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PubMed2005

Oncogenic pathway signatures in human cancers as a guide to targeted therapies.

The development of an oncogenic state is a complex process involving the accumulation of multiple independent mutations that lead to deregulation of cell signalling pathways central to the control of cell growth and cell fate. The ability to define cancer subtypes, recurrence of disease and response to specific therapies using DNA microarray-based gene expression signatures has been demonstrated in multiple studies. Various studies have also demonstrated the potential for using gene expression profiles for the analysis of oncogenic pathways. Here we show that gene expression signatures can be identified that reflect the activation status of several oncogenic pathways. When evaluated in several large collections of human cancers, these gene expression signatures identify patterns of pathway deregulation in tumours and clinically relevant associations with disease outcomes. Combining signature-based predictions across several pathways identifies coordinated patterns of pathway deregulation that distinguish between specific cancers and tumour subtypes. Clustering tumours based on pathway signatures further defines prognosis in respective patient subsets, demonstrating that patterns of oncogenic pathway deregulation underlie the development of the oncogenic phenotype and reflect the biology and outcome of specific cancers. Predictions of pathway deregulation in cancer cell lines are also shown to predict the sensitivity to therapeutic agents that target components of the pathway. Linking pathway deregulation with sensitivity to therapeutics that target components of the pathway provides an opportunity to make use of these oncogenic pathway signatures to guide the use of targeted therapeutics.

Animals↗

PubMed2006

Genomic signatures to guide the use of chemotherapeutics.

Using in vitro drug sensitivity data coupled with Affymetrix microarray data, we developed gene expression signatures that predict sensitivity to individual chemotherapeutic drugs. Each signature was validated with response data from an independent set of cell line studies. We further show that many of these signatures can accurately predict clinical response in individuals treated with these drugs. Notably, signatures developed to predict response to individual agents, when combined, could also predict response to multidrug regimens. Finally, we integrated the chemotherapy response signatures with signatures of oncogenic pathway deregulation to identify new therapeutic strategies that make use of all available drugs. The development of gene expression profiles that can predict response to commonly used cytotoxic agents provides opportunities to better use these drugs, including using them in combination with existing targeted therapies.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Expression profiling defines a recurrence signature in lung squamous cell carcinoma.

Lung cancer remains the leading cause of cancer death worldwide. Overall 5-year survival is approximately 10-15% and despite curative intent surgery, treatment failure is primarily due to recurrent disease. Conventional prognostic markers are unable to determine which patients with completely resected disease within each stage group are likely to relapse. To identify a gene signature associated with recurrent squamous cell carcinoma (SCC) of lung, we analyzed primary tumor gene expression for a total of 51 SCCs (Stages I-III) on 22 323 element microarrays, comparing expression profiles for individuals who remained disease-free for a minimum of 36 months with those from individuals whose disease recurred within 18 months of complete resection. Cox proportional hazards modeling with leave-one-out cross-validation identified a 71-gene signature capable of predicting the likelihood of tumor recurrence and a 79-gene signature predictive for cancer-related death. These two signatures were pooled to generate a 111-gene signature which achieved an overall predictive accuracy for disease recurrence of 72% (77% sensitivity, 67% specificity) in an independent set of 58 (Stages I-III SCCs). This signature also predicted differences in survival [log-rank P=0.0008; hazard ratio (HR), 3.8; 95% confidence interval (CI), 1.6-8.7], and was superior to conventional prognostic markers such as TNM stage or N stage in predicting patient outcome. Genome-wide profiling has revealed a distinct gene-expression profile for recurrent lung SCC which may be clinically useful as a prognostic tool.

Aged↗

PubMed2005

Draft versus finished sequence data for DNA and protein diagnostic signature development.

