have revealed a key pathway related to the spindle assembly checkpoint underlying paclitaxel resistance in ovarian cell lines.

Mur P, De Voer RM, Olivera-Salguero R, et al.
Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are infrequent in familial colorectal cancer and polyposis.
Mol Cancer. 2018; 17(1):23 [PubMed] Free Access to Full Article Related Publications
Germline mutations in BUB1 and BUB3 have been reported to increase the risk of developing colorectal cancer (CRC) at young age, in presence of variegated aneuploidy and reminiscent dysmorphic traits of mosaic variegated aneuploidy syndrome. We performed a mutational analysis of BUB1 and BUB3 in 456 uncharacterized mismatch repair-proficient hereditary non-polyposis CRC families and 88 polyposis cases. Four novel or rare germline variants, one splice-site and three missense, were identified in four families. Neither variegated aneuploidy nor dysmorphic traits were observed in carriers. Evident functional effects in the heterozygous form were observed for c.1965-1G>A, but not for c.2296G>A (p.E766K), in spite of the positive co-segregation in the family. BUB1 c.2473C>T (p.P825S) and BUB3 c.77C>T (p.T26I) remained as variants of uncertain significance. As of today, the rarity of functionally relevant mutations identified in familial and/or early onset series does not support the inclusion of BUB1 and BUB3 testing in routine genetic diagnostics of familial CRC.

Roberto GM, Engel EE, Scrideli CA, et al.
Downregulation of miR-10B* is correlated with altered expression of mitotic kinases in osteosarcoma.
Pathol Res Pract. 2018; 214(2):213-216 [PubMed] Related Publications
Dysregulated mitotic kinases have frequently been associated with cancer. Changes in their expression might result from diverse mechanisms including avoidance of the tight regulation exerted by miRNAs. Herein we show that miR-10b* is downregulated in osteosarcoma samples and demonstrate its correlation with PLK1, PLK4, BUB1, and BUBR1, which are strongly intercorrelated. The selection of miRNAs that coordinately target and regulate multiple members of cancer-related pathways are particularly advantageous to tumors. Thus, even though no associations with clinical parameters were found, our data place miR-10b* as a tumor suppressor that might contribute to guarantee genomic stability, deserving further functional confirmation.

Agarwal R, Narayan J, Bhattacharyya A, et al.
Gene expression profiling, pathway analysis and subtype classification reveal molecular heterogeneity in hepatocellular carcinoma and suggest subtype specific therapeutic targets.
Cancer Genet. 2017; 216-217:37-51 [PubMed] Related Publications
A very low 5-year survival rate among hepatocellular carcinoma (HCC) patients is mainly due to lack of early stage diagnosis, distant metastasis and high risk of postoperative recurrence. Hence ascertaining novel biomarkers for early diagnosis and patient specific therapeutics is crucial and urgent. Here, we have performed a comprehensive analysis of the expression data of 423 HCC patients (373 tumors and 50 controls) downloaded from The Cancer Genome Atlas (TCGA) followed by pathway enrichment by gene ontology annotations, subtype classification and overall survival analysis. The differential gene expression analysis using non-parametric Wilcoxon test revealed a total of 479 up-regulated and 91 down-regulated genes in HCC compared to controls. The list of top differentially expressed genes mainly consists of tumor/cancer associated genes, such as AFP, THBS4, LCN2, GPC3, NUF2, etc. The genes over-expressed in HCC were mainly associated with cell cycle pathways. In total, 59 kinases associated genes were found over-expressed in HCC, including TTK, MELK, BUB1, NEK2, BUB1B, AURKB, PLK1, CDK1, PKMYT1, PBK, etc. Overall four distinct HCC subtypes were predicted using consensus clustering method. Each subtype was unique in terms of gene expression, pathway enrichment and median survival. Conclusively, this study has exposed a number of interesting genes which can be exploited in future as potential markers of HCC, diagnostic as well as prognostic and subtype classification may guide for improved and specific therapy.

