|
| ||
|
|
||
Cancer-related Genes (cancer-related + gene)
Selected AbstractsPopulation-based study of cancer among carriers of a constitutional structural chromosomal rearrangementGENES, CHROMOSOMES AND CANCER, Issue 3 2006Iben Bache We measured the occurrence of cancer in an unselected cohort of carriers of constitutional structural rearrangements in virtually complete nationwide registries for cancer and constitutional cytogenetic abnormalities. We identified 4,816 carriers of a constitutional structural rearrangement in the Danish Cytogenetic Registry and searched for cancer diagnoses by linkage to the Danish Cancer Registry. There was no overall increased risk for cancer among carriers (standardized incidence ratio [SIR], 0.96; 95% confidence interval [CI], 0.84,1.10), and no significant difference from that expected was found in balanced and unbalanced rearrangements or in any subtypes of rearrangements. We found significantly lower risks for carriers with rearrangements involving chromosome 21 (SIR, 0.50; 95% CI, 0.22,0.99) and for paternally inherited rearrangements (SIR, 0.30; 95% CI, 0.06,0.88). Risk estimates for the observed type-specific cancers showed an increased risk for non-Hodgkin lymphoma (SIR, 2.11; 95% CI, 1.09,3.69). However, subgroup analyses were not guided by study hypotheses, and our statistical evaluation of the data should be looked upon as exploratory. In addition, we found 12 constitutional structural rearrangements with a breakpoint potentially associated with a cancer-related gene. Potential new loci associated with type-specific cancers were suggested by the findings of families with more than one affected carrier and by the involvement of the same cytogenetic bands in unrelated carriers. Molecular mapping of these breakpoints might provide new insight into cancer predisposition. © 2005 Wiley-Liss, Inc. [source] Expression of Mina53, a product of a Myc target gene in mouse testisINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 2 2006MAKOTO TSUNEOKA Summary Recently we have identified a novel gene mina53 (mina), which is a direct transcriptional target of oncoprotein Myc. Mina53 protein was shown to be highly expressed in tumour cells and to play a role in cell proliferation. Here we report the expression of Mina53 in mouse testis, which contains proliferating cells and expresses many cancer-related genes. Immunohistochemical studies by using newly produced monoclonal antibody to Mina53 showed that Mina53 was expressed in the nuclei of spermatogonia. Mina53 was also expressed in meiotic prophase cells such as preleptotene, leptotene and zygotene, and weakly in early pachytene spermatocytes, but was absent in late pachytene spermatocytes, spermatids and mature sperm. The expression pattern of Mina53 was quite similar to that of proliferation cell nuclear antigen (PCNA). Using experimental cryptorchid testis, it was found that Mina53 was highly expressed in undifferentiated spermatogonia, which were PCNA-positive. These results suggest that Mina53 is prominently expressed in proliferating, undifferentiated spermatogonia, and plays a role in cell proliferation from the spermatogonial stage to the meiotic prophase in spermatogenesis, but not in meiotic divisions per se. [source] Identification of differentially methylated CpG islands in prostate cancerINTERNATIONAL JOURNAL OF CANCER, Issue 5 2004Yasushi Yamada Abstract Epigenetic change such as DNA methylation is one important mechanism for regulating gene expression as genetic change, such as mutation or loss of heterozygosity. Methylation of cancer-related genes has been shown to play an important role in carcinogenesis and tumor progression. Using methylated CpG island amplification (MCA)/representational difference analysis (RDA), we identified four CpG islands in neurotrophin tyrosine kinase receptor type 2 (NTRK2), Protocadherine Flamingo1 and MFPC (Methylated Fragments in Prostate Cancer) 7 and 8. Bisulfite sequencing revealed that 2 regions of NTRK2 as well as MFPC7 and MFPC8 were aberrantly methylated in prostate cancer cell lines, and COBRA showed that 48 (76.24%), 37 (58.7%) and 14 (22.2%) of 63 prostate cancer tissues were methylated, respectively, for these sites. On the other hand, none of 13 benign prostate samples were methylated, except for 1 (7.7%) with NTRK2. For NTRK2, mRNA expression was negative in prostate cancer cell lines (LNCaP and DU145) but was recovered on a methyltransferase