Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genome wide DNA alterations were evaluated by array CGH in addition to RNA expression profiling in colorectal cancer from patients with excellent and poor survival following primary operations. DNA was used for CGH in BAC and cDNA arrays. Global RNA expression was determined by 44K arrays. DNA and RNA from tumor and normal colon were used from cancer patients grouped according to death, survival or Dukes A, B, C and D tumor stage. Confirmed DNA alterations in all Dukes A - D were judged relevant for carcinogenesis, while changes in Dukes C and D only were regarded relevant for tumor progression. Copy number gain was more common than loss in tumor tissue (p < 0.01). Major tumor DNA alterations occurred in chromosome 8, 13, 18 and 20, where short survival included gain in 8q and loss in 8p. Copy number gains related to tumor progression were most common on chromosome 7, 8, 19, 20, while corresponding major losses appeared in chromosome 8. Losses at chromosome 18 occurred in all Dukes stages. Normal colon tissue from cancer patients displayed gains in chromosome 19 and 20. Mathematical Vector analysis implied a number of BAC-clones in tumor DNA with genes of potential importance for death or survival. The genomic variation in colorectal cancer cells is tremendous and emphasizes that BAC array CGH is presently more powerful than available statistical models to discriminate DNA sequence information related to outcome. Present results suggest that a majority of DNA alterations observed in colorectal cancer are secondary to tumor progression. Therefore, it would require an immense work to distinguish primary from secondary DNA alterations behind colorectal cancer.
 ...
PMID:Tumor genome wide DNA alterations assessed by array CGH in patients with poor and excellent survival following operation for colorectal cancer. 1945 53

Although human embryonic stem cells (hESC) have been shown to present a stable diploid karyotype, many studies have reported that depending on culture conditions they become prone to acquire chromosomal anomalies such as addition of whole or parts of chromosomes. Indeed, during long-term culture, karyotypic alterations are observed when enzymatic or chemical dissociation are used, while manual dissection of colonies for passaging retains a stable karyotype. Besides, changes in the environment such as the removal of feeder cells also seem to compromise the genetic integrity of hESC. Once chromosomal alterations could affect cellular physiology, the characterization of the genetic integrity of hESC in vitro is crucial considering hESC as an essential tool in embryogenesis studies and drug testing. Furthermore, for future therapeutic purposes chromosomal changes are a real concern as it is frequently associated to carcinogenesis. Here we show a simple and useful method to obtain high quality chromosome spreads for subsequent analysis of chromosome set by G-banding, FISH, SKY or CGH techniques. We recommend checking the chromosomal status routinely with intervals of 5 passages in order to monitor the appearance of translocations and aneuploidies.
 ...
PMID:Chromosomal spread preparation of human embryonic stem cells for karyotyping. 1973 41

Aurora kinase A (Aurora-A) belongs to a highly conserved family of mitotis-regulating serine/threonine kinases implicated in epithelial cancers. Initially we examined Aurora-A expression levels at different stages of human skin cancer. Nuclear Aurora-A was detected in benign lesions and became more diffused but broadly expressed in well and poorly differentiated squamous cell carcinomas (SCC), indicating that Aurora-A deregulation may contribute to SCC development. To mimic the overexpression of Aurora-A observed in human skin cancers, we established a gene-switch mouse model in which the human variant of Aurora-A (Phe31Ile) was expressed in the epidermis upon topical application of the inducer RU486 (Aurora-AGS). Overexpression of Aurora-A alone or in combination with the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA), did not result in SCC formation in Aurora-AGS mice. Moreover, Aurora-A overexpression in naive keratinocytes resulted in spindle defects in vitro and marked cell death in vivo, suggesting that the failure of Aurora-A to initiate tumorigenesis was due to induction of catastrophic cell death. However, Aurora-A overexpression combined with exposure to TPA and the mutagen 7,12-dimethylbenz(a)anthracene accelerated SCC development with greater metastatic activity than control mice, indicating that Aurora-A cannot initiate skin carcinogenesis but rather promotes the malignant conversion of skin papillomas. Further characterization of SCCs revealed centrosome amplification and genomic alterations by array CGH analysis, indicating that Aurora-A overexpression induces a high level of genomic instability that favors the development of aggressive and metastatic tumors. Our findings strongly implicate Aurora-A overexpression in the malignant progression of skin tumors and suggest that Aurora-A may be an important therapeutic target.
 ...
PMID:A genetic variant of Aurora kinase A promotes genomic instability leading to highly malignant skin tumors. 1973 56