Peng C, Yang Q, Wei B, et al.
Investigation of crucial genes and microRNAs in conventional osteosarcoma using gene expression profiling analysis.
Mol Med Rep. 2017; 16(5):7617-7624 [PubMed] Related Publications
The present study aimed to screen potential genes associated with conventional osteosarcoma (OS) and obtain further information on the pathogenesis of this disease. The microarray dataset GSE14359 was downloaded from the Gene Expression Omnibus. A total of 10 conventional OS samples and two non‑neoplastic primary osteoblast samples in the dataset were selected to identify the differentially expressed genes (DEGs) using the Linear Models for Microarray Data package. The potential functions of the DEGs were predicted using Gene Ontology (GO) and pathway enrichment analyses. Protein‑protein interaction (PPI) data were also obtained using the Search Tool for the Retrieval of Interacting Genes database, and the PPI network was visualized using Cytoscape. Module analysis was then performed using the Molecular Complex Detection module. Additionally, the potential microRNAs (miRNAs) for the upregulated DEGs in the most significant pathway were predicted using the miRDB database, and the regulatory network for the miRNAs‑DEGs was visualized in Cytoscape. In total, 317 upregulated and 670 downregulated DEGs were screened. Certain DEGs, including cyclin‑dependent kinase 1 (CDK1), mitotic arrest deficient 2 like 1 (MAD2L1) and BUB1 mitotic checkpoint serine/threonine‑protein kinase (BUB1), were significantly enriched in the cell cycle phase and oocyte meiosis pathway. DEGs, including replication factor C subunit 2 (RFC2), RFC3, RFC4 and RFC5, were significantly enriched in DNA replication and interacted with each other. RFC4 also interacted with other DEGs, including CDK1, MAD2L1, NDC80 kinetochore complex and BUB1. In addition, RFC4, RFC3 and RFC5 were targeted by miRNA (miR)‑802, miR‑224‑3p and miR‑522‑3p. The DEGs encoding RFC may be important for the development of conventional OS, and their expression may be regulated by a number of miRNAs, including miR‑802, miR‑224‑3p and miR‑522‑3p.

Li L, Lei Q, Zhang S, et al.
Screening and identification of key biomarkers in hepatocellular carcinoma: Evidence from bioinformatic analysis.
Oncol Rep. 2017; 38(5):2607-2618 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Intense efforts have been made to elucidate the pathogeny, but the molecular mechanisms of HCC are still not well understood. To identify the candidate genes in the carcinogenesis and progression of HCC, microarray datasets GSE19665, GSE33006 and GSE41804 were downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and function enrichment analyses were performed. The protein-protein interaction network (PPI) was constructed and the module analysis was performed using STRING and Cytoscape. A total of 273 DEGs were identified, consisting of 189 downregulated genes and 84 upregulated genes. The enriched functions and pathways of the DEGs include protein activation cascade, complement activation, carbohydrate binding, complement and coagulation cascades, mitotic cell cycle and oocyte meiosis. Sixteen hub genes were identified and biological process analysis revealed that these genes were mainly enriched in cell division, cell cycle and nuclear division. Survival analysis showed that BUB1, CDC20, KIF20A, RACGAP1 and CEP55 may be involved in the carcinogenesis, invasion or recurrence of HCC. In conclusion, DEGs and hub genes identified in the present study help us understand the molecular mechanisms underlying the carcinogenesis and progression of HCC, and provide candidate targets for diagnosis and treatment of HCC.

Goto Y, Kurozumi A, Arai T, et al.
Impact of novel miR-145-3p regulatory networks on survival in patients with castration-resistant prostate cancer.
Br J Cancer. 2017; 117(3):409-420 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Despite recent advancements, metastatic castration-resistant prostate cancer (CRPC) is not considered curative. Novel approaches for identification of therapeutic targets of CRPC are needed.
METHODS: Next-generation sequencing revealed 945-1248 miRNAs from each lethal mCRPC sample. We constructed miRNA expression signatures of CRPC by comparing the expression of miRNAs between CRPC and normal prostate tissue or hormone-sensitive prostate cancer (HSPC). Genome-wide gene expression studies and in silico analyses were carried out to predict miRNA regulation and investigate the functional significance and clinical utility of the novel oncogenic pathways regulated by these miRNAs in prostate cancer (PCa).
RESULTS: Based on the novel miRNA expression signature of CRPC, miR-145-5p and miR-145-3p were downregulated in CRPC. By focusing on miR-145-3p, which is a passenger strand and has not been well studied in previous reports, we showed that miR-145-3p targeted 4 key molecules, i.e., MELK, NCAPG, BUB1, and CDK1, in CPRC. These 4 genes significantly predicted survival in patients with PCa.
CONCLUSIONS: Small RNA sequencing for lethal CRPC and in silico analyses provided novel therapeutic targets for CRPC.