inhibitor (5-Aza-CdR) treatment. The role of NTRK2 within NTRK remains unclear. Our results suggest that these 3 hypermethylated DNA fragments also may be markers of prostate cancer detection. © 2004 Wiley-Liss, Inc. [source] Application of the crypt isolation technique to the assessment of genetic alterations of colorectal carcinomasPATHOLOGY INTERNATIONAL, Issue 10 2002Hiroshi Takahashi The crypt isolation technique (CIT) allows for the isolation of pure tumor crypts from colon tumor tissue. In a previous study we reported on the genetic alterations found in colorectal tumor crypts using the CIT; however, a direct comparison of the genetic alterations found in colorectal carcinomas using either conventional methods (CM) or the CIT has not previously been performed. Here, we analyzed the impact of this method on the genetic analysis of colon tumor cells by comparing the observed frequency of genetic alterations in colon tumors isolated using CM or the CIT. We used a combination of the CIT and the fluorescent polymerase chain reaction assay to accurately assess the incidence of allelic imbalances (AI) at a number of chromosomal loci (17p, 5q, 18q, 1p, 8p, 22q), microsatellite instability (MSI), and mutations of cancer-related genes (p53 and APC genes) in 48 sporadic colorectal carcinomas. In addition, genetic alterations seen in multiploid tumors (defined as tumors with both diploid and aneuploid cell populations) identified by the CIT were also examined. The incidence of AI at the chromosomal loci tested was more frequently detected in samples isolated from tumors using the CIT than in those isolated from the same tumors using CM. In contrast, we observed no differences in the frequency of MSI or cancer-related gene mutation between the two groups. Although there was no difference in the frequency of genetic alterations between tumors with evidence of multiploidy, sorting of diploid and aneuploid populations allowed detection of distinct genetic changes. The crypt isolation method thus appears to be useful in that it allows purification of tumor cells and the accurate assessment of their genetic alterations. In addition, it may also be of benefit in clarifying the genetic profile of multiploid tumor cell populations. [source] Gene expression profiling of colorectal cancer and metastases divides tumours according to their clinicopathological stageTHE JOURNAL OF PATHOLOGY, Issue 1 2004Astrid Koehler Abstract Gene expression profiling of matched colorectal carcinomas and metastases could reveal key molecular events involved in tumour progression and metastasis. Expression profiles have been created from 25 colorectal carcinomas (CRCs, pT1,4), corresponding normal colonic mucosa, and 14 liver metastases using cDNA arrays containing 1176 cancer-related genes (Clontech). Hierarchical clustering clearly distinguished carcinomas from non-cancerous tissues, separated tumours into high-stage (pT4 and extensive lymph node or distant metastases) and low-stage (,pT3) groups, and correlated with the histopathological classification in 87% (33/38 cases). Most primary tumours and matched liver metastases clustered on terminal branches of the dendrogram. Statistical analysis (Mann,Whitney U -test) revealed 40 tumour-specific genes (29 up-regulated, 11 down-regulated) which allowed identification of malignant tissue samples by cluster analysis. A specific expression signature in matching metastases was not found, but a set of 23 classifier genes with statistically significant expression patterns in high- and low-stage tumours was identified. These genes may represent important targets in colorectal carcinogenesis and might provide useful clinicopathological tools in the management of colorectal cancer. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Vitamin D receptor (VDR) gene polymorphisms and haplotypes, interactions with plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and prostate cancer riskTHE PROSTATE, Issue 9 2007Bahar Mikhak Abstract BACKGROUND The vitamin D receptor (VDR) is required for actions of vitamin D. The binding of 1,25-dihydroxyvitamin D to the VDR on prostatic epithelial cells prompts the regulation of cancer-related genes. METHODS We conducted a nested case-control study in the Health Professionals Follow-up Study to investigate the role of the VDR Cdx2, Fok1, and Bsm1 gene polymorphisms and associated haplotypes and their interaction with plasma vitamin D metabolites in