Cancer of the ovary is bilateral in 25%. Cytogenetic analysis could determine whether the disease in bilateral cases is metastatic or two separately occurring primary tumors, but karyotypic information comparing the two cancerous ovaries is limited to a single report with 11 informative cases. We present a series of 32 bilateral ovarian carcinoma cases, analyzed by karyotyping and high-resolution CGH. Our karyotypic findings showed that spreading to the contralateral ovary had occurred in bilateral ovarian cancer cases and that it was a late event in the clonal evolution of the tumors. This was confirmed by the large number of similar changes detected by HR-CGH in the different lesions from the same patient. The chromosomal bands most frequently involved in structural rearrangements were 19p13 (n = 12) and 19q13 (n = 11). The chromosomal bands most frequently gained by both tumorous ovaries were 5p14 (70%), 8q23-24 (65%), 1q23-24 (57%), and 12p12 (48%), whereas the most frequently lost bands were 17p11 (78%), 17p13 (74%), 17p12 (70%), 22q13 (61%), 8p21 and 19q13 (52%), and 8p22-23 (48%). This is the first time that 5p14 is seen gained at such a high frequency in cancer of the ovary; possibly oncogene(s) involved in bilateral ovarian carcinogenesis or tumor progression may reside in this band.
 ...
PMID:Tumor spreading to the contralateral ovary in bilateral ovarian carcinoma is a late event in clonal evolution. 1975 43

Gene copy number aberrations are involved in oral squamous cell carcinoma (OSCC) development. To delineate candidate genes inside critical chromosomal regions, array-CGH was applied to 40 OSCC specimens using a microarray covering the whole human genome with an average resolution of 1 Mb. Gene copy number gains were predominantly found at 1q23 (9 cases), 3q26 (11), 5p15 (13), 7p11 (7), 8q24 (17), 11q13 (15), 14q32 (8), 19p13 (8), 19q12 (7), 19q13 (8), and 20q13 (9), whereas gene copy number losses were detected at 3p21-3p12 (15), 8p32 (11), 10p12 (8), and 18q21-q23 (10). Subsequent mRNA expression analyses by quantitative real time polymerase chain reaction found high mRNA expression of candidate genes SOX2 in 3q26.33, FSLT3 in 19p13.3, and CCNE1 in 19q12. Tissue microarray (TMA) analyses in a representative OSCC collection found gene copy number gain for SOX2 in 52% (115/223) and for CCNE1 in 31% (72/233) of the tumors. Immunohistochemical analyses on TMA sections of the corresponding proteins detected high expression of SOX2 in 18.1% (49/271) and of CyclinE1 in 23.3% (64/275) of tumors analyzed. These findings indicate that SOX2 and CCNE1 might be activated via gene copy number gain and participate in oral carcinogenesis. The combination of array-CGH with TMA analyses allows rapid pinpointing of novel promising candidate genes, which might be used as therapeutic stratification markers or target molecules for therapeutic interference.
 ...
PMID:Recurrent copy number gain of transcription factor SOX2 and corresponding high protein expression in oral squamous cell carcinoma. 1978 84

Cancer is a multifaceted disease that results from dysregulated normal cellular signaling networks caused by genetic, genomic and epigenetic alterations at cell or tissue levels. Uncovering the underlying protein signaling network changes, including cell cycle gene networks in cancer, aids in understanding the molecular mechanism of carcinogenesis and identifies the characteristic signaling network signatures unique for different cancers and specific cancer subtypes. The identified signatures can be used for cancer diagnosis, prognosis, and personalized treatment. During the past several decades, the available technology to study signaling networks has significantly evolved to include such platforms as genomic microarray (expression array, SNP array, CGH array, etc.) and proteomic analysis, which globally assesses genetic, epigenetic, and proteomic alterations in cancer. In this review, we compared Pathway Array analysis with other proteomic approaches in analyzing protein network involved in cancer and its utility serving as cancer biomarkers in diagnosis, prognosis and therapeutic target identification. With the advent of bioinformatics, constructing high complexity signaling networks is possible. As the use of signaling network-based cancer diagnosis, prognosis and treatment is anticipated in the near future, medical and scientific communities should be prepared to apply these techniques to further enhance personalized medicine.
 ...
PMID:Proteomics, pathway array and signaling network-based medicine in cancer. 1986 13

It is now understood that epigenetic alterations occur frequently in sporadic breast carcinogenesis, but little is known about the epigenetic alterations associated with familial breast tumors. We performed genome-wide DNA-methylation profiling on familial breast cancers (n = 33) to identify patterns of methylation specific to the different mutation groups (BRCA1, BRCA2, and BRCAx) or intrinsic subtypes of breast cancer (basal, luminal A, luminal B, HER2-amplified, and normal-like). We used methylated DNA immunoprecipitation (MeDIP) on Affymetrix promoter chips to interrogate methylation profiles across 25,500 distinct transcripts. Using a support vector machine classification algorithm, we demonstrated that genome-wide methylation profiles predicted tumor mutation status with estimated error rates of 19% (BRCA1), 31% (BRCA2), and 36% (BRCAx) but did not accurately predict the intrinsic subtypes defined by gene expression. Furthermore, using unsupervised hierarchical clustering, we identified a distinct subgroup of BRCAx tumors defined by methylation profiles. We validated these findings in the 33 tumors in the test set, as well as in an independent validation set of 47 formalin-fixed, paraffin-embedded familial breast tumors, by pyrosequencing and Epityper. Finally, gene-expression profiling and SNP CGH array previously performed on the same samples allowed full integration of methylation, gene-expression, and copy-number data sets, revealing frequent hypermethylation of genes that also displayed loss of heterozygosity, as well as of genes that show copy-number gains, providing a potential mechanism for expression dosage compensation. Together, these data show that methylation profiles for familial breast cancers are defined by the mutation status and are distinct from the intrinsic subtypes.
 ...
PMID:DNA methylome of familial breast cancer identifies distinct profiles defined by mutation status. 2020 35