Zhao P, Zhang P, Hu W, et al.
Upregulation of cyclin B1 plays potential roles in the invasiveness of pituitary adenomas.
J Clin Neurosci. 2017; 43:267-273 [PubMed] Related Publications
Predicting aggressive or malignant behavior of pituitary adenomas (PAs) remains challenging. Aberrant expression of cyclin B1 (CCNB1) occurred in various tumors including PAs. Our study was aimed to explore its roles in the development of PAs aggressiveness. According to the integrated analysis, the expression of CCNB1 was evaluated. Following bioinformatics analysis was performed to uncover the pathways CCNB1 involved in and the upstream transcriptional regulation factors. The mRNA expression of CCNB1 was verified by qRT-PCR. Immunohistochemistry analysis was conducted to examine the expression of CCNB1 protein in three groups of PAs (non-invasive, invasive and aggressive-invasive). In this study, CCNB1 was up-regulated in PAs versus normal pituitary. Functional annotation revealed CCNB1 was mainly involved in p53 signaling pathway and cell cycle, which affected proliferation and contributed to tumorigenesis. The constructed transcriptional regulatory network contained 22 upstream transcriptional factors for CCNB1. Moreover, the network also suggested the interactions between CCNB1 and other genes implicated in proliferation (BUB1, CDC25C and TTK). Immunohistochemistry showed staining of CCNB1 was positive in PAs, and its expression was gradually enhanced with the increased invasiveness. In conclusion, up-regulation of CCNB1, together with other regulatory molecules in cell cycle, may play roles in the PAs pathology and could be an indicator for invasiveness of PAs.

Vargas-Parra GM, González-Acosta M, Thompson BA, et al.
Elucidating the molecular basis of MSH2-deficient tumors by combined germline and somatic analysis.
Int J Cancer. 2017; 141(7):1365-1380 [PubMed] Related Publications
In a proportion of patients presenting mismatch repair (MMR)-deficient tumors, no germline MMR mutations are identified, the so-called Lynch-like syndrome (LLS). Recently, MMR-deficient tumors have been associated with germline mutations in POLE and MUTYH or double somatic MMR events. Our aim was to elucidate the molecular basis of MSH2-deficient LS-suspected cases using a comprehensive analysis of colorectal cancer (CRC)-associated genes at germline and somatic level. Fifty-eight probands harboring MSH2-deficient tumors were included. Germline mutational analysis of MSH2 (including EPCAM deletions) and MSH6 was performed. Pathogenicity of MSH2 variants was assessed by RNA analysis and multifactorial likelihood calculations. MSH2 cDNA and methylation of MSH2 and MSH6 promoters were studied. Matched blood and tumor DNA were analyzed using a customized next generation sequencing panel. Thirty-five individuals were carriers of pathogenic or probably pathogenic variants in MSH2 and EPCAM. Five patients harbored 4 different MSH2 variants of unknown significance (VUS) and one had 2 novel MSH6 promoter VUS. Pathogenicity assessment allowed the reclassification of the 4 MSH2 VUS and 6 probably pathogenic variants as pathogenic mutations, enabling a total of 40 LS diagnostics. Predicted pathogenic germline variants in BUB1, SETD2, FAN1 and MUTYH were identified in 5 cases. Three patients had double somatic hits in MSH2 or MSH6, and another 2 had somatic alterations in other MMR genes and/or proofreading polymerases. In conclusion, our comprehensive strategy combining germline and somatic mutational status of CRC-associated genes by means of a subexome panel allows the elucidation of up to 86% of MSH2-deficient suspected LS tumors.

