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Results for “molecular profiling”

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PubMed2006

Molecular profiling of CD34+ cells in idiopathic myelofibrosis identifies a set of disease-associated genes and reveals the clinical significance of Wilms' tumor gene 1 (WT1).

This study was aimed at the characterization of a gene expression signature of the pluripotent hematopoietic CD34(+) stem cell in idiopathic myelofibrosis (IM), which would eventually provide novel pathogenetic insights and/or diagnostic/prognostic information. Aberrantly regulated genes were revealed by transcriptome comparative microarray analysis of normal and IM CD34(+) cells; selected genes were also assayed in granulocytes. One-hundred seventy four differentially expressed genes were identified and in part validated by quantitative polymerase chain reaction. Altered gene expression was corroborated by the detection of abnormally high CD9 or CD164, and low CXCR4, membrane protein expression in IM CD34(+) cells. According to class prediction analysis, a set of eight genes (CD9, GAS2, DLK1, CDH1, WT1, NFE2, HMGA2, and CXCR4) properly recognized IM from normal CD34(+) cells. These genes were aberrantly regulated also in IM granulocytes that could be reliably differentiated from control polycythemia vera and essential thrombocythemia granulocytes in 100% and 81% of cases, respectively. Abnormal expression of HMGA2 and CXCR4 in IM granulocytes was dependent on the presence and the mutational status of JAK2(V617F) mutation. The expression levels of both CD9 and DLK1 were associated with the platelet count, whereas higher WT1 expression levels identified IM patients with more active disease, as revealed by elevated CD34(+) cell count and higher severity score. In conclusion, molecular profiling of IM CD34(+) cells uncovered a limited number of genes with altered expression that, beyond their putative role in disease pathogenesis, are associated with patients' clinical characteristics and may have potential prognostic application.

Algorithms↗

PubMed2006

Genetics and molecular profiling of multiple myeloma: novel tools for clinical management?

The understanding of molecular events involved in multiple myeloma (MM) development as well as of mechanisms underlying sensitivity/resistance to anticancer drugs has been dramatically increased by the wide-spread use of modern technologies for genetic analysis, global gene expression and proteomic profiling. Such analytical approaches, which are presently supported by reliable bioinformatic tools, have depicted a new scenario for the development of molecular-based anti-MM agents and for predicting clinical outcome. IgH translocations or a hyperdiploid state are emerging as early genetic signatures of MM which lead to deregulated expression of cyclin D. At present however, the major challenge remains the definition of the potential role of cytogenetic techniques and molecular profiling technologies in individual patient management. Here we will describe the prospective potential and current achievements of such technologies which might produce major advancements in the treatment of this still incurable disease.

Chromosome Aberrations↗

PubMed2004

Molecular profiling of silkworm biodiversity in India.

Molecular tools opened a new vista to understand nature's bio-diversity and its relevance and the same approach was availed of to build-up the foundation work on the bio-diversity of silkworm spp in India. It is well established that the heritage of usage of silk for dress materials in India, Russia and China dates back to premedieval period and in spite of industrial development resulting to de-forestation, India still can claim as the owner of wide bio-diversity, espicially in northern India for silkworm spp. The molecular diversity was assessed among Antheraea mylitta, A. assama, A. pernyi, A. provlei, A. roylei and Philcosomia cynthia wiht 11 ISSR and 8 non-random primers on agarose gel. Nei's statistics as also Euclidean distance matrix was applied to find the genetic diversity between the six species, wherein the closest relationship between A. pernyi and A. proylei is established. With the help of POPGEN statistics, the average genetic heterozygosity appeared as 0.271 while Shanon's index is 0.4312 and alleles with segregation ratios of 3:1, 2:1, 1:1, 9:1 (generated with ISSR primers) were identified which can be utilized for future molecular breeding porgram. Further, and attempt was made to isolate a number of bands generated with 3 ISSR and six non-random primers, specific for different species and 22 such markers have been characterized through sequencing which will be made available through international public domain database.

Animals↗

PubMed2002

Molecular profiles of group B streptococcal surface protein antigen genes: relationship to molecular serotypes.