Chromosomal amplifications and deletions are thought to be important events in spontaneous and radiation-induced carcinogenesis. To clarify how ionizing radiation induces mammary carcinogenesis, we characterized genomic copy number aberrations for gamma-ray-induced rat mammary carcinomas using microarray-based comparative genomic hybridization. We examined 14 carcinomas induced by gamma radiation (2 Gy) and found 26 aberrations, including trisomies of chromosomes 4 and 10 for three and one carcinomas, respectively, an amplification of the chromosomal region 1q12 in two carcinomas, and deletions of the chromosomal regions 3q35q36, 5q32 and 7q11 in two, two and four carcinomas, respectively. These aberrations were not observed in seven spontaneous mammary carcinomas. The expression of p16Ink4a and p19Arf, which are located in the chromosomal region 5q32, was always up-regulated except for a carcinoma with a homozygous deletion of region 5q32. The up-regulation was not accounted for by gene mutations or promoter hypomethylation. However, the amounts of Rb and its mRNA were down-regulated in these carcinomas, indicating a disruption of the p16Ink4a/Rb pathway. This is the first report of array CGH analysis for radiation-induced mammary tumors, which reveals that they show distinct DNA copy number aberration patterns that are different from those of spontaneous tumors and those reported previously for chemically induced tumors.
 ...
PMID:DNA copy number aberrations and disruption of the p16Ink4a/Rb pathway in radiation-induced and spontaneous rat mammary carcinomas. 2068 87

Alterations of chromosome 19 are among the most frequent cytogenetic changes in ovarian carcinomas. They usually occur as added extra material of unknown origin to 19p or, less frequently, 19q but sometimes as homogeneously staining regions. The precise nature of these markers, i.e., exactly which regions of chromosome 19 are involved and from which chromosome(s) the additional material comes, could only rarely be established. We have investigated by high resolution array-CGH a series of 29 chromosome 19 markers after previous microdissection of ovarian carcinoma metaphases followed by FISH to determine where in chromosome 19 the rearrangements took place as well as from which partner chromosomes the additional material stems, obtaining informative results on 23 markers from 18 carcinomas. Along the entire chromosome 19, a total of nine regions were found gained in 10 or more carcinomas (from 10 to 16) whereas 15 regions were gained in 6 to 10 markers. The most commonly gained region (16 markers) was observed in 19p13 between 20.80 Mbp and 20.85 Mbp from 19pter. According to the human genome 18 (hg18) NCBI 36, a total of 43 genes reside in the most commonly gained regions. Most of them (n = 31) code for zinc finger proteins. None of these genes is known to be involved in human neoplasia (the only exception is the ZNF91, which is found highly expressed in seminomas) but their frequent gain in the examined tumors makes all of them candidates for a pathogenetic role in ovarian carcinogenesis.
 ...
PMID:Array-CGH analysis of microdissected chromosome 19 markers in ovarian carcinoma identifies candidate target genes. 2072 91

Cancer susceptibility is due to interactions between inherited genetic factors and exposure to environmental carcinogens. The genetic component is constituted mainly by weakly acting low-penetrance genetic variants that interact among themselves, as well as with the environment. These low susceptibility genes can be categorized into two main groups: one includes those that control intrinsic tumor cell activities (i.e. apoptosis, proliferation or DNA repair), and the other contains those that modulate the function of extrinsic tumor cell compartments (i.e. stroma, angiogenesis, or endocrine and immune systems). Genome-Wide Association Studies (GWAS) of human populations have identified numerous genetic loci linked with cancer risk and behavior, but nevertheless the major component of cancer heritability remains to be explained. One reason may be that GWAS cannot readily capture gene-gene or gene-environment interactions. Mouse model approaches offer an alternative or complementary strategy, because of our ability to control both the genetic and environmental components of risk. Recently developed genetic tools, including high-throughput technologies such as SNP, CGH and gene expression microarrays, have led to more powerful strategies for refining quantitative trait loci (QTL) and identifying the critical genes. In particular, the cross-species approaches will help to refine locations of QTLs, and reveal their genetic and environmental interactions. The identification of human tumor susceptibility genes and discovery of their roles in carcinogenesis will ultimately be important for the development of methods for prediction of risk, diagnosis, prevention and therapy for human cancers.
 ...
PMID:Cancer evolution and individual susceptibility. 2126 4


<< Previous 1 2 3 4 5 Next >>