Biomedical subjects

Mattias Höglund

Publications and source records attributed to Mattias Höglund.

At least 19 recordsLinked to original sources

PubMed2006

On the origin of syn- and metachronous urothelial carcinomas.

OBJECTIVE: To evaluate existing models for the origin of meta- and synchronous urothelial carcinomas in light of the accumulated genetic data. METHODS: Published studies on the clonal origin and genetic relationships of syn- and metachronous tumors, genetic aberrations in normal and premalignant urothelial lesions, as well as histologic and genetic mapping studies of cystectomized bladder samples are reviewed. RESULTS: The most common models for the origin of syn- and metachronous tumors are found to conform less well to the accumulated genetic data. A new model is proposed, the field-first-tumor-later model, in which aberrant cells with a stem cell, or stem cell-like, origin spread in the urothelium by cellular displacement, creating fields of premalignant cells. Tumor growth is suggested to be initiated by critical genetic events occurring in individual cells in such fields. Hence, recurring tumors are proposed to originate from a shared field of premalignant cells and not from previous overt tumors. CONCLUSIONS: The proposed model can better account for the existing genetic and histological data on syn- and metachronous urothelial carcinomas.

Humans↗

PubMed2006

Analysis of promoter regions of co-expressed genes identified by microarray analysis.

BACKGROUND: The use of global gene expression profiling to identify sets of genes with similar expression patterns is rapidly becoming a widespread approach for understanding biological processes. A logical and systematic approach to study co-expressed genes is to analyze their promoter sequences to identify transcription factors that may be involved in establishing specific profiles and that may be experimentally investigated. RESULTS: We introduce promoter clustering i.e. grouping of promoters with respect to their high scoring motif content, and show that this approach greatly enhances the identification of common and significant transcription factor binding sites (TFBS) in co-expressed genes. We apply this method to two different dataset, one consisting of micro array data from 108 leukemias (AMLs) and a second from a time series experiment, and show that biologically relevant promoter patterns may be obtained using phylogenetic foot-printing methodology. In addition, we also found that 15% of the analyzed promoter regions contained transcription factors start sites for additional genes transcribed in the opposite direction. CONCLUSION: Promoter clustering based on global promoter features greatly improve the identification of shared TFBS in co-expressed genes. We believe that the outlined approach may be a useful first step to identify transcription factors that contribute to specific features of gene expression profiles.

Acute Disease↗

PubMed2006

Independent component analysis reveals new and biologically significant structures in micro array data.

BACKGROUND: An alternative to standard approaches to uncover biologically meaningful structures in micro array data is to treat the data as a blind source separation (BSS) problem. BSS attempts to separate a mixture of signals into their different sources and refers to the problem of recovering signals from several observed linear mixtures. In the context of micro array data, "sources" may correspond to specific cellular responses or to co-regulated genes. RESULTS: We applied independent component analysis (ICA) to three different microarray data sets; two tumor data sets and one time series experiment. To obtain reliable components we used iterated ICA to estimate component centrotypes. We found that many of the low ranking components indeed may show a strong biological coherence and hence be of biological significance. Generally ICA achieved a higher resolution when compared with results based on correlated expression and a larger number of gene clusters with significantly enriched for gene ontology (GO) categories. In addition, components characteristic for molecular subtypes and for tumors with specific chromosomal translocations were identified. ICA also identified more than one gene clusters significant for the same GO categories and hence disclosed a higher level of biological heterogeneity, even within coherent groups of genes. CONCLUSION: Although the ICA approach primarily detects hidden variables, these surfaced as highly correlated genes in time series data and in one instance in the tumor data. This further strengthens the biological relevance of latent variables detected by ICA.

Algorithms↗

PubMed2006

Bladder cancer, a two phased disease?