The study of surface protein antigens of group B streptococci (GBS) is important for understanding of the pathogenesis and epidemiology of infection, and several of these antigens have been proposed as components of GBS conjugate vaccines. In a previous study, we developed a novel PCR-and-sequencing system for identification of GBS serotypes and serosubtypes based on the capsular polysaccharide synthesis (cps) gene cluster. In this study, we used published sequences to develop PCR assays for identification of genes encoding GBS surface proteins including C alpha (bca), C alpha-like proteins 2 and 3 (alp2 and alp3), Rib (rib), and C beta (bac). We showed that the prototype R reference strain, Prague 25/60, contained a novel alpha-like protein antigen gene (the proposed alp4), which presumably encodes an atypical, but antigenically similar, R-like protein. Initial evaluation of these gene-specific assays showed excellent specificity. By combining cps serotypes, serosubtypes, and surface protein gene profiles, we were able to divide 224 GBS isolates into 31 serovariants. GBS bac-positive strains could be further subtyped into 11 groups and 20 subgroups. Our results confirmed and extended reported associations between some cps serotypes and serosubtypes, on the one hand, and surface protein genes, on the other: serosubtypes III-1 and III-2 were associated with rib, serosubtype III-3 with alp2, serotype Ib with bca and bac, and serotype V with alp3. The associations between serotype Ia and bca, bca repetitive unit, and bca repetitive unit-like sequence-containing genes need to be studied further. These PCR-based methods will provide an alternative and objective tool for subtyping of GBS based on surface protein antigen genes.

Antigens, Bacterial↗

PubMed2003

Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer.

The molecular basis of pancreatic cancer is not understood. Previous attempts to determine the specific genes expressed in pancreatic cancer have been hampered by similarities between adenocarcinoma and chronic pancreatitis. In the current study, microarrays (Affymetrix) were used to profile gene expression in pancreatic adenocarcinoma (10), pancreatic cancer cell lines (7), chronic pancreatitis (5), and normal pancreas (5). Molecular profiling indicated a large number of genes differentially expressed between pancreatic cancer and normal pancreas but many fewer differences between pancreatic cancer and chronic pancreatitis, likely because of the shared stromal influences in the two diseases. To specifically identify genes expressed in neoplastic epithelium, we selected genes more highly expressed (>2-fold, p < 0.01) in adenocarcinoma compared with both normal pancreas and chronic pancreatitis and which were also highly expressed in pancreatic cancer cell lines. This strategy yielded 158 genes, of which 124 were not previously associated with pancreatic cancer. Quantitative-reverse transcription-PCR for two molecules, S100P and 14-3-3sigma, validated the microarray data. Support for the success of the neoplastic cell gene expression identification strategy was obtained by immunocytochemical localization of four representative genes, 14-3-3sigma, S100P, S100A6, and beta4 integrin, to neoplastic cells in pancreatic tumors. Thus, comparisons between pancreatic adenocarcinoma, pancreatic cancer cell lines, normal pancreas, and chronic pancreatitis have identified genes that are selectively expressed in the neoplastic epithelium of pancreatic adenocarcinoma. These data provide new insights into the molecular pathology of pancreatic cancer that may be useful for detection, diagnosis, and treatment.

Adenocarcinoma↗

PubMed2004

Phenotypical and molecular profiling of the extraneuronal cholinergic system of the skin.

We present molecular and protein profiling of all acetylcholine receptors (ACh-R) in human scalp skin using PCR, in situ hybridization and double-labeling immunofluorescence. Within the epidermis, the nicotinic (n)ACh-R subunits, alpha3, alpha5, beta2, and beta4 were expressed in the basal cell layer (BCL) and in a single cell layer in the stratum granulosum; alpha9 was expressed in the basal and lower spinous layers. alpha7, alpha10, and beta1 were preferentially detected in the upper spinous and granular layers. Of the muscarinic (m)ACh-R, m1 and m4 were found in the suprabasal layers, whereas m2, m3, and m5 remained restricted to the lower layers. In the outer root sheath of the hair follicle, all ACh-R except alpha9, beta1, and m4 were found in the BCL whereas the alpha9, m4, and m5 ACh-R were restricted to the central cell layer. The alpha5, beta1, beta2, m1-m4 chains were strongly expressed in the inner root sheath. Undifferentiated sebocytes expressed the alpha3, alpha9, beta4, m3-m5 ACh-R whereas alpha7, beta2, beta4, m2, and m4 were found in mature sebocytes. In sweat glands, the alpha3*, alpha7, and m2-m5 ACh-R were most prominent in the myoepithelial cells whereas alpha9, beta2, m1, m3, and m4 ACh-R were present in the acinar cells. Taken together, our data result in a complete molecular map of the extraneuronal cholinergic system of the skin that may be translated into distinct functional reaction patterns.

