Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cancer genomics”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 343 records · Page 19Linked to original sources
PubMed2025

CCDC137 knockdown suppresses bladder cancer progression by downregulating SCD.

BACKGROUND: The Coiled-coil domain-containing (CCDC) family, due to its unique protein structural domain and broad involvement in diverse biological processes, has emerged as a focus in oncology research. Nevertheless, its clinical significance and function in bladder cancer (BLCA) remain poorly defined. METHODS: Machine learning algorithms were employed to identify pivotal CCDC genes in the cancer genome atlas (TCGA), and a prognostic model was subsequently constructed. Multi-omics data encompassing pan-cancer cohorts, single-cell sequencing, and spatial transcriptomics were integrated to characterize the expression patterns and prognostic significance of Coiled-coil domain-containing 137 (CCDC137), a previously uncharacterized CCDC family member in BLCA. Tissue microarray confirmed CCDC137 abnormal expression in bladder carcinoma specimens. The effect of CCDC137 knockdown on BLCA progression was evaluated through CCK8 assay, clonogenic formation, wound healing, Transwell, and subcutaneous xenograft models. RNA sequencing, quantitative RT-PCR, and western blot were utilized to delineate its regulatory network. RESULTS: A prognostic model incorporating 10 CCDC genes was successfully established in the TCGA-BLCA cohort. Then, we found that CCDC137 exhibited pan-cancer overexpression and usually correlation with poor clinical outcomes. Immunohistochemistry further substantiated its dysregulation in bladder carcinoma. Integrated multi-omics analyses suggested associations between CCDC137 expression and a tumor immunosuppressive microenvironment. CCDC137 knockdown significantly suppressed bladder cancer cell proliferation and migratory capacity in vitro. Correspondingly, subcutaneous xenograft tumor growth was inhibited in vivo. Moreover, decreased expression of stearoyl-CoA desaturase (SCD), a key lipid metabolic enzyme, accompanied CCDC137 depletion. These findings collectively suggest a cancer-promoting role for CCDC137 in bladder carcinoma. CONCLUSIONS: This systematic investigation combining multi-omics bioinformatics analyses and experimental validation demonstrates the role of CCDC137 in bladder carcinoma progression, providing novel mechanistic insights into the pathogenesis of BLCA and offering a theoretical foundation for therapeutic targeting of CCDC137 in urothelial malignancies.

Urinary Bladder Neoplasms↗
PubMed2025

Rhythm profiling using COFE reveals multi-omic circadian rhythms in human cancers in vivo.

The study of ubiquitous circadian rhythms in human physiology requires regular measurements across time. Repeated sampling of the different internal tissues that house circadian clocks is both practically and ethically infeasible. Here, we present a novel unsupervised machine learning approach (COFE) that can use single high-throughput omics samples (without time labels) from individuals to reconstruct circadian rhythms across cohorts. COFE can simultaneously assign time labels to samples and identify rhythmic data features used for temporal reconstruction, while also detecting invalid orderings. With COFE, we discovered widespread de novo circadian gene expression rhythms in 11 different human adenocarcinomas using data from The Cancer Genome Atlas (TCGA) database. The arrangement of peak times of core clock gene expression was conserved across cancers and resembled a healthy functional clock except for the mistiming of a few key genes. Moreover, rhythms in the transcriptome were strongly associated with the cancer-relevant proteome. The rhythmic genes and proteins common to all cancers were involved in metabolism and the cell cycle. Although these rhythms were synchronized with the cell cycle in many cancers, they were uncoupled with clocks in healthy matched tissue. The targets of most of FDA-approved and potential anti-cancer drugs were rhythmic in tumor tissue with different amplitudes and peak times. These findings emphasize the utility of considering "time" in cancer therapy, and suggest a focus on clocks in healthy tissue rather than free-running clocks in cancer tissue. Our approach thus creates new opportunities to repurpose data without time labels to study circadian rhythms.