relation to prostate cancer (PC) risk. RESULTS No association was found between these SNPs or their associated haplotypes and all PC subtypes except that haplotype 2 (A-f-b) with Cdx2 A, Fok1 f, and Bsm1 b alleles and haplotype 3 (A-F-B) with Cdx2 A, Fok1 F and Bsm1 B alleles compared to the most common haplotype (A-F-b), were associated with reduced risk of aggressive PC (high stage or Gleason sum ,7; P,=,0.02), both with two alleles suspected of being low risk. Carriers of the variant Cdx2 A allele who were deficient in plasma 25-hydroxyvitamin D (,15 ng/ml) compared to non-carriers with normal 25-hydroxyvitamin D, had a lower risk of total and poorly differentiated PCs (Gleason sum ,7) (P for interaction,=,0.02 and 0.04, respectively). Plasma 1,25-dihydroxyvitamin D deficiency (,26 pg/ml) was associated with a threefold risk of poorly differentiated PC (P for interaction,=,0.01) when comparing carriers of the Cdx2 A allele to non-carriers with normal 1,25-dihydroxyvitamin D. CONCLUSION In this population of men, none of the VDR polymorphisms studied was associated with susceptibility to PC. Prostate 67: 911,923, 2007. © 2007 Wiley-Liss, Inc. [source] Genetic and epigenetic alterations in the differential diagnosis of malignant melanoma and spitzoid lesionBRITISH JOURNAL OF DERMATOLOGY, Issue 6 2007M. Takata Summary Background, The histopathological differentiation of malignant melanoma and Spitz naevus often presents diagnostic problems. Objectives, We aimed to find out applicable diagnostic parameters other than routine pathology. Methods, The cases included conventional melanomas and Spitz naevi as well as atypical spitzoid lesions that had posed diagnostic difficulties. We examined hotspots of mutation in the BRAF, NRAS and HRAS genes by polymerase chain reaction-based direct sequencing. We also analysed DNA copy number aberrations and the methylation of CpG sequences in several cancer-related genes by utilizing a novel methylation-specific multiplex ligation-dependent probe amplification method. Results, Twenty three of 24 conventional melanomas showed at least one of the genetic and epigenetic alterations examined, although one acral melanoma did not show any alteration. By sharp contrast, 12 Spitz naevi with an unambiguous histopathology showed no or few chromosomal aberrations, no oncogene mutations and no methylation of CpG sequences. Of the 16 ambiguous spitzoid lesions, most of which were designated atypical Spitz tumour by one of the authors, all but one showed no mutations, no methylations and few copy number aberrations. However, three tumours showed copy number loss of the cyclin-dependent kinase inhibitor 2A gene (CDKN2A), an alteration observed frequently in melanomas but not found in conventional Spitz naevi. These results show that, although most atypical Spitz tumours do not differ from conventional Spitz naevi showing virtually no genetic and epigenetic aberrations, some cases may have chromosomal aberrations that include copy number loss of the CDKN2A gene. Conclusions, Genetic and epigenetic analyses may be useful as an additional diagnostic tool to distinguish between melanoma and Spitz naevus, and may help to define subgroups in atypical Spitz tumours. [source] MutationView/KMcancerDB: A database for cancer gene mutationsCANCER SCIENCE, Issue 3 2007Nobuyoshi Shimizu It is known that cancers are caused by accumulated mutations in various genes and consequent functional alterations of proteins that are important for maintenance of normal cellular functions. The changes in nucleotide sequences and expression patterns of cancer-related genes are being extensively studied to better understand the mechanisms of tumorigenesis and to develop methods for DNA protein diagnosis and drug discovery. At present, a number of computer databases for molecular information on cancer-related genes are available publicly through the internet. These databases deal with familial cancer and sporadic cancer at the levels of germline mutation or somatic mutation, genomic or chromosomal abnormalities, and changes in the expression levels of relevant genes. Previously, we constructed a human gene mutation database named MutationView (http://mutview.dmb.med.keio.ac.jp/) and have accumulated mutation data for ,300 genes that are involved mainly in monogenic diseases. Forty-two genes are cancer-related and therefore a separate cancer database named KMcancerDB was constructed. MutationView/KMcancerDB