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PubMedDate not supplied

In search of a stem cell hierarchy in the human breast and its relevance to breast cancer evolution.

By deliberate analogy with the well-established concept of hematopoiesis, the term "mammopoiesis" is occasionally used to describe the development of the different cellular lineages and functional units in the mammary gland. The use of this term signifies a strong bias towards the idea that tissue homeostasis during mammary development, pregnancy, lactation and involution is brought about by the action of somatic stem cells characterized by longevity and multipotency. The progenies hereof eventually differentiate into structurally and functionally well-defined ductal-lobular units. During the past two decades evidence of such a notion in the mouse has developed from being largely circumstantial based on non-clonal in vivo experiments to a quite elaborate characterization of individual candidate stem cells by a number of different properties. Within tumor biology this has led to a renaissance of the concept of tumors as caricatures of tissue renewal. Thus, recent molecular classification of breast cancer based on genome wide expression analysis operates with different subtypes with specific reference to the normal luminal epithelial and myoepithelial/basal lineages in the breast. Apparently some tumors are lineage restricted and others differentiate more broadly as if they have preserved some stem-like properties. This holds promise for the existence of a stem cell hierarchy, the understanding of which may prove to be instrumental in further dissecting the histogenesis of breast cancer evolution. Most attention has been devoted to the question of different cellular origins of cancer subtypes and different susceptibilities of possible stem cells to gain or loss of oncogenes and tumor suppressor genes, respectively. Invaluable progress has been made over the past two decades in culture technology not only in terms of population doubling and clonal growth, but also the availability of lineage specific markers, cell sorting, and three-dimensional functional assays for tissue specific morphogenesis. Transcriptional profiling of stem cell zones has unraveled a hitherto unknown preservation of signaling pathways for maintenance of stem cell properties across tissue boundaries and species. Somatic stem cells have therefore been narrowed down to specific anatomic locations not only in rapidly renewing tissues such as skin and skin derivatives, but also in tissues with slower turnover times, such as lung, kidney and prostate. It is therefore now possible to integrate this information in a search for similar cells within the breast. Even if cell turnover after birth is provided exclusively by dividing lineage-restricted cells, more information about the robustness of breast differentiation programs during tumor progression is still very much required. Complete knowledge of the primary cell of origin of breast cancer and the mechanisms that influence differentiation programs during tumor initiation, promotion and progression may be crucial for the development of novel non-toxic therapies that influence tumor cell behaviour. The scope of this review is to discuss reports that have begun to elucidate the topographic location, key cellular type and lineage fidelity in culture and xenograft models of candidate human breast stem cells and their differentiated progenies with particular emphasis on comparison with the differentiation programs of tumor subtypes.

Animals↗
PubMed1987

Isolation of molecular hybridisation probes for early myeloid lineage RNAs.

Recombinant plasmid cDNA libraries representing the polyadenylated RNAs in the myeloid cell lines KG1 and ML1 have been constructed. The screening protocol has identified several clones which contain sequences homologous to RNAs expressed at high abundance in one or more of the myeloid cell lines KG1, ML1 and HL60. The relative abundances of RNAs homologous to three recombinants, pML15, pKG21 and pKGA/F5 were measured by an RNA dot hybridisation method in total RNAs isolated from peripheral blood leukocytes from leukaemic patients and normal individuals. High levels of these RNAs were observed mainly in ANLL and acute phase CML samples. The data suggest that these probes have the potential to sub-divide the ANLLs and to extend a molecular classification of the myeloid leukaemias.

Acute Disease↗
PubMed2000

Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family.