Sequencing pathogen genomes is costly, demanding careful allocation of limited sequencing resources. We built a computational Sequencing Analysis Pipeline (SAP) to guide decisions regarding the amount of genomic sequencing necessary to develop high-quality diagnostic DNA and protein signatures. SAP uses simulations to estimate the number of target genomes and close phylogenetic relatives (near neighbors or NNs) to sequence. We use SAP to assess whether draft data are sufficient or finished sequencing is required using Marburg and variola virus sequences. Simulations indicate that intermediate to high-quality draft with error rates of 10(-3)-10(-5) (approximately 8x coverage) of target organisms is suitable for DNA signature prediction. Low-quality draft with error rates of approximately 1% (3x to 6x coverage) of target isolates is inadequate for DNA signature prediction, although low-quality draft of NNs is sufficient, as long as the target genomes are of high quality. For protein signature prediction, sequencing errors in target genomes substantially reduce the detection of amino acid sequence conservation, even if the draft is of high quality. In summary, high-quality draft of target and low-quality draft of NNs appears to be a cost-effective investment for DNA signature prediction, but may lead to underestimation of predicted protein signatures.

Computational Biology↗

PubMed2001

Effects of a signature on rates of change: a randomized controlled trial involving continuing education and the commitment-to-change model.

PURPOSE: Physicians frequently are asked to sign commitments to change practice, based upon their involvement in continuing medical education (CME) activities. Although use of the commitment-to-change model is increasingly widespread in CME, the effect of signing such commitments on rates of change is not well understood. METHOD: Immediately after a CME session, 110 physicians were asked to specify a change they intended to make in practice and to designate a level of commitment to change. To determine the effects of a signature on rates of change, physicians were randomly assigned to control (signature) and experimental (non-signature) groups. Follow-up surveys were conducted at two and three months to determine rates of change. RESULTS: In all, 88 physicians completed the first questionnaire, and 64 of them completed the follow-up. Consistent with prior studies involving the commitment-to-change model, those expressing an intention to change were significantly more likely to change on follow-up (p =.035). There was no significant difference between signature and non-signature groups (p =.99), regardless of age or gender. CONCLUSIONS: Signatures appear unimportant to assuring compliance with commitments to change used in CME conferences. A physician's behavior can be expected to change if the specified change is consistent with the physician's beliefs and sense of what is important. The relative influences of components of the commitment-to-change model require further study to determine more clearly their roles in causation and measurement.

Adult↗

PubMed2002

Protein signatures distinctive of chlamydial species: horizontal transfers of cell wall biosynthesis genes glmU from archaea to chlamydiae and murA between chlamydiae and Streptomyces.

Chlamydiae are major human and animal pathogens. Based on alignments of different protein sequences, a number of conserved indels (insertion/deletions) were identified that appear to be unique and distinctive characteristics of the chlamydial species. The identified signatures include one 16 aa and two single aa inserts in the enzyme UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA), a 1 aa insert in protein synthesis elongation factor P (EF-P), a 1 aa insert in the Mg(2+) transport protein (MgtE), a 1 aa insert in the carboxy-terminal protease and a 1 aa deletion in the tRNA (guanine-N(1)-)-methyltransferase (TrmD) protein. The homologues of these proteins are found in all major groups of bacteria and the observed indels are present in all available chlamydial sequences but not in any other species (except for the large insert in MurA in Streptomyces). The validity of three of these signatures (MurA, EF-P and MgtE) was tested by PCR amplifying the signature regions from several chlamydial species for which no sequence information was available. All Chlamydiaceae species for which specific fragments could be amplified (Chlamydia suis, Chlamydophila abortus, Chlamydophila psittaci, Chlamydophila felis) contained the expected signatures. Additionally, a fragment of the murA gene from Waddlia chondrophila and the efp gene from Simkania negevensis, two chlamydia-like species, were also cloned and sequenced. The presence of respective indels in these species provides strong evidence that they are specifically related to the traditional chlamydial species, and that these signatures may be distinctive of the entire Chlamydiales order. A 17 aa conserved indel was also identified in the cell wall biosynthesis enzyme UDP-N-acetylglucosamine pyrophosphorylase (GlmU), which is shared by all archaeal and chlamydial homologues. The gene for this protein is indicated to have been horizontally transferred from an archaeon to a common ancestor of the chlamydiae. The results also support a lateral transfer of the murA gene between chlamydiae and STREPTOMYCES: The large inserts in these peptidoglycan synthesis related genes in chlamydiae could account for their unusual cell-wall characteristics. These signatures are also potentially useful for screening of the chlamydiae species.