Animals↗

PubMed2004

Molecular profiles as predictive marker for the effect of overall treatment time of radiotherapy in supraglottic larynx squamous cell carcinomas.

BACKGROUND AND PURPOSE: Reduction of the overall treatment time of radiotherapy increases the probability of local tumour control, but it does not benefit all patients. Identification of molecular marker profiles may aid in the selection of patients likely to benefit from accelerated radiotherapy. PATIENTS AND METHODS: Two hundred and nine patients with SCC of the supraglottic larynx received primary radiotherapy in the randomised DAHANCA trials to 66-68 Gy, 2 Gy/fx but with different overall treatment times of 9.5 week, 6.5 week and 5.5 week. Formalin-fixed paraffin embedded tumour slides were assessed by immunohistochemistry for expression of EGFr, E-cadherin, KI-67 and Bcl-2 and the TP53 mutation profile was determined using PCR-amplification, DHPLC and sequencing. The profiles were established using a hierarchical clustering algorithm with a Bayesian information criterion for cluster number optimisation. RESULTS: Full data-set were available for 158 patients and four almost equally sized clusters were identified. One of these clusters differed significantly with respect to local control compared to the other clusters: the cluster (n=36) characterised by wild type TP53, low expression of E-cadherin and Bcl-2, moderate KI-67 and EGFr, was not influenced by a reduction in the overall treatment time (P=0.6) whereas the other clusters showed an increase in local control when the overall treatment time of radiotherapy was reduced. This was also partially seen with disease specific survival as the endpoint. CONCLUSIONS: Molecular marker profiling may aid in the selection of patients that will benefit of a reduction in overall treatment time of radiotherapy in SCC of the supraglottic larynx.

Algorithms↗

PubMed2002

Molecular profiling of non-small cell lung cancer and correlation with disease-free survival.

Recent studies have suggested that information from gene expression profiles could be used to develop molecular classifications of cancer. We hypothesized that expression levels of specific genes in operative specimens could be correlated to recurrence risk in non-small cell lung cancer (NSCLC). We performed expression profiling using 19.2 K cDNA microarrays on tumor specimens from a total of 39 NSCLC patients with known clinical follow-up information. Statistical analysis and clustering approaches were used to determine patterns of gene expression segregating with clinical outcome. The results provide evidence that molecular subtyping of NSCLC can identify distinct profiles of gene expression correlating with disease-free survival.

Adult↗

PubMed2005

Improving cancer therapeutics by molecular profiling.

The individualized medicine aims to identify the molecular basis of the individual's response to different therapeutic treatments. Individualized medicine is very relevant for human diseases such as cancer and it has become a major task to accomplish more efficient and specific therapeutics. An individualized response to treatment could underline therapeutic success or failure and, even more, could support the rationale for good or bad prognosis. The use of up to date genomic approaches is changing the way we understand modern medicine in terms of drug efficacy, toxicity and diagnosis. Results from genetic polymorphism studies, gene expression profiling and epigenetics illustrate how pharmacogenomic testing will contribute to the goal of individualized medicine. Antineoplastic drugs are designed to block the anomalous activity of specific molecules (therapeutic targets) that regulate cellular processes such as cell cycle. Understanding the relationship between molecular changes in therapeutic targets and enhanced antitumoral response or chemotherapeutic resistance is crucial to establish the clinical relevance of genomic approaches. The goal of this review is to discuss the basic and the clinical significance of genomic research on drug targets and its impact on the early diagnosis and treatment of cancer. We will also assess how these methodologies could contribute to individualized medicine in oncology. A special focus will be put on oncogenes and tumor suppressor genes. Aspects such as drug efficacy, side effects and the diagnostic value of antineoplastic pharmacogenomic research will be also considered.