The processes of intraepithelial migration, intraluminal seeding, and field cancerization as models for initiation, spread, and recurrences of urothelial cell carcinoma (UCC) are reviewed in light of recent molecular investigations. The accumulated molecular data on synchronous and metachronous tumors indicate that the majority of recurrent and multiple tumors are monoclonal. Molecular data has also shown the presence of chromosomal and genetic changes in precursor lesions as well as in normal urothelial cells. Genetic-histological mapping of cystectomized bladders has shown that overt tumors occur as local events in areas of genetically altered urothelium. A model is put forward in which the tumor process is initiated by genetically altered but histologically normal cells that produce fields of altered cells by intraepithelial displacement. By the accumulation of further genetic changes the fields of altered urothelium reaches a state of criticality, which locally may produce frank tumors.

Carcinoma↗

PubMed2006

New probabilistic network models and algorithms for oncogenesis.

Chromosomal aberrations in solid tumors appear in complex patterns. It is important to understand how these patterns develop, the dynamics of the process, the temporal or even causal order between aberrations, and the involved pathways. Here we present network models for chromosomal aberrations and algorithms for training models based on observed data. Our models are generative probabilistic models that can be used to study dynamical aspects of chromosomal evolution in cancer cells. They are well suited for a graphical representation that conveys the pathways found in a dataset. By allowing only pairwise dependencies and partition aberrations into modules, in which all aberrations are restricted to have the same dependencies, we reduce the number of parameters so that datasets sizes relevant to cancer applications can be handled. We apply our framework to a dataset of colorectal cancer tumor karyotypes. The obtained model explains the data significantly better than a model where independence between the aberrations is assumed. In fact, the obtained model performs very well with respect to several measures of goodness of fit and is, with respect to repetition of the training, more or less unique.

Algorithms↗

PubMed2005

Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations.

Global expression profiles of a consecutive series of 121 childhood acute leukemias (87 B lineage acute lymphoblastic leukemias, 11 T cell acute lymphoblastic leukemias, and 23 acute myeloid leukemias), six normal bone marrows, and 10 normal hematopoietic subpopulations of different lineages and maturations were ascertained by using 27K cDNA microarrays. Unsupervised analyses revealed segregation according to lineages and primary genetic changes, i.e., TCF3(E2A)/PBX1, IGH@/MYC, ETV6(TEL)/RUNX1(AML1), 11q23/MLL, and hyperdiploidy (>50 chromosomes). Supervised discriminatory analyses were used to identify differentially expressed genes correlating with lineage and primary genetic change. The gene-expression profiles of normal hematopoietic cells were also studied. By using principal component analyses (PCA), a differentiation axis was exposed, reflecting lineages and maturation stages of normal hematopoietic cells. By applying the three principal components obtained from PCA of the normal cells on the leukemic samples, similarities between malignant and normal cell lineages and maturations were investigated. Apart from showing that leukemias segregate according to lineage and genetic subtype, we provide an extensive study of the genes correlating with primary genetic changes. We also investigated the expression pattern of these genes in normal hematopoietic cells of different lineages and maturations, identifying genes preferentially expressed by the leukemic cells, suggesting an ectopic activation of a large number of genes, likely to reflect regulatory networks of pathogenetic importance that also may provide attractive targets for future directed therapies.

Bone Marrow↗

PubMed2005

Ewing tumours and synovial sarcomas have critical features of karyotype evolution in common with epithelial tumours.

We have analysed the accumulated cytogenetic data on karyotypic evolution in Ewing tumours (ET) and synovial sarcomas (SS). Both tumour types frequently show balanced translocations, t(11;22) and t(X;18), respectively, that result in specific fusion genes. The analyses revealed +8, +12, +1q, and 16q- as important secondary changes to t(11;22) in ET and the imbalances showed a distinct temporal order. By principal component analysis, one major karyotypic pathway dominated by gains and one minor dominated by losses were identified. The kartyotypic evolution pattern in SS was less distinct. Both ET and SS showed a power law distribution of the number of acquired aberrations, which in both tumour types conformed to a distribution with an exponent equal to 1. Similar distributions are frequently found in epithelial tumours. ET and SS differ in this respect from other malignancies with balanced translocations resulting in fusion genes, which typically show a power law distribution of the number of acquired aberrations with exponents close to 2. This suggests that chromosome changes in ET and SS may develop through mechanisms more similar to those in epithelial tumours lacking recurrent balanced rearrangements than in haematological malignancies characterised by balanced translocations leading to fusion genes.