Sun Q, Zhao H, Zhang C, et al.
Gene co-expression network reveals shared modules predictive of stage and grade in serous ovarian cancers.
Oncotarget. 2017; 8(26):42983-42996 [PubMed] Free Access to Full Article Related Publications
Serous ovarian cancer (SOC) is the most lethal gynecological cancer. Clinical studies have revealed an association between tumor stage and grade and clinical prognosis. Identification of meaningful clusters of co-expressed genes or representative biomarkers related to stage or grade may help to reveal mechanisms of tumorigenesis and cancer development, and aid in predicting SOC patient prognosis. We therefore performed a weighted gene co-expression network analysis (WGCNA) and calculated module-trait correlations based on three public microarray datasets (GSE26193, GSE9891, and TCGA), which included 788 samples and 10402 genes. We detected four modules related to one or more clinical features significantly shared across all modeling datasets, and identified one stage-associated module and one grade-associated module. Our analysis showed that MMP2, COL3A1, COL1A2, FBN1, COL5A1, COL5A2, and AEBP1 are top hub genes related to stage, while CDK1, BUB1, BUB1B, BIRC5, AURKB, CENPA, and CDC20 are top hub genes related to grade. Gene and pathway enrichment analyses of the regulatory networks involving hub genes suggest that extracellular matrix interactions and mitotic signaling pathways are crucial determinants of tumor stage and grade. The relationships between gene expression modules and tumor stage or grade were validated in five independent datasets. These results could potentially be developed into a more objective scoring system to improve prediction of SOC outcomes.

Li M, Sun Q, Wang X
Transcriptional landscape of human cancers.
Oncotarget. 2017; 8(21):34534-34551 [PubMed] Free Access to Full Article Related Publications
The homogeneity and heterogeneity in somatic mutations, copy number alterations and methylation across different cancer types have been extensively explored. However, the related exploration based on transcriptome data is lacking. In this study we explored gene expression profiles across 33 human cancer types using The Cancer Genome Atlas (TCGA) data. We identified consistently upregulated genes (such as E2F1, EZH2, FOXM1, MYBL2, PLK1, TTK, AURKA/B and BUB1) and consistently downregulated genes (such as SCARA5, MYOM1, NKAPL, PEG3, USP2, SLC5A7 and HMGCLL1) across various cancers. The dysregulation of these genes is likely to be associated with poor clinical outcomes in cancer. The dysregulated pathways commonly in cancers include cell cycle, DNA replication, repair, and recombination, Notch signaling, p53 signaling, Wnt signaling, TGFβ signaling, immune response etc. We also identified genes consistently upregulated or downregulated in highly-advanced cancers compared to lowly-advanced cancers. The highly (low) expressed genes in highly-advanced cancers are likely to have higher (lower) expression levels in cancers than in normal tissue, indicating that common gene expression perturbations drive cancer initiation and cancer progression. In addition, we identified a substantial number of genes exclusively dysregulated in a single cancer type or inconsistently dysregulated in different cancer types, demonstrating the intertumor heterogeneity. More importantly, we found a number of genes commonly dysregulated in various cancers such as PLP1, MYOM1, NKAPL and USP2 which were investigated in few cancer related studies, and thus represent our novel findings. Our study provides comprehensive portraits of transcriptional landscape of human cancers.

Suh YJ, Choe JY, Park HJ
Malignancy in Pheochromocytoma or Paraganglioma: Integrative Analysis of 176 Cases in TCGA.
Endocr Pathol. 2017; 28(2):159-164 [PubMed] Related Publications
Methods of diagnosing malignant pheochromocytoma (PCC) or paraganglioma (PGL) are needed. However, there are no reliable histopathologic criteria to distinguish malignant PCC/PGLs. The recent genomic analysis of The Cancer Genome Atlas (TCGA) provides in-depth information enabling more accurate diagnosis of disease entities. Therefore, we investigated genomic expression differences and mutational differences of malignant PCC/PGLs with TCGA. As of December 2014, TCGA had acquired multigenomic analysis of 176 PCC/PGL samples. Clinical information, mutation status, and 20,531 gene messenger RNA (mRNA) expression dataset of normalized RNA-sequencing mRNA read counts were downloaded from TCGA, and integrated into a table. Of the 176 PCC/PGL samples in the dataset, 14 had metastasis and 162 exhibited no metastasis. mRNA expression and mutations were compared in these two groups. There were 76 males in the dataset of 176 TCGA samples. Mean age was 47.6 ± 15.2 years (19-83 years). There was no significant gender or race difference between metastatic and non-metastatic groups. mRNA expression of malignant PCC/PGLs was upregulated in five pathways of cell cycle (BUB1, BUB1B, CCNB2, CDC2, ESPL1), calcium signaling (CCNB2, CDC2, PRKCB1), regulation of actin cytoskeleton (DIAPH3, FGF18, IQGAP3), gap junction (CDC2, PRKCB1), and phosphatidylinositol (PRKCB1, TTK). Disease-free survival rates were significantly correlated with the presence or absence of mutations, such as RP11-798G7.5, HERC2, SETD2, TGDS, TRHDE, FKBP9, and BMS1. TCGA showed differences in mRNA expression and mutations between metastatic and non-metastatic PCC/PGLs. The improved recognition of genetic causes can help to achieve proper diagnosis and provide appropriate treatment of PCC/PGL.