Humans↗
PubMed2026

Methyltransferase 3 promotes v-set and transmembrane domain-containing 2-like protein expression to intensify ferroptosis-mediated prostate adenocarcinoma progression through the m6A methylation modification.

BACKGROUND: Prostate adenocarcinoma (PRAD) is a common malignancy with high incidence in men. The role of v-set and transmembrane domain-containing 2-like protein (VSTM2L) in PRAD remains largely unreported. METHODS: Gene expression was analyzed using The Cancer Genome Atlas (TCGA), the Tumor Immune Estimation Resource (TIMER) 2.0, and the University of Alabama at Birmingham CANcer data analysis Portal (UALCAN) databases, and validated by quantitative real-time PCR (qRT-PCR) and western blot. Cell proliferation was assessed by 5-ethynyl-2'-deoxyuridine (EdU) staining. Apoptosis and mitochondrial membrane potential were examined by flow cytometry. Intracellular iron, Fe2+, and reactive oxygen species (ROS) levels were measured using commercial kits and flow cytometry. The role of VSTM2L in tumor growth was evaluated using xenograft mouse models, with protein expression in tumors evaluated by immunohistochemistry (IHC). The N6-methyladenosine (m6A) modification sites on VSTM2L mRNA were predicted using the sequence-based RNA adenosine methylation site predictor (SRAMP) website. The interaction between methyltransferase 3 (METTL3) and VSTM2L was confirmed by methylated RNA immunoprecipitation (MeRIP) and dual-luciferase reporter assay. Correlation analysis was performed using the TCGA database. RESULTS: VSTM2L was overexpressed in PRAD tissues and cell lines. Silencing VSTM2L inhibited PRAD cell proliferation, promoted apoptosis, and enhanced ferroptosis and oxidative stress in vitro. Consistently, VSTM2L knockdown suppressed tumor growth in vivo. Mechanically, METTL3 mediated m6A methylation to stabilize VSTM2L mRNA. Furthermore, METTL3 promoted proliferation and inhibited apoptosis, ferroptosis, and oxidative stress in PRAD cells via a VSTM2L-dependent manner. CONCLUSION: METTL3 promotes PRAD progression by stabilizing VSTM2L expression through m6A methylation, thereby inhibiting ferroptosis. This study establishes a direct link between RNA methylation and ferroptosis in PRAD, revealing the METTL3/VSTM2L axis as a novel regulatory pathway and a potential therapeutic target.

Male↗
PubMed2005

An integrated mBAND and submegabase resolution tiling set (SMRT) CGH array analysis of focal amplification, microdeletions, and ladder structures consistent with breakage-fusion-bridge cycle events in osteosarcoma.

Osteosarcoma (OS) is characterized by chromosomal instability and high-copy-number gene amplification. The breakage-fusion-bridge (BFB) cycle is a well-established mechanism of genomic instability in tumors and in vitro models used to study the origins of complex chromosomal rearrangements and cancer genome amplification. However, until now, there have been no high-resolution cytogenetic or genomic array studies of BFB events in OS. In the present study, multicolor banding (mBAND) FISH and submegabase resolution tiling set (SMRT) array comparative genomic hybridization (CGH) were used to identify and map genomic signatures of BFB events in four OS cell lines and one patient tumor. The expected intermediates associated with BFB-dicentric chromosomes, inverted duplications, and intra- and interchromosomal amplifications-were identified. mBAND analysis provided detailed mapping of rearrangements in 1p, 6p, and 8q and showed that translocation junctions were often in close proximity to fragile sites. More detailed mBAND studies of OS cell line MG-63 revealed ladderlike FISH signals of equally spaced interchromosomal coamplifications of 6p21, 8q24, and 9p21-p22 in a homogeneously staining region (hsr). Focal amplifications that concordantly mapped to the hsr were localized to discrete genomic intervals by SMRT array CGH. The complex amplicon structure in this hsr suggests focal amplifications immediately adjacent to microdeletions. Moreover, the genomic regions in which there was deletion/amplification had a preponderance of fragile sites. In summary, this study has provided further support for the role of the BFB mechanism and fragile sites in facilitating gene amplification and chromosomal rearrangement in OS.