Bone Neoplasms↗

PubMed2005

Structural and numerical chromosome changes in colon cancer develop through telomere-mediated anaphase bridges, not through mitotic multipolarity.

Telomere dysfunction has been associated with chromosomal instability in colorectal carcinoma, but the consequences of telomere-dependent instability for chromosome integrity and clonal evolution have been little explored. We show here that abnormally short telomeres lead to a wide spectrum of mitotic disturbances in colorectal cancer cell lines, including anaphase bridging, whole-chromosome lagging, and mitotic multipolarity. These abnormalities were found in both the presence and absence of microsatellite instability. The mean telomere length varied extensively between cells from the same tumor, allowing the establishment of tumor cell subpopulations with highly different frequencies of mitotic disturbances. Anaphase bridging typically resulted in either inter-centromeric chromatin fragmentation or centromere detachment, leading to pericentromeric chromosome rearrangements and loss of whole chromosomes, respectively. There was a strong correlation between anaphase bridges and multipolar mitoses, and the induction of dicentric chromosomes by gamma irradiation and telomerase inhibition led to an elevated frequency of multipolar mitotic spindles, suggesting that multipolarity could result from polyploidization triggered by anaphase bridging. Chromatid segregation in multipolar mitoses was close to random, resulting in frequent nullisomies and nonviable daughter cells. In contrast, there was a high clonogenic survival among cells having gone through anaphase bridging in bipolar mitoses. Bridging of telomere-deficient chromosomes could thus be a major mutational mechanism in colorectal cancer, whereas mitotic multipolarity appears to be a secondary phenomenon that rarely, if ever, contributes to clonal evolution.

Anaphase↗

PubMed2005

Microarray analyses reveal strong influence of DNA copy number alterations on the transcriptional patterns in pancreatic cancer: implications for the interpretation of genomic amplifications.

DNA copy number alterations are believed to play a major role in the development and progression of human neoplasms. Although most of these genomic imbalances have been associated with dysregulation of individual genes, their large-scale transcriptional consequences remain unclear. Pancreatic carcinomas frequently display gene copy number variation of entire chromosomes as well as of chromosomal subregions. These changes range from homozygous deletions to high-level amplifications and are believed to constitute key genetic alterations in the cellular transformation of this tumor type. To investigate the transcriptional consequences of the most drastic genomic changes, that is, genomic amplifications, and to analyse the genome-wide transcriptional effects of DNA copy number changes, we performed expression profiling of 29 pancreatic carcinoma cell lines and compared the results with matching genomic profiling data. We show that a strong association between DNA copy numbers and mRNA expression levels is present in pancreatic cancer, and demonstrate that as much as 60% of the genes within highly amplified genomic regions display associated overexpression. Consequently, we identified 67 recurrently overexpressed genes located in seven precisely mapped commonly amplified regions. The presented findings indicate that more than one putative target gene may be of importance in most pancreatic cancer amplicons.

Chromosome Mapping↗

PubMed2005

Constitutional short telomeres are strong genetic susceptibility markers for bladder cancer.