Song H, Wu F, Li S, et al.
Microarray expression analysis of MYCN-amplified neuroblastoma cells after inhibition of CDK2.
Neoplasma. 2017; 64(3):351-357 [PubMed] Related Publications
The study aimed to explore the underlying molecular mechanisms of CDK2 inhibition in neuroblastoma by bioinformatics analysis. Gene expression profile GSE16480 was downloaded from the Gene Expression Omnibus. The differentially expressed genes (DEGs) were identified from IMR32 between each time point and average expression of all time points. Gene significance was calculated using dSVDsig algorithm of dnet package. Protein-protein interaction (PPI) network was built. Then, integrated with gene significance, a core PPI network was detected by dNetPipeline algorithm in dnet package. Finally, pathway enrichment analysis was performed for genes in network. Totally, 1524 DEGs were identified. CCNA2 (cyclin A2), EXO1 (exonuclease 1), RAD51AP1 (RAD51 associated protein 1), TOP2A (topoisomerase (DNA) II alpha) and CDK1 (cyclin-dependent kinase 1) were selected as DEGs with higher connectivity after PPI network analysis. In the network, CCNA2, CDK1, BUB1B (BUB1 mitotic checkpoint serine/threonine kinase B) and CCNB1 (cyclin B1) were involved in cell cycle pathway. Additionally, CCNB1, CDK1, CCNE2 (Cyclin E2), and RRM2B (ribonucleotide reductase subunit M2B) were involved in p53 signaling pathway. Cell cycle and p53 signaling pathway were closely associated with neuroblastoma after CDK2 inhibition. The DEGs, such as CCNA2, CCNB1, CDK1 and RRM2B may be the potential targets for neuroblastoma.

Yan H, Li Z, Shen Q, et al.
Aberrant expression of cell cycle and material metabolism related genes contributes to hepatocellular carcinoma occurrence.
Pathol Res Pract. 2017; 213(4):316-321 [PubMed] Related Publications
This study aims to deepen our understanding of the molecular mechanism underlying the occurrence of hepatocellular carcinoma (HCC). We first downloaded a gene expression profile dataset GSE29721 (10 HCC and 10 control samples) from Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo/). Differentially expressed genes (DEGs) were identified by the paired t-test using limma package. Pathway and functional enrichment analyses were performed with DAVID tools. Transcription factors were annotated with TRANSFAC database and tumor associated genes (TAGs) were annotated with TAG and TSGene databases. Protein-protein interaction (PPI) network was conducted using STRING online tool and function module was further identified with BioNet package. Totally, 527 up-regulated DEGs and 587 down-regulated DEGs were identified. GO functional and KEGG pathway enrichment analyses showed that the up-regulated DEGs were mainly related to cell division and cell cycle, while the down-regulated DEGs were largely related to material metabolism, especially secondary metabolism. Proteins encoded by DEGs CDK1, BUB1, CDC20, NCAPG, NDC80, CDCA8, MAD2L1, CCNB1, CCNA2 and BIRC5 were hub genes with high degrees in the PPI network; further module analysis detected a subnetwork consisting of 55 proteins, such as CYP2B6, ACAA1, BHMT and ALDH2. Taken together, aberrant expression of cell cycle related genes (e.g., CDK1, CCNA2, CCNB1, BUB1, MAD2L1 and CDC20) and material metabolism related genes (e.g., CYP2B6, ACAA1, BHMT and ALDH2) may contribute to HCC occurrence.