Cell Line, Tumor↗
PubMed2006

The breakage-fusion-bridge (BFB) cycle as a mechanism for generating genetic heterogeneity in osteosarcoma.

Osteosarcoma (OS) is characterized by chromosomal instability and high copy number gene amplification. The breakage-fusion-bridge (BFB) cycle is a well-established mechanism of genome instability in tumors and in vitro models used to study the origins of complex chromosomal rearrangements and cancer genome amplification. To determine whether the BFB cycle could be increasing the de novo rate of formation of cytogenetic aberrations in OS, the frequency of anaphase bridge configurations and dicentric chromosomes in four OS cell lines was quantified. An increased level of anaphase bridges and dicentrics was observed in all the OS cell lines. There was also a strong association between the frequencies of anaphase bridges, dicentrics, centrosomal anomalies, and multipolar mitotic figures in all the OS cell lines, indicating a possible link in the mechanisms that led to the structural and numerical instabilities observed in OS. In summary, this study has provided strong support for the role of the BFB cycle in generating the extensive structural chromosome aberrations, as well as cell-to-cell cytogenetic variation observed in OS, thus conferring the genetic diversity for OS tumor progression.

Anaphase↗
PubMed2025

iSoMAs: Finding isoform expression and somatic mutation associations in human cancers.

Aberrant alternative splicing, prevalent in cancer, impacts various cancer hallmarks involving proliferation, angiogenesis, and invasion. Splicing disruption often results from somatic point mutations rewiring functional pathways to support cancer cell survival. We introduce iSoMAs (iSoform expression and somatic Mutation Association), an efficient computational pipeline leveraging principal component analysis technique, to explore how somatic mutations influence transcriptome-wide gene expression at the isoform level. Applying iSoMAs to 33 cancer types comprising 9,738 tumor samples in The Cancer Genome Atlas, we identified 908 somatically mutated genes significantly associated with altered isoform expression across three or more cancer types. Mutations linked to differential isoform expression occurred through both cis- and trans-acting mechanisms, involving well-known oncogenes/suppressor genes, RNA binding protein and splicing factor genes. With wet-lab experiments, we verified direct association between TP53 mutations and differential isoform expression in cell cycle genes. Additional iSoMAs genes have been validated in the literature with independent cohorts and/or methods. Despite the complexity of cancer, iSoMAs attains computational efficiency via dimension reduction strategy and reveals critical associations between regulatory factors and transcriptional landscapes.

Humans↗
PubMed2024

Assessment of Gene Set Enrichment Analysis using curated RNA-seq-based benchmarks.

Pathway enrichment analysis is a ubiquitous computational biology method to interpret a list of genes (typically derived from the association of large-scale omics data with phenotypes of interest) in terms of higher-level, predefined gene sets that share biological function, chromosomal location, or other common features. Among many tools developed so far, Gene Set Enrichment Analysis (GSEA) stands out as one of the pioneering and most widely used methods. Although originally developed for microarray data, GSEA is nowadays extensively utilized for RNA-seq data analysis. Here, we quantitatively assessed the performance of a variety of GSEA modalities and provide guidance in the practical use of GSEA in RNA-seq experiments. We leveraged harmonized RNA-seq datasets available from The Cancer Genome Atlas (TCGA) in combination with large, curated pathway collections from the Molecular Signatures Database to obtain cancer-type-specific target pathway lists across multiple cancer types. We carried out a detailed analysis of GSEA performance using both gene-set and phenotype permutations combined with four different choices for the Kolmogorov-Smirnov enrichment statistic. Based on our benchmarks, we conclude that the classic/unweighted gene-set permutation approach offered comparable or better sensitivity-vs-specificity tradeoffs across cancer types compared with other, more complex and computationally intensive permutation methods. Finally, we analyzed other large cohorts for thyroid cancer and hepatocellular carcinoma. We utilized a new consensus metric, the Enrichment Evidence Score (EES), which showed a remarkable agreement between pathways identified in TCGA and those from other sources, despite differences in cancer etiology. This finding suggests an EES-based strategy to identify a core set of pathways that may be complemented by an expanded set of pathways for downstream exploratory analysis. This work fills the existing gap in current guidelines and benchmarks for the use of GSEA with RNA-seq data and provides a framework to enable detailed benchmarking of other RNA-seq-based pathway analysis tools.