Antineoplastic Agents↗

PubMed2007

Impact of molecular profiling on clinical trial design for glioblastoma.

This review highlights the ways in which molecular and genetic profiling of malignant gliomas has led to intelligent clinical trial design. The review also highlights known resistance mechanisms to conventional therapies in malignant gliomas and potential strategies to overcome these mechanisms with the use of targeted therapy.

Antineoplastic Agents↗

PubMed2006

Molecular profiling of chronic myeloid leukemia in eastern India.

Molecular breakpoint of the BCR-ABL fusion gene has been characterized for 122 chronic myeloid leukemia patients. Out of 122 cases, 33 b2a2, 69 b3a2, 2 e1a2, and 2 e19a2 cases have been detected. Six coexpressed both b2a2 and b3a2 transcripts. All the coexpressing samples had an A>G polymorphism at the putative splice branchpoint in intron 13. The T>C polymorphism in exon 13, reported to be linked to coexpression, was not present in all the coexpressing patients. No correlation of transcript type with platelet count was detected. Those expressing b2a2 transcript were diagnosed at relatively younger age and with higher white blood cell count, in agreement with other reports. However, the correlation was not statistically significant.

Adult↗

PubMed2007

BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays.

A distinct morphologic and molecular phenotype has been reported for BRCA1-associated breast cancers; however, the phenotype of BRCA2-associated breast cancers is less certain. To comprehensively characterize BRCA2-associated breast cancers we performed a retrospective case control study using tumors accrued through the Breast Cancer Family Registry. We examined the tumor morphology and hormone receptor status in 157 hereditary breast cancers with germline mutations in BRCA2 and 314 control tumors negative for BRCA1 and BRCA2 mutations that were matched for age and ethnicity. Tissue microarrays were constructed from 64 BRCA2-associated and 185 control tumors. Tissue microarray sections were examined for HER2/neu protein overexpression, p53 status and the expression of basal markers, luminal markers, cyclin D1, bcl2, and MIB1 by immunohistochemistry. The majority of BRCA2-associated tumors and control tumors were invasive ductal, no special-type tumors. In contrast to control tumors, BRCA2-associated cancers were more likely to be high grade (P<0.0001) and to have pushing tumor margins (P=0.0005). Adjusting for grade, BRCA2-associated tumors were more often estrogen receptor positive (P=0.008) and exhibited a luminal phenotype (P=0.003). They were less likely than controls to express the basal cytokeratin CK5 (P=0.03) or to overexpress HER2/neu protein (P=0.06). There was no difference in p53, bcl2, MIB1, or cyclin D1 expression between BRCA2-associated and control tumors. We have demonstrated, in the largest series of BRCA2-associated breast cancers studied to date, that these tumors are predominantly high-grade invasive ductal carcinomas of no special type and they demonstrate a luminal phenotype despite their high histologic grade.

Adult↗

PubMed2026

Molecular Profiling Across 80,000 Patients With Lung Cancer.