Lack of functional telomeres can cause chromosomal aberrations. This type of genetic instability may promote tumorigenesis. We have investigated the association between mean telomere length in buccal cells (assessed with quantitative real-time PCR) and bladder cancer risk in a case-control study. Patients with bladder cancer displayed significantly shorter telomeres than control subjects (P = 0.001). Median telomere length ratio was 0.95 (range 0.53-3.2) for cases and 1.1 (0.51-2.4) for controls. Moreover, the adjusted odds ratio (OR) for bladder cancer was significantly increased in the quartile with the shortest telomere length OR = 4.5 [95% confidence interval (CI) 1.7-12]. It is known that oxidative stress, alkylation or UV radiation increases shortening of telomeres. Therefore, we also analyzed whether environmental and genetic factors associated with DNA damage, i.e. smoking and polymorphisms in the genes involved in the metabolism of genotoxic carcinogens (EPHX1, GSTA1, GSTM1, GSTP1, GSTT1, NAT1, NAT2 and NQO1) or DNA repair (APE1, NBS1, XPC, XPD, XRCC1, XRCC3 and XRCC4), could modify the association between telomere length and cancer risk. A clear effect of smoking and telomere length could be observed. Current smokers with short telomeres had more than six times as higher risk as non-smokers/former smokers with long telomeres (OR = 6.3, 95% CI 1.7-23). Lack of the biotransformation gene GSTM1 and short telomeres were associated with OR = 6.5 (95% CI 2.4-18), whereas homozygous carriers of 312Asn in the DNA repair gene XPD, with short telomeres, displayed an OR of 17 (95% CI 1.9-150). However, no significant interaction for cancer risk could be proven for telomere length, smoking and susceptibility genotypes of metabolizing and DNA-repairing genes.

Adult↗

PubMed2005

Telomere-mediated mitotic disturbances in immortalized ovarian epithelial cells reproduce chromosomal losses and breakpoints from ovarian carcinoma.

Ovarian carcinomas (OCs) often exhibit highly complex cytogenetic changes. Abnormal chromosome segregation at mitosis is one potential mechanism for genomic rearrangements in tumors. In this study, OCs were demonstrated to have dysfunctional short telomeres, anaphase bridging, and multipolar mitoses with supernumerary centrosomes. When normal human ovarian surface epithelial (HOSE) cells were transfected with human papilloma virus 16 e6/e7 genes and subsequently driven into telomere crisis, the same set of mitotic disturbances occurred in a distinct sequence, initiated by telomere dysfunction, followed by anaphase bridging, and then supernumerary centrosomes and multipolar mitoses. The anaphase bridges resolved either by kinetochore-spindle detachment, corresponding to whole-chromosome losses in the HOSE karyotypes, or by extensive fragmentation of intercentromeric DNA sequences, corresponding to a high frequency of pericentromeric rearrangements. At later passages, the high degree of instability at telomere crisis was moderated by telomerase expression and centrosome coalescence, ultimately leading to a level of mitotic instability that was highly similar to that in OC cell lines and to complex karyotypes that were similar to those observed in high-grade OCs. This suggests that a significant proportion of the structural chromosome changes and genomic losses in OC are caused by a specific sequence of mitotic disturbances triggered by telomere crisis. That the model did not produce any of the whole-chromosome gains observed in OC indicates that these changes develop through a different mechanism.

Cell Cycle↗

PubMed2005

Statistical behavior of complex cancer karyotypes.

Epithelial tumors commonly show complex and variable karyotypes that obscure the identification of general patterns of the karyotypic evolution. To overcome some of these problems, we previously systematically analyzed the accumulated cytogenetic data from individual tumor types by using various statistical means. In the present study, we compare previous results obtained for nine tumor types and perform several meta-analyses of data obtained from a number of epithelial tumors, including head and neck, kidney, bladder, breast, colorectal, ovarian, and lung cancer, as well as from malignant melanoma and Wilms tumor, with the specific aim of discovering common patterns of karyotypic evolution. We show that these tumors frequently develop through a hypo- or a hyperdiploid pathway and progress by an increasing number of alternative imbalances through at least two karyotypic phases, Phases I and II, and possibly through a third, Phase III. During Phase I, the karyotypes exhibited a power law distribution of both the number of changes per tumor and the frequency distribution at which bands were involved in breaks. At the transition from Phase I to Phase II/III, the observed power law distributions were lost, indicating a transition from an ordered and highly structured process to a disordered and chaotic pattern. The change in karyotypic orderliness at the transition from Phase I to Phase II/III was also shown by a drastic difference in karyotypic entropy.

Biological Evolution↗

PubMed2005

Connecting mitotic instability and chromosome aberrations in cancer--can telomeres bridge the gap?