Humans↗
PubMed2026

Reduced VEPH1 expression is associated with an invasive phenotype and poor prognosis in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) remains a clinically heterogeneous urologic malignancy, and improved biomarkers are needed to refine prognostic stratification. VEPH1 has been implicated in cancer biology, but its role in ccRCC is incompletely defined. This study aimed to investigate the expression, prognostic relevance, and functional effects of VEPH1 in ccRCC. METHODS: VEPH1 transcript expression and prognostic relevance were evaluated using The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) dataset and the University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) and validated in paired ccRCC and adjacent normal renal tissues. The ability of VEPH1 transcript expression to distinguish tumor from normal tissues within the TCGA-KIRC dataset was assessed by receiver operating characteristic analysis. Gain- and loss-of-function experiments were performed in 786-O and 769-P ccRCC cells to determine the effects of VEPH1 on epithelial-mesenchymal transition (EMT)-related markers, migration, and invasion. AKT and ERK phosphorylation was evaluated by western blotting. RESULTS: VEPH1 transcript expression was significantly lower in ccRCC tissues than in normal renal tissues and distinguished tumor from normal samples within the TCGA-KIRC dataset. Low VEPH1 transcript expression was associated with poorer overall survival. Validation in 11 paired clinical specimens confirmed reduced VEPH1 messenger RNA (mRNA) and VEPH1 protein expression in tumor tissues. Functionally, VEPH1 overexpression increased E-cadherin, decreased N-cadherin, and suppressed migration and invasion, whereas partial VEPH1 knockdown produced the opposite changes. In exploratory signaling analyses, VEPH1 overexpression was associated with reduced AKT and ERK phosphorylation without altering total AKT or ERK levels. CONCLUSIONS: Reduced VEPH1 transcript expression was associated with poorer overall survival, whereas experimental VEPH1 depletion was associated with invasive and EMT-related features in ccRCC cells. VEPH1 may represent a candidate prognostic indicator in ccRCC; however, its relationship with AKT and ERK signaling and its clinical relevance require further mechanistic and independent-cohort validation.

Clear cell renal cell carcinoma (ccRCC)↗
PubMed2005

[Markers for diagnosis, prediction and prognosis of prostate cancer].

BACKGROUND: Prostate cancer is the most frequent new cancer diagnosis in the western world today. There is an urgent need to obtain validated molecular markers that can identify clinically significant prostate cancer. MATERIAL AND METHODS: The article represents our view of the current status of molecular markers in diagnosis of prostate cancer based on literature searches (PubMed). RESULTS AND INTERPRETATION: Prostate specific antigen (PSA) is a sensitive serum marker for pathology in the prostate (cancer, infection, benign hyperplasia). The level of PSA, however, is poorly correlated with grade and stage of prostate cancer. Genomic and proteomic methodology has recently been used to discover more then 200 putative new markers for prostate cancer like alpha-methylacyl CoA racemase (AMACR), hepsin, glutathione S-transferase pi, EZH2 and DD3(PCA3). To date, none of these markers have been adequately validated for clinical use. Knowledge about the role of these candidates in prostate cancer biology and evaluation of their correlation to clinical parameters will be of importance in the validation process.

Biomarkers, Tumor↗
PubMed2003

Chromatin as a tool for the study of genome function in cancer.