BACKGROUND: Primary pulmonary hypertension (PPH), resulting from occlusion of small pulmonary arteries, is a devastating condition. Mutations of the bone morphogenetic protein receptor type II gene (BMPR2), a component of the transforming growth factor beta (TGF-beta) family which plays a key role in cell growth, have recently been identified as causing familial PPH. We have searched for BMPR2 gene mutations in sporadic PPH patients to determine whether the same genetic defect underlies the more common form of the disorder. METHODS: We investigated 50 unrelated patients, with a clinical diagnosis of PPH and no identifiable family history of pulmonary hypertension, by direct sequencing of the entire coding region and intron/exon boundaries of the BMPR2 gene. DNA from available parent pairs (n=5) was used to assess the occurrence of spontaneous (de novo) mutations contributing to sporadic PPH. RESULTS: We found a total of 11 different heterozygous germline mutations of the BMPR2 gene in 13 of the 50 PPH patients studied, including missense (n=3), nonsense (n=3), and frameshift (n=5) mutations each predicted to alter the cell signalling response to specific ligands. Parental analysis showed three occurrences of paternal transmission and two of de novo mutation of the BMPR2 gene in sporadic PPH. CONCLUSION: The sporadic form of PPH is associated with germline mutations of the gene encoding the receptor protein BMPR-II in at least 26% of cases. A molecular classification of PPH, based upon the presence or absence of BMPR2 mutations, has important implications for patient management and screening of relatives.

Adolescent↗
PubMed2003

Wnt ligand expression in malignant melanoma: pilot study indicating correlation with histopathological features.

AIMS: Secreted Wnt ligands are key proteins regulating cell-cell interactions and cell growth and differentiation. These proteins, along with other components of the Wnt signalling pathway, are involved in the malignant transformation of various human cancers, including malignant melanoma. This study defines the expression of several members of the Wnt ligand family and correlates their expression with histological characteristics. METHODS: The expression of Wnt2, Wnt5a, Wnt5b, Wnt7b, and Wnt10b was defined by in situ, antisense RNA hybridisation of paraffin wax embedded sections of benign naevi and malignant melanoma. Immunoperoxidase based antibody staining was used to define the expression of frizzled (Fz) receptors. RESULTS: All naevi tested strongly expressed Wnt2, Wnt5a, Wnt7b, and Wnt10b. Melanomas characterised by small, uniform cells expressed each of the Wnts in a pattern similar to that seen for benign naevi. In contrast, melanomas characterised by large, pleomorphic cells expressed Wnt10b but did not express Wnt2 and had low levels of expression of Wnt5a. Expression of Wnt7b was variable in these melanomas. Fz receptor expression was present at a low level in normal epithelium and all naevi and melanomas. CONCLUSIONS: The expression pattern of Wnt ligands in malignant melanoma correlates with histopathological features and may provide a basis for the molecular classification of this disease.

Biomarkers, Tumor↗
PubMed2002

Pharmacogenomic biomarkers.

Pharmacogenomic biomarkers hold great promise for the future of medicine and have been touted as a means to personalize prescriptions. Genetic biomarkers for disease susceptibility including both Mendelian and complex disease promise to result in improved understanding of the pathophysiology of disease, identification of new potential therapeutic targets, and improved molecular classification of disease. However essential to fulfilling the promise of individualized therapeutic intervention is the identification of drug activity biomarkers that stratify individuals based on likely response to a particular therapeutic, both positive response, efficacy, and negative response, development of side effect or toxicity. Prior to the widespread clinical application of a genetic biomarker multiple scientific studies must be completed to identify the genetic variants and delineate their functional significance in the pathophysiology of a carefully defined phenotype. The applicability of the genetic biomarker in the human population must then be verified through both retrospective studies utilizing stored or clinical trial samples, and through clinical trials prospectively stratifying patients based on the biomarker. The risk conferred by the polymorphism and the applicability in the general population must be clearly understood. Thus, the development and widespread application of a pharmacogenomic biomarker is an involved process and for most disease states we are just at the beginning of the journey towards individualized therapy and improved clinical outcome.

Drug Design↗
PubMed2006

[Molecular diagnosis of retinoblastoma: molecular epidemiology and genetic counseling].