INTRODUCTION: Biomarker testing is an essential component of optimal therapeutic management in NSCLC, enabling the use of both Food and Drug Administration-approved and emerging targeted therapies. Despite well-established biomarker testing guidelines and the availability of many approved targeted therapies, a substantial proportion of patients with advanced NSCLC are not benefiting from precision oncology. In this study, we analyze the distribution of actionable genomic alterations across histologic subtypes and clinicodemographic subgroups of NSCLC using data in 82,328 samples profiled with a single comprehensive genomic profiling assay, aiming to support universal molecular testing across all NSCLC subtypes to ensure equitable access to available therapeutics. METHODS: This is an observational retrospective analysis on histologically confirmed NSCLC cases tested with comprehensive genomic profiling by next-generation sequencing between 2014 and 2022 using Foundation One/Foundation CDx. All cases were centrally reviewed by board-certified anatomic pathologist to determine histologic type and subtype. RESULTS: A total of 82,328 patients with NSCLC were included. An actionable genomic alteration (GA) was found in 35.1% of the cases. Lung adenocarcinoma (LUAD) and adenosquamous carcinoma were more frequently associated with actionable GA (45.8% and 40.9%, respectively) as compared with sarcomatoid (29.1%), not otherwise specified (27.6%), large cell (21.1%), and squamous cell (6.5%) histologies. Sarcomatoid histology had the highest METex14 skipping mutation (mut) frequency (9.95% versus 2.43% in LUAD). Tumor mutation burden more than or equal to 10 mut/Mb was associated with histology (50.91% in large cell, 40.79% in not otherwise specified, 39.08% in squamous cell, and 36.30% in sarcomatoid versus 31.22% in LUAD and 29.22% in adenosquamous carcinoma). Patients with actionable GA had usually a low tumor mutation burden (80.88%). A significant correlation (p < 0.005) between age and actionable GA was reported for BRAF/ERBB2 muts, ALK/RET/ROS1 rearrangements, and MET amplification. EGFR actionable muts and KRAS G12C were more frequently observed in females, whereas no significant correlation between sex and other GA was observed. Finally, genetic ancestry analyses revealed a strong correlation for EGFR actionable muts and South/East Asia and America, but not for other GA. CONCLUSIONS: This is the largest NSCLC data set analyzed for biomarker distribution across histologies, age, sex, and genetic ancestry. This data set confirms sufficient enough biomarker prevalence across many histologic subtypes of NSCLC, providing reassurance that all NSCLC cases should be considered for biomarker workup.

Humans↗

PubMed2006

Molecular profiling of a rat model of colitis: validation of known inflammatory genes and identification of novel disease-associated targets.

BACKGROUND: Inflammatory bowel disease (IBD) is a disease of unknown etiology characterized by acute and chronic relapsing inflammation. The most suitable animal model for studying this disease is still under debate. Microarray transcript profiling has the potential to illuminate the molecular processes that are involved in both the human condition and animal models. AIM: To identify differentially expressed genes in the 2,4,6-trinitrobenzene sulfonic acid (TNBS) model of experimental colitis and compare gene expression profiles with that reported in patients. METHODS: Colitis was induced by TNBS administration (30 mg in 50% ethanol) in female Sprague-Dawley rats. Controls received the vehicle. Seventy-two hours later, the animals were killed, the colons were removed and scored for damage, and total RNA was isolated. Gene expression levels were analyzed after hybridizing experimental and control cDNA to PIQOR Toxicology Rat Microarrays containing 1,252 genes. Genes with 2-fold or more higher or 0.5-fold or less lower expression levels were selected as significantly differentially expressed. Results were validated using real-time reverse-transcription polymerase chain reaction (RT-PCR). RESULTS: We observed increased expression of genes that have previously been shown to be up-regulated in IBD patients, including chemokines/cytokines, extracellular matrix/remodeling genes, transcription factors and tumor necrosis factor family members. Using real-time RT-PCR, we validated 9 of 10 critical genes identified by DNA microarray. Fibulin 2 and lysyl oxidase are among some of the novel genes not previously associated with IBD that could potentially be related to the pathogenesis of this condition. CONCLUSION: We provide evidence supporting the TNBS colitis model as an appropriate tool to study the pathology of IBD and identify molecular targets with clinical relevance.

Animals↗

PubMed2005

Clinical application of molecular profiling in breast cancer.

Breast cancer is the leading type of cancer and second leading cause of cancer death in women. Breast cancer mortality has declined over the past 10 years largely due to early detection by mammographic screening, but also in part due to the increasing use of adjuvant hormonal therapy and chemotherapy. Indications for adjuvant chemotherapy have now expanded to include women who are at low risk of recurrence, resulting in overtreatment of most women to benefit a few, particularly those with favorable clinical features. New techniques have been evaluated that identify specific molecular signatures that may more accurately predict prognosis than clinical features, and that may also identify individuals who are more likely to benefit from endocrine therapy and/or chemotherapy. This review will focus on the clinical applications of these novel techniques reported to date, and how this may lead to the incorporation of molecular diagnostics into clinical practice. Two prospective, multicenter, multinational Phase III trials evaluating tumor genomic profiling in breast cancer are currently in development, and will be initiated within the forthcoming year. The completion of these important studies will represent the first step toward integrating molecular profiling into treatment selection for adjuvant therapy in breast cancer.

Antineoplastic Agents↗

PubMed2002

The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma.