Alkyl and Aryl Transferases↗

PubMed2025

Identification and Validation of a Previously Missed Mutational Signature in Colorectal Cancer.

Mutational signature analysis has greatly enhanced our understanding of the mutagenic processes found in cancer and normal tissues. As part of a recent study, we analyzed 802 treatment-naïve, microsatellite-stable colorectal cancers (CRC) and identified a de novo signature, SBS_D, which was conservatively decomposed into SBS18, a signature associated with reactive oxygen species. Here, we re-evaluate this decomposition and provide evidence that SBS_D represents a distinct mutational process from that of SBS18. Through an independent analysis of 2,616 whole-genome sequenced microsatellite-stable CRCs across three distinct cohorts, we demonstrate that SBS_D is consistently present at a similar prevalence, suggesting that this signature may have been previously overlooked. Using a naïve decomposition approach, we demonstrate that the pattern of SBS_D better aligns with signatures previously associated with deficiencies in DNA polymerase delta (POLD1) proofreading and mismatch repair. However, multiple lines of evidence, including the absence of pathogenic mutations in the exonuclease domain of POLD1 or in mismatch repair-associated genes, indicate that SBS_D is not driven by canonical defects in these DNA repair pathways. Overall, this study identifies a previously unrecognized mutational signature in microsatellite-stable CRC and proposes that its etiology may be linked to DNA repair infidelity emerging late in tumor development in samples without canonical defects in DNA repair pathways.

Journal Article↗

PubMed2006

A library of gene expression signatures to illuminate normal and pathological lymphoid biology.

Genomics has provided a lever to pry open lymphoid cells and examine their regulatory biology. The large body of available gene expression data has also allowed us to define the of coordinately expressed genes, termed gene expression signatures, which characterize the states of cellular physiology that reflect cellular differentiation, activation of signaling pathways, and the action of transcription factors. Gene expression signatures that reflect the action of individual transcription factors can be defined by perturbing transcription factor function using RNA interference (RNAi), small-molecule inhibition, and dominant-negative approaches. We have used this methodology to define gene expression signatures of various transcription factors controlling B-cell differentiation and activation, including BCL-6, B lymphocyte-induced maturation protein-1 (Blimp-1), X-box binding protein-1 (XBP1), nuclear factor-kappaB (NF-kappaB), and c-myc. We have also curated a wide variety of gene expression signatures from the literature and assembled these into a signature database. Statistical methods can define whether any signature in this database is differentially expressed in independent biological samples, an approach we have used to gain mechanistic insights into the origin and clinical behavior of B-cell lymphomas. We also discuss the use of genomic-scale RNAi libraries to identify genes and pathways that may serve as therapeutic targets in B-cell malignancies.

Gene Expression↗

PubMed2006

Visual attention and expertise for forensic signature analysis.

Eye tracking was used to measure visual attention of nine forensic document examiners (FDEs) and 12 control subjects on a blind signature comparison trial. Subjects evaluated 32 questioned signatures (16 genuine, eight disguised, and eight forged) which were compared, on screen, with four known signatures of the specimen provider while their eye movements, response times, and opinions were recorded. FDEs' opinions were significantly more accurate than controls, providing further evidence of FDE expertise. Both control and FDE subjects looked at signature features in a very similar way and the difference in the accuracy of their opinions can be accounted for by different cognitive processing of the visual information that they extract from the images. In a separate experiment the FDEs re-examined a reordered set of the same 32 questioned signatures. In this phase each signature was presented for only 100 msec to test if eye movements are relevant in forming opinions; performance significantly dropped, but not to chance levels indicating that the examination process comprises a combination of both global and local feature extraction strategies.

Adult↗

PubMed2005

Evolutionary and experimental analyses of inorganic phosphate transporter PiT family reveals two related signature sequences harboring highly conserved aspartic acids critical for sodium-dependent phosphate transport function of human PiT2.