The transition to malignancy requires an extensive reconfiguration of the genome's expression program that does not result entirely from actual changes in primary DNA sequence-i.e., mutation. Epigenetic-meta-DNA-gene expression states result from an assembly over a given locus of a poorly understood nucleoprotein entity that includes histones and other architectural components of chromatin, nonhistone DNA-bound regulators, and additional chromatin-bound polypeptides. This structure is rapidly reestablished in the wake of the DNA replication fork, thus ensuring its persistence in rapidly proliferating cells and thereby yielding an exceptionally stable mode of gene expression. Chromatin is the perfect vehicle for enabling such genome control. During S phase both covalently modified histones and histone-associated regulatory proteins distribute to the newly synthesized daughter chromatids in a form of "molecular dowry" inherited from the G(1) state of the genome, and impose a specific mode of function on the underlying DNA. An extensively studied example of chromatin-based epigenetic inheritance connects DNA methylation to the targeting of chromatin remodeling and modification. In a broad sense, however, genome reprogramming in cancer is associated with the remodeling of a multitude of regulatory DNA stretches-e.g., promoters, enhancers, locus control regions (LCRs), insulators, etc.-into a specific chromatin architecture. This architectural entity provides a general molecular signature of the cancer epigenome that complements and significantly expands its DNA methylation-based component.

Chromatin↗
PubMedDate not supplied

Clustering of molecular alterations in gastroesophageal carcinomas.

Gene expression levels are regulated at many levels. Integration of genome-wide analyses for the study of DNA and RNA provides a unique tool to detect genetic alterations in the cancer genome. In this study, we generated and integrated DNA amplification data from comparative genomic hybridization (CGH) and serial analyses of gene expression (SAGE) in order to obtain a molecular profile of gastroesophageal junction (GEJ) carcinomas. DNA amplifications mapped to specific chromosomal regions and were frequently seen at 1q, 4q, 5q, 6p, 7p, 8q, 17q, and 20q. Using SAGE, we obtained over 156,432 tags from GEJ adenocarcinomas and normal gastric mucosa. These tags were assigned to UniGene clusters. Chromosomal positions for overexpressed genes were obtained to produce a GEJ carcinoma transcriptome map. A total of 123 genes was significantly overexpressed (more than fivefold; P <.01) in one or more SAGE libraries. This gene overexpression map was integrated and compared to the chromosomal CGH ideogram. Several chromosomal arms that had frequent DNA amplifications showed frequent gene expression alterations such as chromosomes 1 (15 genes), 2 (9 genes), 6 (6 genes), 11 (6 genes), 12 (8 genes), and 17 (13 genes). Despite the relatively large DNA amplification regions, overexpressed genes frequently mapped and clustered to small chromosomal regions at early-replicating (Giemsa light) bands such as 1q21.3 (nine genes), 6p21.3 (five genes), and 17q21 (eight genes). These results provide a comprehensive tool to search for DNA amplifications and overexpressed genes in GEJ carcinoma. The observed phenomenon of the presence of large amplification areas, yet clustering of overexpressed genes to relatively small loci, may suggest a high organization of chromatin and cancer-related genes in the nucleus.

Adenocarcinoma↗
PubMed2025

What is on the Horizon Beyond Platinum and Immunotherapy for Patients With Advanced Non-Small Cell Lung Cancer Without Actionable Genomic Aberrations?

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide. While targeted therapy and immunotherapy have transformed first-line management, most patients without actionable genomic alterations (AGAs) will experience disease progression within the first year of their initial treatment. Here, we review pivotal trials, emerging strategies, challenges, and unmet needs for patients with advanced NSCLC without AGAs. Docetaxel with or without ramucirumab is the standard second-line therapy for patients who have progressed after platinum-based chemotherapy and immunotherapy. Targeted therapy is only suitable for patients with specific AGAs. Understanding the hallmarks of cancer immune evasion is key to developing new strategies beyond chemoimmunotherapy. The combination of antiangiogenic agents with immune checkpoint inhibitors (ICIs) has shown mixed results after progression on platinum and ICI. Bispecific antibodies, particularly ivonescimab, have shown encouraging early efficacy in this space. Artificial intelligence-driven pathomics and radiomics tools may help to refine treatment selection in the future. Chimeric antigen receptor T-cell therapy remains investigational. Patients with advanced NSCLC without AGAs who progressed after chemoimmunotherapy have limited treatment options. Novel therapies such as specific antibodies have shown promising results. Future progress will depend on the development of predictive biomarkers and understanding the mechanisms of resistance to ICIs to guide drug development.