BACKGROUND: The survival of patients with diffuse large-B-cell lymphoma after chemotherapy is influenced by molecular features of the tumors. We used the gene-expression profiles of these lymphomas to develop a molecular predictor of survival. METHODS: Biopsy samples of diffuse large-B-cell lymphoma from 240 patients were examined for gene expression with the use of DNA microarrays and analyzed for genomic abnormalities. Subgroups with distinctive gene-expression profiles were defined on the basis of hierarchical clustering. A molecular predictor of risk was constructed with the use of genes with expression patterns that were associated with survival in a preliminary group of 160 patients and was then tested in a validation group of 80 patients. The accuracy of this predictor was compared with that of the international prognostic index. RESULTS: Three gene-expression subgroups--germinal-center B-cell-like, activated B-cell-like, and type 3 diffuse large-B-cell lymphoma--were identified. Two common oncogenic events in diffuse large-B-cell lymphoma, bcl-2 translocation and c-rel amplification, were detected only in the germinal-center B-cell-like subgroup. Patients in this subgroup had the highest five-year survival rate. To identify other molecular determinants of outcome, we searched for individual genes with expression patterns that correlated with survival in the preliminary group of patients. Most of these genes fell within four gene-expression signatures characteristic of germinal-center B cells, proliferating cells, reactive stromal and immune cells in the lymph node, or major-histocompatibility-complex class II complex. We used 17 genes to construct a predictor of overall survival after chemotherapy. This gene-based predictor and the international prognostic index were independent prognostic indicators. CONCLUSIONS: DNA microarrays can be used to formulate a molecular predictor of survival after chemotherapy for diffuse large-B-cell lymphoma.

Antibiotics, Antineoplastic↗

PubMed2001

A molecular profile of the mouse gastric parietal cell with and without exposure to Helicobacter pylori.

The parietal cell (PC) plays an important role in normal gastric physiology and in common diseases of the stomach. Although the genes involved in acid secretion are well known, there is limited molecular information about other aspects of PC function. We have generated a comprehensive database of genes expressed preferentially in PCs relative to other gastric mucosal cell lineages. PCs were purified from FVB/N mouse stomachs by lectin panning. cRNA generated from PC-enriched (PC(+)) and PC-depleted (PC(-)) populations were used to query oligonucleotide-based microarrays. False-positive signals were filtered by using a new algorithm for noise reduction and selected results independently audited by real-time quantitative reverse transcription (RT)-PCR. The annotated database of 240 genes reveals previously unappreciated aspects of cellular function, including factors that may mediate PC regulation of gastric stem cell proliferation. PC(+) and PC(-) expression profiles were also prepared from germ-free mice 2 and 8 weeks after colonization with a clinical isolate of Helicobacter pylori (Hp)--the pathogen that produces acid-peptic disease (gastritis, ulcers) in humans. Whereas PC(+) gene expression was remarkably constant, the PC(-) fractions demonstrated a robust, evolving host response, with increased expression of genes involved in cell motility/migration, extracellular matrix interactions, and IFN responses. The consistency of PC(+) gene expression allowed identification of a cohort of 92 genes enriched in PCs under all conditions studied. These genes provide a molecular profile that can be used to define this epithelial lineage under a variety of physiologic, pharmacologic, and pathologic stimuli.

Animals↗

PubMed2003

Protein microarrays: molecular profiling technologies for clinical specimens.

Proteomics, the study of protein function within biologic systems, will further our understanding of cancer pathogenesis. Coupled with transcript profiling, proteomics can herald the advent of molecular therapy tailored to the individual patient's neoplasm. Protein microarrays, one emerging class of proteomic technologies, have broad applications for discovery and quantitative analysis. This technology is uniquely suited to gather information about the post-translational modifications of proteins reflecting the activity state of signal pathways and networks. Protein microarrays now make it feasible to conduct signal network profiling within cellular samples. Nevertheless, to be successful, design and use of protein microarrays must take into consideration enormous analytical challenges. A subclass of protein microarrays, Reverse Phase Arrays, created to meet these challenges, has been optimized for use with tissue specimens, and is now in use for the analysis of biopsy samples for clinical trial research.

Antibodies↗