BACKGROUND AND OBJECTIVE: Retinoblastoma, a prototype of hereditary cancer, is the most common intraocular tumor in children and a potential cause of blindness from therapeutic eye ablation, second tumors in germ line mutation carriers, and even death when untreated. The molecular scanning of RB1 in search of germ line mutations in 213 retinoblastoma patients from Spain, Cuba, Colombia and Serbia, has led to the detection of 106 mutations whose knowledge is important for genetic counselling and characterization of phenotypic-genotypic relations. PATIENTS AND METHOD: Mutational study (PCR-sequentiation and microsatellites analysis) in patients with retinoblastoma, from Spain, Cuba, Colombia and Serbia. RESULTS: 45% of mutations, including most of the frame shift (FS), missense (MS) and splicing (SP), were new, while all nonsense mutations (NS) corresponded to hypermutable sites in RB1. Germ line mutations were found in 22% of unilateral sporadic patients. The incidence of SP plus MS mutations in this group of patients was greater (p = 0.018) than in bilateral patients. The frequency of SP mutations was higher (p = 0.0003) in Spain and France than in Germany and United Kingdom, while the incidence of NS mutations was lower (p = 0.0006). SP mutations were associated with the low penetrance phenotype and were also overrepresented (p = 0.018) in patients with delayed retinoblastoma onset. CONCLUSIONS: Mutational scanning of unilateral patients is important for genetic counselling and may help decipher the molecular mechanisms leading to low penetrance or expressivity. The functional characterization of mutations associated with low-penetrance or expressivity phenotypes and the molecular classification of tumors using multiple expression profiling is important for a better understanding of the retinoblastoma pathogenesis.

Child↗
PubMed2004

Loss of heterozygosity and its correlation with expression profiles in subclasses of invasive breast cancers.

Gene expression array profiles identify subclasses of breast cancers with different clinical outcomes and different molecular features. The present study attempted to correlate genomic alterations (loss of heterozygosity; LOH) with subclasses of breast cancers having distinct gene expression signatures. Hierarchical clustering of expression array data from 89 invasive breast cancers identified four major expression subclasses. Thirty-four of these cases representative of the four subclasses were microdissected and allelotyped using genome-wide single nucleotide polymorphism detection arrays (Affymetrix, Inc.). LOH was determined by comparing tumor and normal single nucleotide polymorphism allelotypes. A newly developed statistical tool was used to determine the chromosomal regions of frequent LOH. We found that breast cancers were highly heterogeneous, with the proportion of LOH ranging widely from 0.3% to >60% of heterozygous markers. The most common sites of LOH were on 17p, 17q, 16q, 11q, and 14q, sites reported in previous LOH studies. Signature LOH events were discovered in certain expression subclasses. Unique regions of LOH on 5q and 4p marked a subclass of breast cancers with "basal-like" expression profiles, distinct from other subclasses. LOH on 1p and 16q occurred preferentially in a subclass of estrogen receptor-positive breast cancers. Finding unique LOH patterns in different groups of breast cancer, in part defined by expression signatures, adds confidence to newer schemes of molecular classification. Furthermore, exclusive association between biological subclasses and restricted LOH events provides rationale to search for targeted genes.

Breast Neoplasms↗
PubMed2004

Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death.

Melanomas are notoriously difficult to classify because of a lack of discrete clinical and pathological stages. Here, we show that primary uveal melanomas surprisingly cluster into two distinct molecular classes based on gene expression profile. Genes that discriminate class 1 (low-grade) from class 2 (high-grade) include highly significant clusters of down-regulated genes on chromosome 3 and up-regulated genes on chromosome 8q, which is consistent with previous cytogenetic studies. A three-gene signature allows biopsy-size tumor samples to be assigned accurately to tumor classes using either array or PCR platforms. Most importantly, this molecular classification strongly predicts metastatic death and outperforms other clinical and pathological prognostic indicators. These studies offer new insights into melanoma pathogenesis, and they provide a practical foundation for effective clinical predictive testing.

Chromosome Aberrations↗
PubMed2005

Integrated array-comparative genomic hybridization and expression array profiles identify clinically relevant molecular subtypes of glioblastoma.