Humans↗
PubMed2003

Immunotherapy for prostate cancer.

While androgen deprivation has remained the cornerstone of therapy for advanced prostate cancer over the last 60 years, novel therapies are being developed that may expand upon currently available treatments. The identification of antigens expressed by prostate tissue and/or prostate cancer that are recognized by T cells creates opportunities to develop novel immunotherapeutic approaches, including tumor vaccines. Improved understanding of immune recognition and antigen presentation may lead to effective immunotherapies for prostate cancer. Identified proteins expressed in prostate cancer, including prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), and prostate-specific membrane antigen (PSMA), have been used as immunologic targets for immunotherapy. Moreover, innovations in cancer genomics and proteomics will also aid in the identification of immunologic targets. Immunotherapy trials have already demonstrated evidence of not only immunogenicity, but also clinical efficacy, and future studies will be directed at capitalizing on these findings.

Acid Phosphatase↗
PubMed2006

Mining ORESTES no-match database: can we still contribute to cancer transcriptome?

The Human Cancer Genome Project generated about 1 million expressed sequence tags by the ORESTES method, principally with the aim of obtaining data from cancer. Of this total, 341,680 showed no similarity with sequences in the public transcript databases, referred to as "no-match". Some of them represent low abundance or difficult to detect human transcripts, but part of these sequences represent genomic contamination or immature mRNA. We performed a bioinformatics pipeline to determine the novelty of ORESTES "no-match" datasets from prostate or breast tissues. We started with 14,908 clusters mapped on the human genome. A total of 2226 clusters originating from more than two libraries or singletons with gaps upon genome alignment were selected. Ninety-four clusters with canonical splice sites representing the most stringent criteria to be considered a gene were subjected to manual inspection regarding genomic hits. Of the manually inspected clusters, 49.6% contained new sequences where 42.2% were probable low-expression alternative forms of the characterized genes and 7.4% unpredicted genes. RT-PCR followed by sequencing was performed to validate the largest spliced sequence from 8 clusters, resulting in the confirmation of five sequences as true human transcript fragments. Some of them were differentially expressed between tumor and normal tissue by an in silico analysis. We can conclude that after clean up of the no-match dataset, we still have about 939 new exons and 165 unpredicted genes that could complete the prostate or breast transcriptome.

Breast Neoplasms↗
PubMed2001

Detection of chromosomal alterations in bladder cancer by comparative genomic hybridization.

OBJECTIVES: To characterize which genomic alterations occur in bladder cancers of different grades and stages, and to evaluate the prognostic implication of chromosomal imbalances. Materials and methods Twelve transitional cell carcinoma cell lines were used to study chromosomal aberrations, using comparative genomic hybridization to examine metaphase cells. RESULTS: There was a mean of 6.0 aberrations per tumour with 4.9 gains and 1.08 deletions per tumour cell line. The mean number of aberrations was the same in grade 2 and 3 tumours. High-stage (>/= T2) carcinomas had markedly more genomic gains than had low-stage (T1) tumours, with 7.2 gains and 1.3 deletions per >/= T2 tumour, and 2.7 gains and 0.8 deletions per T1 tumour, although the difference was not statistically significant. The most frequent changes were gains of chromosome 1 (seven), 9 and 16 (six), and losses of chromosomes 14 (three), 21 and Y (two). The changes 1p+, 3p+, 9q+, 14p-, 16q+ and Yp- were significantly more frequent in low-grade tumours, with 1p+, 3p+ and Yq- the most frequent in stage T1 tumours, and 16p+, 9q+ and 13q- the most frequent in stage >/= T2 tumours. Conclusion These findings indicate several genomic regions in chromosomes 1, 9, 14 and 16 that may carry genes for the development and progression of bladder cancers.