Gross mitotic disturbances are often found in malignant tumours, but not until recently have the molecular causes and the genomic consequences of these abnormalities started to become known. One potential source of mitotic instability is chromosomes with dysfunctional telomeres, giving rise to a high rate of chromatin bridges at anaphase. These bridges could lead either to structural chromosome rearrangements through chromatin fragmentation or to whole-chromosome losses through kinetochore-spindle detachment. Statistical meta-analyses have recently revealed that tumours with high rates of anaphase bridging, such as ovarian, head and neck, and pancreatic carcinomas, are characterised by multimodal distributions of genomic imbalances, consistent with a dramatically increased rate of chromosome rearrangements. In contrast, tumours without gross cell division disturbances are characterised by a monotonously decreasing distribution of genomic changes. This distribution follows a power-law, best described by a preferential attachment model in which the tolerance for chromosomal changes increases steadily with tumour growth. Even though many common cancers, such as breast, colorectal, and renal cell carcinomas adhere to this simple power-law dynamics, the underlying molecular mechanisms remain elusive.

Chromosome Aberrations↗

PubMed2004

Statistical dissection of cytogenetic patterns in lung cancer reveals multiple modes of karyotypic evolution independent of histological classification.

Lung carcinomas are cytogenetically highly complex. In spite of this, patterns of recurrent chromosome aberrations have emerged. Apart from the frequent loss of 3p, losses of 4q, 5q, 8p, 9p, 10q, 13q, and 17p are common and gains often include 1q, 3q, 5p, and 8q. In the present study, we retrieved all aberrant lung carcinoma karyotypes, in total 432 cases, from the Mitelman Database of Chromosome Aberrations in Cancer and identified the most frequent imbalances. Each case was then classified with respect to the presence or absence of these imbalances and the data were statistically analyzed by means of principal component analysis, multidimensional scaling, and hierarchical cluster analysis. The analyses suggest that lung cancer develops through three pathways, initiated by +7, 3p-, and +12, respectively, and that the 3p- pathway is dominated by losses and the +12 pathway by gains. Gain of chromosome 7 was shown to be both important in the 3p- pathway and also forming a group of tumors containing +7 and +20 (with few additional changes). The distribution of the number of imbalances per tumor indicated that the karyotypic evolution might pass through three different phases. Phase I is characterized by tumors with few changes and by well-separated 3p- and +12 pathways. Phase II cases have an increased number of imbalances and exhibit less distinct 3p- and +12 pathways. Phase III tumors are polyploid and highly complex. No marked differences between the karyotypic profiles were found among morphologic subtypes, suggesting that lung cancer morphology is independent of the particular cytogenetic pathway operating in the tumor cells.

Adenocarcinoma↗

PubMed2004

Genome-wide array-based comparative genomic hybridization reveals multiple amplification targets and novel homozygous deletions in pancreatic carcinoma cell lines.

Pancreatic carcinomas display highly complex chromosomal abnormalities, including many structural and numerical aberrations. There is ample evidence indicating that some of these abnormalities, such as recurrent amplifications and homozygous deletions, contribute to tumorigenesis by altering expression levels of critical oncogenes and tumor suppressor genes. To increase the understanding of gene copy number changes in pancreatic carcinomas and to identify key amplification/deletion targets, we applied genome-wide array-based comparative genomic hybridization to 31 pancreatic carcinoma cell lines. Two different microarrays were used, one containing 3,565 fluorescence in situ hybridization-verified bacterial artificial chromosome clones and one containing 25,468 cDNA clones representing 17,494 UniGene clusters. Overall, the analyses revealed a high genomic complexity, with several copy number changes detected in each case. Specifically, 60 amplicons at 32 different locations were identified, most frequently located within 8q (8 cases), 12p (7 cases), 7q (5 cases), 18q (5 cases), 19q (5 cases), 6p (4 cases), and 8p (4 cases). Amplifications of 8q and 12p were mainly clustered at 8q23-24 and 12p11-12, respectively, whereas amplifications on other chromosome arms were more dispersed. Furthermore, our analyses identified several novel homozygously deleted segments located to 9p24, 9p21, 9q32, 10p12, 10q22, 12q24, and 18q23. The individual complexity and aberration patterns varied substantially among cases, i.e., some cell lines were characterized mainly by high-level amplifications, whereas others showed primarily whole-arm imbalances and homozygous deletions. The described amplification and deletion targets are likely to contain genes important in pancreatic tumorigenesis.