Glioblastoma, the most aggressive primary brain tumor in humans, exhibits a large degree of molecular heterogeneity. Understanding the molecular pathology of a tumor and its linkage to behavior is an important foundation for developing and evaluating approaches to clinical management. Here we integrate array-comparative genomic hybridization and array-based gene expression profiles to identify relationships between DNA copy number aberrations, gene expression alterations, and survival in 34 patients with glioblastoma. Unsupervised clustering on either profile resulted in similar groups of patients, and groups defined by either method were associated with survival. The high concordance between these separate molecular classifications suggested a strong association between alterations on the DNA and RNA levels. We therefore investigated relationships between DNA copy number and gene expression changes. Loss of chromosome 10, a predominant genetic change, was associated not only with changes in the expression of genes located on chromosome 10 but also with genome-wide differences in gene expression. We found that CHI3L1/YKL-40 was significantly associated with both chromosome 10 copy number loss and poorer survival. Immortalized human astrocytes stably transfected with CHI3L1/YKL-40 exhibited changes in gene expression similar to patterns observed in human tumors and conferred radioresistance and increased invasion in vitro. Taken together, the results indicate that integrating DNA and mRNA-based tumor profiles offers the potential for a clinically relevant classification more robust than either method alone and provides a basis for identifying genes important in glioma pathogenesis.

Adipokines↗
PubMed2006

Cytosine methylation profiles as a molecular marker in non-small cell lung cancer.

Aberrant promoter methylation is frequently observed in different types of lung cancer. Epigenetic modifications are believed to occur before the clinical onset of the disease and hence hold a great promise as early detection markers. Extensive analysis of DNA methylation has been impeded by methods that are either too labor intensive to allow large-scale studies or not sufficiently quantitative to measure subtle changes in the degree of methylation. We used a novel quantitative DNA methylation analysis technology to complete a large-scale cytosine methylation profiling study involving 47 gene promoter regions in 96 lung cancer patients. Each individual contributed a lung cancer specimen and corresponding adjacent normal tissue. The study identified six genes with statistically significant differences in methylation between normal and tumor tissue (P < 10(-6)). We explored the quantitative methylation data using an unsupervised hierarchical clustering algorithm. The data analysis revealed that methylation patterns differentiate normal from tumor tissue. For validation of our approach, we divided the samples to train a classifier and test its performance. We were able to distinguish normal from lung cancer tissue with >95% sensitivity and specificity. These results show that quantitative cytosine methylation profiling can be used to identify molecular classification markers in lung cancer.

Biomarkers, Tumor↗
PubMed2005

Separation of tissue proteins of human lung carcinomas by partial-filling capillary electrophoresis.

Tissue proteins from human squamous cell lung carcinomas (SQCLC) and small cell lung carcinomas (SCLC) were separated in 0.01% hydroxypylmethyl cellulose (HPMC) linear polymer sieving solutions in the inlet portion of the capillary and next to the outlet of the capillary, followed by capillary zone electrophoresis (CZE) in 40 mM phosphate buffer, pH 2.5. A proper HPMC concentration could cause a molecular sieving effect through the formation of an entangled polymer network. The migration time of the analyte in this matrix depended on the size and electrophoretic mobility of the analyte, the mesh size, and the electric field strength. In the CZE separation, the electroosmotic flow and the charge-to-size ratio of the analyte were important parameters. HPMC concentration and zone length were examined to optimize the separation. Applying this partial-filling technique to the separation of water-soluble proteins from human lung tissues, we found a greatly improved resolution and increased peak intensity. The capillary electrophoresis patterns of normal, SQCLC, and SCLC were obtained and compared for their molecular classifications.

Carcinoma, Small Cell↗
PubMed2005

Defining smooth muscle cells and smooth muscle injury.

For 3 decades, terms such as synthetic phenotype and contractile phenotype have been used to imply the existence of a specific mechanism for smooth muscle cell (SMC) responses to injury. In this issue of the JCI, Hendrix et al. offer a far more precise approach to examining the mechanisms of SMC responses to injury, focused not on general changes in phenotype but on effects of injury on a single promoter element, the CArG [CC(A/T)6GG] box, in a single gene encoding smooth muscle (SM) alpha-actin. Since CArG box structures are present in some, but not all, SMC genes, these data suggest that we may be progressing toward establishing a systematic, molecular classification of both SMC subsets and the response of SMCs to different injuries.

Actins↗
PubMedDate not supplied

The promise of microarray technology in melanoma care.