The mammalian members of the inorganic phosphate (P(i)) transporter (PiT) family, the type III sodium-dependent phosphate (NaP(i)) transporters PiT1 and PiT2, have been assigned housekeeping P(i) transport functions and are suggested to be involved in chondroblastic and osteoblastic mineralization and ectopic calcification. The PiT family members are conserved throughout all kingdoms and use either sodium (Na+) or proton (H+) gradients to transport P(i). Sequence logo analyses revealed that independent of their cation dependency these proteins harbor conserved signature sequences in their N- and C-terminal ends with the common core consensus sequence GANDVANA. With the exception of 10 proteins from extremophiles all 109 proteins analyzed carry an aspartic acid in one or both of the signature sequences. We changed either of the highly conserved aspartates, Asp28 and Asp506, in the N- and C-terminal signature sequences, respectively, of human PiT2 to asparagine and analyzed P(i) uptake function in Xenopus laevis oocytes. Both mutant proteins were expressed at the cell surface of the oocytes but exhibited knocked out NaP(i) transport function. Human PiT2 is also a retroviral receptor and we have previously shown that this function can be exploited as a control for proper processing and folding of mutant proteins. Both mutant transporters displayed wild-type receptor functions implying that their overall architecture is undisturbed. Thus the presence of an aspartic acid in either of the PiT family signature sequences is critical for the Na+-dependent P(i) transport function of human PiT2. The conservation of the aspartates among proteins using either Na+- or H+-gradients for P(i) transport suggests that they are involved in H+-dependent P(i) transport as well. Current results favor a membrane topology model in which the N- and C-terminal PiT family signature sequences are positioned in intra- and extracellular loops, respectively, suggesting that they are involved in related functions on either side of the membrane. The present data are in agreement with a possible role of the signature sequences in translocation of cations.

Amino Acid Sequence↗

PubMed2026

Bayesian Integration of Tumor Mutational Signatures and Somatic Features Refines Pathogenicity Assessment of Germline Mismatch Repair Variants.

Variants of uncertain significance (VUS) in mismatch repair (MMR) genes represent a persistent bottleneck in germline interpretation for Lynch syndrome, creating a critical opportunity to leverage tumor biology to refine pathogenicity assessment. Although tumor features such as microsatellite instability (MSI) and immunohistochemistry (IHC) are routinely evaluated, they are typically interpreted separately from germline classification, and their quantitative contribution within ACMG/AMP frameworks remains poorly defined. We therefore analyzed paired germline and tumor sequencing data from 1110 tumors across 1073 patients with colorectal or endometrial cancer to determine whether mismatch repair-deficient (MMR-d) mutational signatures can be quantitatively integrated into Bayesian germline variant interpretation. Using COSMIC single-base substitution signatures, tumors were classified as MMR-d or MMR proficient, and an empirically derived likelihood ratio (LR) quantified the association between MMR-d signatures and pathogenic germline MMR variants. The presence of an MMR-d signature increased the likelihood of an underlying pathogenic germline MMR variant approximately eightfold (LR ≈ 8; log10 LR ≈ 0.90), whereas its absence provided moderate-to-strong benign evidence (LR ≈ 0.156; log10 LR ≈ -0.81). Applying this integrative framework to 45 germline MMR VUS, joint modeling of tumor mutational signatures with additional somatic and variant-level evidence resulted in clinically significant reclassification of 38 (84.4%) variants, including three reclassified as pathogenic or likely pathogenic and 35 as likely benign. A total of 16 downgraded variants were independently downgraded by Invitae. These findings demonstrate that tumor mutational signatures can be formally incorporated into Bayesian germline interpretation, transforming tumor data into quantitative pathogenicity evidence and offering a principled strategy to reduce VUS burden in hereditary cancer genetics.

Humans↗

PubMed2004

Identification of a gene expression signature associated with recurrent disease in squamous cell carcinoma of the head and neck.