Tong H, Wang J, Chen H, et al.
Transcriptomic analysis of gene expression profiles of stomach carcinoma reveal abnormal expression of mitotic components.
Life Sci. 2017; 170:41-49 [PubMed] Related Publications
AIMS: In order to explore the etiology of gastric cancer on global gene expression level, we developed advanced bioinformatic analysis to investigate the variations of global gene expression and the interactions among them.
MAIN METHODS: We downloaded the dataset GSE63288 from Gene Expression Omnibus (GEO) database which included 22 human gastric cancer and 22 healthy control samples. We identified the differential expression genes, and explored the Gene ontology (GO) and pathways of the differentially expressed genes. Furthermore, integrative interaction network and co-expression network were employed to identify the key genes which may contribute to gastric cancer progression.
KEY FINDINGS: The results indicated that 5 kinases including BUB1, TTK protein kinase, Citron Rho-interacting kinase (CIT), ZAK and NEK2 were upregulated in gastric cancer. Interestingly, BUB1, TTK, CIT and NEK2 have shown high expression similarities and bound with each other, and participated in multiple phases of mitosis. Moreover, a subnet of co-expression genes e.g. KIF14, PRC1, CENPF and CENPI was also involved in mitosis which was functionally coupled with the kinases above. By validation assays, the results indicated that CIT, PRC1, TTK and KIF14 were significantly upregulated in gastric cancer.
SIGNIFICANCE: These evidences have suggested that aberrant expression of these genes may drive gastric cancer including progression, invasion and metastasis. Although the causal relationships between gastric cancer and the genes are still lacking, it was reasonable to take them as biomarkers for diagnosis of gastric cancer.

Broderick P, Dobbins SE, Chubb D, et al.
Validation of Recently Proposed Colorectal Cancer Susceptibility Gene Variants in an Analysis of Families and Patients-a Systematic Review.
Gastroenterology. 2017; 152(1):75-77.e4 [PubMed] Free Access to Full Article Related Publications
High-throughput sequencing analysis has accelerated searches for genes associated with risk for colorectal cancer (CRC); germline mutations in NTHL1, RPS20, FANCM, FAN1, TP53, BUB1, BUB3, LRP6, and PTPN12 have been recently proposed to increase CRC risk. We attempted to validate the association between variants in these genes and development of CRC in a systematic review of 11 publications, using sequence data from 863 familial CRC cases and 1604 individuals without CRC (controls). All cases were diagnosed at an age of 55 years or younger and did not carry mutations in an established CRC predisposition gene. We found sufficient evidence for NTHL1 to be considered a CRC predisposition gene-members of 3 unrelated Dutch families were homozygous for inactivating p.Gln90Ter mutations; a Canadian woman with polyposis, CRC, and multiple tumors was reported to be heterozygous for the inactivating NTHL1 p.Gln90Ter/c.709+1G>A mutations; and a man with polyposis was reported to carry p.Gln90Ter/p.Gln287Ter; whereas no inactivating homozygous or compound heterozygous mutations were detected in controls. Variants that disrupted RPS20 were detected in a Finnish family with early-onset CRC (p.Val50SerfsTer23), a 39-year old individual with metachronous CRC (p.Leu61GlufsTer11 mutation), and a 41-year-old individual with CRC (missense p.Val54Leu), but not in controls. We therefore found published evidence to support the association between variants in NTHL1 and RPS20 with CRC, but not of other recently reported CRC susceptibility variants. We urge the research community to adopt rigorous statistical and biological approaches coupled with independent replication before making claims of pathogenicity.

Li T, Chen L, Cheng J, et al.
SUMOylated NKAP is essential for chromosome alignment by anchoring CENP-E to kinetochores.
Nat Commun. 2016; 7:12969 [PubMed] Free Access to Full Article Related Publications
Chromosome alignment is required for accurate chromosome segregation. Chromosome misalignment can result in genomic instability and tumorigenesis. Here, we show that NF-κB activating protein (NKAP) is critical for chromosome alignment through anchoring CENP-E to kinetochores. NKAP knockdown causes chromosome misalignment and prometaphase arrest in human cells. NKAP dynamically localizes to kinetochores, and is required for CENP-E kinetochore localization. NKAP is SUMOylated predominantly in mitosis and the SUMOylation is needed for NKAP to bind CENP-E. A SUMOylation-deficient mutant of NKAP cannot support the localization of CENP-E on kinetochores or proper chromosome alignment. Moreover, Bub3 recruits NKAP to stabilize the binding of CENP-E to BubR1 at kinetochores. Importantly, loss of NKAP expression causes aneuploidy in cultured cells, and is observed in human soft tissue sarcomas. These findings indicate that NKAP is a novel and key regulator of mitosis, and its dysregulation might contribute to tumorigenesis by causing chromosomal instability.