BACKGROUND: Genetic aberration is responsible for the development of neoplastic potential in a number of malignancies. These DNA alterations result in significant changes in gene expression that may now be measured and catalogued. The microarray technique screens and identifies expressed genes that may be responsible for tumorigenesis. METHODS: The authors review the application of the microarray technique in malignant melanoma. RESULTS: Candidate melanoma suppressor genes have been identified in melanoma cell lines using this technique. Furthermore, molecular classification using gene expression profiling may improve the accuracy of the staging system for determining prognosis. CONCLUSIONS: The microarray technique is in its initial development for clinical application in a variety of tumor models. Melanoma is an ideal system to study the genetic changes associated with the stepwise progression of malignancy. It may be possible to efficiently screen the entire human genome to identify the particular aberrations in gene expression responsible for tumorigenesis in melanoma.

Clinical Trials as Topic↗
PubMed2006

ROKU: a novel method for identification of tissue-specific genes.

BACKGROUND: One of the important goals of microarray research is the identification of genes whose expression is considerably higher or lower in some tissues than in others. We would like to have ways of identifying such tissue-specific genes. RESULTS: We describe a method, ROKU, which selects tissue-specific patterns from gene expression data for many tissues and thousands of genes. ROKU ranks genes according to their overall tissue specificity using Shannon entropy and detects tissues specific to each gene if any exist using an outlier detection method. We evaluated the capacity for the detection of various specific expression patterns using synthetic and real data. We observed that ROKU was superior to a conventional entropy-based method in its ability to rank genes according to overall tissue specificity and to detect genes whose expression pattern are specific only to objective tissues. CONCLUSION: ROKU is useful for the detection of various tissue-specific expression patterns. The framework is also directly applicable to the selection of diagnostic markers for molecular classification of multiple classes.

Algorithms↗
PubMed2006

A biphasic pattern of gene expression during mouse retina development.

BACKGROUND: Between embryonic day 12 and postnatal day 21, six major neuronal and one glia cell type are generated from multipotential progenitors in a characteristic sequence during mouse retina development. We investigated expression patterns of retina transcripts during the major embryonic and postnatal developmental stages to provide a systematic view of normal mouse retina development, RESULTS: A tissue-specific cDNA microarray was generated using a set of sequence non-redundant EST clones collected from mouse retina. Eleven stages of mouse retina, from embryonic day 12.5 (El2.5) to postnatal day 21 (PN21), were collected for RNA isolation. Non-amplified RNAs were labeled for microarray experiments and three sets of data were analyzed for significance, hierarchical relationships, and functional clustering. Six individual gene expression clusters were identified based on expression patterns of transcripts through retina development. Two developmental phases were clearly divided with postnatal day 5 (PN5) as a separate cluster. Among 4,180 transcripts that changed significantly during development, approximately 2/3 of the genes were expressed at high levels up until PN5 and then declined whereas the other 1/3 of the genes increased expression from PN5 and remained at the higher levels until at least PN21. Less than 1% of the genes observed showed a peak of expression between the two phases. Among the later increased population, only about 40% genes are correlated with rod photoreceptors, indicating that multiple cell types contributed to gene expression in this phase. Within the same functional classes, however, different gene populations were expressed in distinct developmental phases. A correlation coefficient analysis of gene expression during retina development between previous SAGE studies and this study was also carried out. CONCLUSION: This study provides a complementary genome-wide view of common gene dynamics and a broad molecular classification of mouse retina development. Different genes in the same functional clusters are expressed in the different developmental stages, suggesting that cells might change gene expression profiles from differentiation to maturation stages. We propose that large-scale changes in gene regulation during development are necessary for the final maturation and function of the retina.

Animals↗
PubMed2006

Comprehensive copy number profiles of breast cancer cell model genomes.