utilizes a graphic display function for both queries and search results much more often than other existing databases, making the system quite user friendly. MutationView/KMcancerDB provides a highly sophisticated search function for all genes through a single internet URL. In the present paper, we briefly review various useful databases for cancer-related genes, and describe MutationView/KMcancerDB in more detail. (Cancer Sci 2007; 98: 259,267) [source] ETS transcription factors: Possible targets for cancer therapyCANCER SCIENCE, Issue 8 2004Tsuneyuki Oikawa Ets family (ETS) transcription factors, characterized by an evolutionally conserved Ets domain, play important roles in cell development, cell differentiation, cell proliferation, apoptosis and tissue remodeling. Most of them are downstream nuclear targets of Ras-MAP kinase signaling, and the deregulation of ETS genes results in the malignant transformation of cells. Several ETS genes are rearranged in human leukemia and Ewing tumors to produce chimeric oncoproteins. Furthermore, the aberrant expression of several ETS genes is often observed in various types of human malignant tumors. Considering that some ETS transcription factors are involved in malignant transformation and tumor progression, including invasion, metastasis and neo-angiogenesis through the activation of cancer-related genes, they could be potential molecular targets for selective cancer therapy. [source] Conditional gene silencing utilizing the lac repressor reveals a role of SHP-2 in cagA -positive Helicobacter pylori pathogenicityCANCER SCIENCE, Issue 5 2004Megumi Higuchi RNA interference (RNAi) is a newly described biological phenomenon mediated by small interfering RNA (siRNA) that targets mRNA for degradation by cellular enzymes and has become a powerful method for studying gene functions in mammalian systems. The development of systems for inducing siRNA expression should enable examination of acute loss-of-function phenotypes in a cell of interest without the need to consider lethality or epigenetic adaptation of cells. We describe in this report an inducible siRNA expression system made by combined utilization of the RNA polymerase III-dependent promoter H1 and the bacterial lac repressor. Using this system, we established AGS gastric epithelial cells in which expression of SHP-2, a cellular tyrosine phosphatase known to specifically bind the Helicobacter pylori virulence factor CagA, is conditionally and reversibly silenced by the lactose analog isopropyl-1-thio-,-D-galactopyranoside (IPTG). Upon expression in AGS cells, CagA provoked a morphological transformation, termed the hummingbird phenotype, which is associated with CagA virulence. This morphogenetic activity of CagA was totally abolished when SHP-2 expression was silenced by inducible siRNA expression in AGS cells. Our results indicate that SHP-2 is a critical downstream effector of H. pylori CagA. The conditional gene silencing system described here should become a powerful tool for investigating the roles of cancer-related genes through a reversed genetic approach. [source] Aberrant methylation of the vascular endothelial growth factor receptor-1 gene in prostate cancerCANCER SCIENCE, Issue 6 2003Yasushi Yamada Transcriptional silencing of cancer-related genes by DNA methylation is observed in various cancers. To identify genes controlled by methylation in prostate cancer, we used cDNA microarray analysis to investigate gene expression in prostate cancer cell lines LNCaP and DU145 treated with a methyltransferase inhibitor alone or together with a histone deacetylase inhibitor. We detected significant changes (3.4,5.7%) in gene expression in prostate cancer cell lines with the drug treatments. Among the affected genes, that for the vascular endothelial growth factor receptor 1 (VEGFR-1) was re-expressed in LNCaP and DU145 after the drug treatments. Bisulfite sequencing revealed the promoter and exon 1 of the VEGFR-1 to be hypermethylated in the cell lines. These results support the idea that methylation is associated with loss of VEGFR-1 mRNA expression in prostate cancer cell lines. Combined bisulfite restriction analysis (COBRA) showed the gene to be methylated in 24 (38.1%) of 63 primary local prostate cancer samples, while in all 13 benign prostate samples it was not. These findings indicate that methylation of VEGFR-1 is related with prostatic carcinogenesis. [source] | ||||||||||||||||||||||