Carcinoma, Transitional Cell↗
PubMed2006

RNA interference-based functional dissection of the 17q12 amplicon in breast cancer reveals contribution of coamplified genes.

DNA amplification is a frequent occurrence in cancer genomes. While tumor amplicons may harbor known oncogenes "driving" amplification, amplicons rarely comprise only single genes. The potential functional contribution of coamplified genes remains largely unexplored. In breast cancer, 20-30% of tumors exhibit amplification within chromosome band 17q12, containing the ERBB2 oncogene. Analysis of array-based comparative genomic hybridization and expression profiling data indicate that the minimum region of recurrent amplification (i.e., the amplicon "core") at 17q12 includes two other genes, GRB7 and STARD3, which exhibit elevated expression when amplified. Western blot analysis confirms overexpression of each at the protein level in breast cancer cell lines SKBR3 and BT474 harboring amplification. In these cell lines (but not in control MCF7 breast cancer cells lacking 17q12 amplification), targeted knockdown of ERBB2 expression using RNA interference (RNAi) methods results in decreased cell proliferation, decreased cell-cycle progression, and increased apoptosis. Notably, targeted knockdown of either GRB7 or STARD3 also leads to decreased cell proliferation and cell-cycle progression, albeit to a lesser extent compared with ERBB2 knockdown. We conclude that the amplification and resultant overexpression of genes coamplified with ERBB2 at 17q12 can contribute to proliferation levels of breast cancer cells. Our findings validate the utility of RNAi in the functional interrogation of tumor amplicons, and provide evidence for a contribution of coamplified genes to tumor phenotypes.

Breast Neoplasms↗
PubMed2006

Characterization of the MCT-1 pseudogene: identification and implication of its location in a highly amplified region of chromosome 20.

The MCT-1 oncogene was initially identified as an amplified gene on chromosome Xq22-24 in a T-cell lymphoma. MCT-1 is over-expressed in a subset of diffuse large B-cell lymphoma (DLBCL), a common form of Non-Hodgkin's Lymphoma (NHL). We have identified a pseudogene for MCT-1 (PsiMCT-1) that is located on chromosome 20q11.2, a region within an amplicon containing several important genes frequently amplified in certain breast and ovarian cancers. Genomic analysis revealed that PsiMCT-1 is a processed pseudogene. Interestingly, both MCT-1 and its pseudogene are located on regions of the genome that are frequently amplified in several different human malignancies. MCT-1 is the oldest known oncogene and its insertion as a pseudogene occurred at a later time point in evolution. Existence of PsiMCT-1 should be considered when analyzing genomic amplification and or expression of MCT-1. Analysis of MCT-1 and PsiMCT-1 might provide clues to cancer genes and their evolution across species.

Amino Acid Sequence↗
PubMed2001

Searching for microsatellite mutations in coding regions in lung, breast, ovarian and colorectal cancers.

RepX represents a new informatics approach to probe the UniGene database for potentially polymorphic repeat sequences in the open reading frame (ORF) of genes, 56% of which were found to be actually polymorphic. We now have performed mutational analysis of 17 such sites in genes not found to be polymorphic (<0.03 frequency) in a large panel of human cancer genomic DNAs derived from 31 lung, 21 breast, seven ovarian, 21 (13 microsatellite instability (MSI)+ and eight MSI-) colorectal cancer cell lines. In the lung, breast and ovarian tumor DNAs we found no mutations (<0.03-0.04 rate of tumor associated open reading frame mutations) in these sequences. By contrast, 18 MSI+ colorectal cancers (13 cancer cell lines and five primary tumors) with mismatch repair defects exhibited six mutations in three of the 17 genes (SREBP-2, TAN-1, GR6) (P<0.000003 compared to all other cancers tested). We conclude that coding region microsatellite alterations are rare in lung, breast, ovarian carcinomas and MSI (-) colorectal cancers, but are relatively frequent in MSI (+) colorectal cancers with mismatch repair deficits.

Base Pair Mismatch↗