INTRODUCTION: Breast cancer is the most commonly diagnosed cancer in women worldwide and consequently has been extensively investigated in terms of histopathology, immunochemistry and familial history. Advances in genome-wide approaches have contributed to molecular classification with respect to genomic changes and their subsequent effects on gene expression. Cell lines have provided a renewable resource that is readily used as model systems for breast cancer cell biology. A thorough characterization of their genomes to identify regions of segmental DNA loss (potential tumor-suppressor-containing loci) and gain (potential oncogenic loci) would greatly facilitate the interpretation of biological data derived from such cells. In this study we characterized the genomes of seven of the most commonly used breast cancer model cell lines at unprecedented resolution using a newly developed whole-genome tiling path genomic DNA array. METHODS: Breast cancer model cell lines MCF-7, BT-474, MDA-MB-231, T47D, SK-BR-3, UACC-893 and ZR-75-30 were investigated for genomic alterations with the submegabase-resolution tiling array (SMRT) array comparative genomic hybridization (CGH) platform. SMRT array CGH provides tiling coverage of the human genome permitting break-point detection at about 80 kilobases resolution. Two novel discrete alterations identified by array CGH were verified by fluorescence in situ hybridization. RESULTS: Whole-genome tiling path array CGH analysis identified novel high-level alterations and fine-mapped previously reported regions yielding candidate genes. In brief, 75 high-level gains and 48 losses were observed and their respective boundaries were documented. Complex alterations involving multiple levels of change were observed on chromosome arms 1p, 8q, 9p, 11q, 15q, 17q and 20q. Furthermore, alignment of whole-genome profiles enabled simultaneous assessment of copy number status of multiple components of the same biological pathway. Investigation of about 60 loci containing genes associated with the epidermal growth factor family (epidermal growth factor receptor, HER2, HER3 and HER4) revealed that all seven cell lines harbor copy number changes to multiple genes in these pathways. CONCLUSION: The intrinsic genetic differences between these cell lines will influence their biologic and pharmacologic response as an experimental model. Knowledge of segmental changes in these genomes deduced from our study will facilitate the interpretation of biological data derived from such cells.

Breast Neoplasms↗
PubMed2005

Australian sporadic CJD analysis supports endogenous determinants of molecular-clinical profiles.

OBJECTIVE: To define the protease-resistant prion protein (PrPres) types and associated clinical profiles in Australian patients with sporadic Creutzfeldt-Jakob disease (CJD) to allow comparison with those reported from other continents and concomitantly reaffirm absence of variant CJD (vCJD). METHODS: Reassessment of available clinical and neuropathologic data on patients referred to the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR) who died between January 1, 1992, and June 30, 2003, was conducted. Molecular classification of PrPres was determined by immunoblot analysis of available frozen brain tissue. Brain homogenate pH and codon 129 genotype on the prion protein gene (PRNP) were established. RESULTS: PrPres patterns in 35 of 37 patients with sporadic CJD conformed to one of three common reported types. Of a range of clinical features assessed, illness duration was the only clinical feature significantly associated with PrPres type. Two patients displayed coexistence of more than one PrP type, with one displaying a novel pattern of three PrPres types in a single brain region. The absence of vCJD was reconfirmed, supported by the lack of the typical PrPres glycoform pattern. CONCLUSIONS: Given Australia's geographic isolation and environmental uniqueness, the general congruity of these results with those reported from other continents suggests that endogenous factors predominantly determine sporadic Creutzfeldt-Jakob disease (CJD) phenotypic subtypes or "strains." These results support a clinicopathologic classification system whereby both PrPres type and codon 129 genotype are utilized to most accurately depict phenotypic subtypes or strains of sporadic CJD.

Adult↗
PubMed2004

Novel insertional mutation in the bone morphogenetic protein receptor type II associated with sporadic primary pulmonary hypertension.

Primary pulmonary hypertension (PPH), which results from occlusion of small pulmonary arteries, is a devastating condition. Mutations of the bone morphogenetic protein receptor type II gene (BMPR2), a component of the transforming growth factor- beta (TGF-beta) family, which plays a key role in cell growth, have recently been identified as causing familial and sporadic PPH. The first case of BMPR2 mutation found in Japan is reported here in a 19-year-old woman with a clinical diagnosis of PPH and no identifiable family history of pulmonary hypertension. Direct sequencing of the entire coding region and intron/exon boundaries of BMPR2 revealed a frameshift mutation predicted to alter the cell signaling response to specific ligands. A molecular classification of PPH, based upon the presence or absence of BMPR2 mutations, might have important implications for patient management and screening of relatives.

Adult↗