Cell Line, Tumor↗

PubMed2004

Statistical analyses of karyotypic complexity in head and neck squamous cell carcinoma.

More than 250 head and neck squamous cell carcinomas (HNSCCs) with clonal chromosomal abnormalities have been reported. Even though the pattern of aberrations is nonrandom, no specific primary or secondary karyotypic abnormalities have been identified. One explanation for the still-rudimentary understanding of the cytogenetic evolution in HNSCC could be the pronounced karyotypic complexity seen in these tumors. In an attempt to overcome this difficulty, we have applied several statistical methods such as hierarchical cluster analysis, multidimensional scaling, and k-means clustering, which allow the identification and interpretation of karyotypic pathways, as well as establishing a temporal order of chromosomal imbalances on 241 published and 70 previously unpublished HNSCC karyotypes. From the analysis of the distribution of the number of imbalances per tumor we suggest that the carcinomas evolve through three phases representing different stages of chromosomal instability. Two major cytogenetic pathways, one dominated by gains and another by losses, were identified by means of principal component analysis. These were initiated by +7 and by any of the aberrations 1p-, 3p-, or 7q-, respectively.

Allelic Imbalance↗

PubMed2004

Wilms tumors develop through two distinct karyotypic pathways.

Wilms tumor is an embryonic neoplasm characterized by a large variation in histologic patterns. Cytogenetic investigations have identified nonrandom chromosomal changes characteristic for this tumor type, of which numerical changes, mostly trisomies for chromosomes 7, 8, and 12, are particularly frequent. Despite the abundance of cytogenetic information, with more than 350 published karyotypes, very little is known about the mode of karyotypic evolution. In this investigation, we have used 355 karyotypes of Wilms tumor to identify frequent imbalances. The most frequent were +1q, +6, +7q, +8, +12, +13, -11, and -16. Tumor cases were then classified with respect to the presence or absence of these imbalances and statistically analyzed to assess the order of appearance of chromosomal imbalances, as well as possible karyotypic pathways. We show that Wilms tumors develop through one major mode of karyotypic evolution, common to both low- and high-complex tumors, and that polyploid cases are relatively rare. We also establish a temporal order by which the different imbalances occur and show that at least two cytogenetic pathways exist, one dominated by gains and another by losses. We also show that these pathways are well separated and do not share a common set of late imbalances.

Biological Evolution↗

PubMed2004

Approximate geodesic distances reveal biologically relevant structures in microarray data.

MOTIVATION: Genome-wide gene expression measurements, as currently determined by the microarray technology, can be represented mathematically as points in a high-dimensional gene expression space. Genes interact with each other in regulatory networks, restricting the cellular gene expression profiles to a certain manifold, or surface, in gene expression space. To obtain knowledge about this manifold, various dimensionality reduction methods and distance metrics are used. For data points distributed on curved manifolds, a sensible distance measure would be the geodesic distance along the manifold. In this work, we examine whether an approximate geodesic distance measure captures biological similarities better than the traditionally used Euclidean distance. RESULTS: We computed approximate geodesic distances, determined by the Isomap algorithm, for one set of lymphoma and one set of lung cancer microarray samples. Compared with the ordinary Euclidean distance metric, this distance measure produced more instructive, biologically relevant, visualizations when applying multidimensional scaling. This suggests the Isomap algorithm as a promising tool for the interpretation of microarray data. Furthermore, the results demonstrate the benefit and importance of taking nonlinearities in gene expression data into account.

Algorithms↗