Wills ES, Cnossen WR, Veltman JA, et al.
Chromosomal abnormalities in hepatic cysts point to novel polycystic liver disease genes.
Eur J Hum Genet. 2016; 24(12):1707-1714 [PubMed] Free Access to Full Article Related Publications
Autosomal dominant polycystic liver disease (ADPLD) is caused by variants in PRKCSH, SEC63, and LRP5, whereas autosomal dominant polycystic kidney disease is caused by variants in PKD1 and PKD2. Liver cyst development in these disorders is explained by somatic loss-of-heterozygosity (LOH) of the wild-type allele in the developing cyst. We hypothesize that we can use this mechanism to identify novel disease genes that reside in LOH regions. In this study, we aim to map abnormal genomic regions using high-density SNP microarrays to find novel PLD genes. We collected 46 cysts from 23 patients with polycystic or sporadic hepatic cysts, and analyzed DNA from those cysts using high-resolution microarray (n=24) or Sanger sequencing (n=22). We here focused on regions of homozygosity on the autosomes (>3.0 Mb) and large CNVs (>1.0 Mb). We found frequent LOH in PRKCSH (22/29) and PKD1/PKD2 (2/3) cysts of patients with known heterozygous germline variants in the respective genes. In the total cohort, 12/23 patients harbored abnormalities outside of familiar areas. In individual ADPLD cases, we identified germline events: a 2q13 complex rearrangement resulting in BUB1 haploinsufficiency, a 47XXX karyotype, chromosome 9q copy-number loss, and LOH on chromosome 3p. The latter region was overlapping with an LOH region identified in two other cysts. Unique germline and somatic abnormalities occur frequently in and outside of known genes underlying cysts. Each liver cyst has a unique genetic makeup. LOH driver gene BUB1 may imply germline causes of genetic instability in PLD.

Rao CV, Asch AS, Yamada HY
Emerging links among Chromosome Instability (CIN), cancer, and aging.
Mol Carcinog. 2017; 56(3):791-803 [PubMed] Related Publications
Aneuploidy was predicted to cause cancer. To test the prediction, various Chromosome Instability (CIN) mice models that carry transgenic mutations in mitotic regulators have been created. The availability of these mice has aided researchers in discovering connections between CIN, cancer, and aging. This review will focus on recent interdisciplinary findings regarding how CIN and aneuploidy affect carcinogenesis, immune dysfunction, and aging. High CIN can be generated in vivo by various intrinsic alterations (e.g., gene mutation, epigenetic modification) and extrinsic/environmental challenges (e.g., biological, chemical, biophysical), while immune surveillance, cell death, and natural turnover can remove cells with CIN. CIN itself is mutagenic and may cause further cellular mutations, which can be carcinogenic. Mitotically damaged cells can activate senescence-related tumor suppressors (e.g., p21

Weaver RL, Limzerwala JF, Naylor RM, et al.
BubR1 alterations that reinforce mitotic surveillance act against aneuploidy and cancer.
Elife. 2016; 5 [PubMed] Free Access to Full Article Related Publications
BubR1 is a key component of the spindle assembly checkpoint (SAC). Mutations that reduce BubR1 abundance cause aneuploidization and tumorigenesis in humans and mice, whereas BubR1 overexpression protects against these. However, how supranormal BubR1 expression exerts these beneficial physiological impacts is poorly understood. Here, we used Bub1b mutant transgenic mice to explore the role of the amino-terminal (BubR1(N)) and internal (BubR1(I)) Cdc20-binding domains of BubR1 in preventing aneuploidy and safeguarding against cancer. BubR1(N) was necessary, but not sufficient to protect against aneuploidy and cancer. In contrast, BubR1 lacking the internal Cdc20-binding domain provided protection against both, which coincided with improved microtubule-kinetochore attachment error correction and SAC activity. Maximal SAC reinforcement occurred when both the Phe- and D-box of BubR1(I) were disrupted. Thus, while under- or overexpression of most mitotic regulators impairs chromosome segregation fidelity, certain manipulations of BubR1 can positively impact this process and therefore be therapeutically exploited.

Hahn MM, Vreede L, Bemelmans SA, et al.
Prevalence of germline mutations in the spindle assembly checkpoint gene BUB1B in individuals with early-onset colorectal cancer.
Genes Chromosomes Cancer. 2016; 55(11):855-63 [PubMed] Related Publications
Germline mutations in BUB1B, encoding BUBR1, one of the crucial components of the spindle assembly checkpoint (SAC), have been shown to cause variable phenotypes, including the recessive mosaic variegated aneuploidy (MVA) syndrome, which predisposes to cancer. Reduced levels of the wild-type BUBR1 protein have been linked to the development of gastrointestinal neoplasms. To determine whether mutations in BUB1B are enriched in individuals with colorectal cancer (CRC), we performed amplicon-based targeted next-generation sequencing of BUB1B on germline DNA of 192 individuals with early-onset CRC (≤50 years). None of the individuals was found to be homozygous or compound heterozygous for mutations in BUB1B. However, we did identify two rare heterozygous variants, p.Glu390del and p.Cys945Tyr, in patients who developed CRC at the ages of 41 and 43 years, respectively. Both variants were shown not to affect BUBR1 protein expression levels and protein localization. Since the p.Glu390del variant is located in the BUB3-binding domain, we also performed immunoprecipitation to examine whether this variant affects the binding of BUB1 or BUB3 to BUBR1 but, compared to wild-type BUBR1, no difference was observed. Our data suggest that mutations in BUB1B do not occur frequently in the germline of individuals with CRC and that BUB1B unlikely plays a major role in the predisposition to early-onset CRC. Whether carriers of pathogenic BUB1B mutations, such as the parents of MVA syndrome patients, have an increased risk for cancer remains of interest, as studies in mice have suggested that haploinsufficiency of BUB1B may cause an increase in carcinogen-induced tumors. © 2016 Wiley Periodicals, Inc.

Yamamoto Y, Oga A, Akao J, et al.
BUBR1 overexpression predicts disease-specific survival after nephroureterectomy in patients with upper tract urothelial carcinoma.
Jpn J Clin Oncol. 2016; 46(8):754-61 [PubMed] Related Publications
OBJECTIVE: To date, there are few reliable markers to distinguish tumors with aggressive characteristics in upper tract urothelial carcinoma. The purpose of this study was to identify a biomarker related to genetic instability (chromosomal instability or microsatellite instability) with prognostic value, in patients with upper tract urothelial carcinoma.
METHODS: Expression of chromosomal instability-related markers (BUBR1, p53, polo-like kinase 1) and microsatellite instability-related markers (mismatch repair proteins, MLH1 and MSH2) were assessed by immunohistochemistry in 100 patients who had radical nephroureterectomy for upper tract urothelial carcinoma. Numerical aberrations of chromosomes 7, 9 and 17 were evaluated by fluorescence in situ hybridization, which allowed an estimation of the degree of chromosomal instability. BUB1B copy number was examined by array-based comparative genomic hybridization in 32 patients with upper tract urothelial carcinoma.
RESULTS: BUBR1 status was most significantly correlated with chromosomal instability-related and low mismatch repair parameters, according to the molecular biomarkers examined. Overexpression of BUBR1 is frequently detected in tumors with higher histological grade (P < 0.0001) and is significantly associated with chromosomal instability (P = 0.0071). Array-based comparative genomic hybridization revealed that no tumors (0%) showed BUB1B amplification and gain, indicating that overexpression of BUBR1 was independent of BUB1B copy number. For disease-specific survival, BUBR1 overexpression, lymphovascular invasion, pathological tumor stage, pathological lymph node involvement and low MSH2 expression were significant prognostic factors in univariate analyses. In multivariate analyses, BUBR1 overexpression was an independent prognostic factor for disease-specific survival (P = 0.0483, risk ratio 3.76, 95% confidence interval: 1.01-18.43).
CONCLUSIONS: BUBR1 may have significant potential as a biomarker for estimating disease-specific survival in patients with upper tract urothelial carcinoma treated by radical nephroureterectomy.

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