Molecular studies of squamous cell carcinoma of the head and neck (HNSCC) have demonstrated multiple genetic abnormalities such as activation of various oncogenes (Ras, Myc, epidermal growth factor receptor, and cyclin D1), tumor suppressor gene inactivation (TP53 and p16), and loss of heterozygosity at numerous chromosomal locations. Despite these observations, accurate and reliable biomarkers that predict patients at highest risk for local recurrence have yet to be defined. In an effort to identify gene expression signatures that may serve as biomarkers, we studied 41 squamous cell carcinoma tumors (25 primary and 16 locally recurrent) from various anatomical sites and 13 normal oral mucosal biopsy samples from healthy volunteers with microarray analysis using Affymetrix U133A GeneChip arrays. Differentially expressed genes were identified by calculating generalized t tests (P < 0.001) and applying a series of filtering criteria to yield a highly discriminant list of 2890 genes. Hierarchical clustering and image generation using standard software were used to visualize gene expression signatures. Several gene expression signatures were readily identifiable in the HNSCC tumors, including signatures associated with proliferation, extracellular matrix production, cytokine/chemokine expression, and immune response. Of particular interest was the association of a gene expression signature enriched for genes involved in tumor invasion and metastasis with patients experiencing locally recurrent disease. Notably, these tumors also demonstrated a marked absence of an immune response signature suggesting that modulation of tumor-specific immune responses may play a role in local treatment failure. These data provide evidence for a new gene expression-based biomarker of local treatment failure in HNSCC.

Base Sequence↗

PubMed1984

Signature size in the psychiatric diagnosis: a significant clinical sign?

To test the hypothesis that patients' signatures may have a useful potential in making psychiatric diagnoses, the authors conducted a correlation study between signature sizes and psychiatric diagnoses. 252 medical records at St. Louis State Hospital in Missouri, USA, were randomized for the measurement of the signature sizes and assessment of DSM-III diagnoses. Analysis of variance and pair-wise comparison show that the signature size in the manic group is significantly larger than those of any other categories of psychiatric diagnoses (p less than 0.05), and that the signature size of organic mental disorder is significantly larger than those of the normal group (p less than 0.05). The authors suggest that further studies are needed to develop the clinical significance, if any, for interpreting patients' signatures.

Bipolar Disorder↗

PubMed2006

Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype.

Identification of specific gene expression signatures characteristic of oncogenic pathways is an important step toward molecular classification of human malignancies. Aberrant activation of the Met signaling pathway is frequently associated with tumor progression and metastasis. In this study, we defined the Met-dependent gene expression signature using global gene expression profiling of WT and Met-deficient primary mouse hepatocytes. Newly identified transcriptional targets of the Met pathway included genes involved in the regulation of oxidative stress responses as well as cell motility, cytoskeletal organization, and angiogenesis. To assess the importance of a Met-regulated gene expression signature, a comparative functional genomic approach was applied to 242 human hepatocellular carcinomas (HCCs) and 7 metastatic liver lesions. Cluster analysis revealed that a subset of human HCCs and all liver metastases shared the Met-induced expression signature. Furthermore, the presence of the Met signature showed significant correlation with increased vascular invasion rate and microvessel density as well as with decreased mean survival time of HCC patients. We conclude that the genetically defined gene expression signatures in combination with comparative functional genomics constitute an attractive paradigm for defining both the function of oncogenic pathways and the clinically relevant subgroups of human cancers.

Animals↗

PubMed2006

From description to causality: mechanisms of gene expression signatures in cancer.

Global gene expression profiles of thousands of cancer samples have been completed, giving rise to hundreds of gene expression signatures (GES). Although many expression signatures show promise in predicting patient prognosis or response to therapies, the usefulness of the signatures in understanding the underlying mechanisms of cancer has not been fully exploited. While "reverse genomic" methods can test specific hypotheses of gene regulation, they fare less well in deciphering novel or combinatorial mechanisms of gene regulation. Recently we described SLAMS (stepwise linkage analysis of microarray signatures), a novel method that can prospectively identify genetic regulators of gene expression signatures in cancer. Applying SLAMS on a poor-prognosis wound signature in human breast cancer, we identified CSN5-mediated ubiquitination of MYC as a novel mechanism to activate a biological program favoring metastasis.

Breast Neoplasms↗

PubMed2001

[The electronic signature].

This article explains the basic concept of electronic signatures, raises the question of encryption standards ("asymmetrische Kryptographie") and analyzes the legal requirements for a safe IT-infrastructure. The "Gesetz über die elektronische Signatur" focuses on trust centers (certification-service-providers) identifying their customers, generating private and public keys and being responsible for the "online-identity" of their customers. In addition, the German Government has proposed a "Formanpassungsgesetz" in order to implement the EC-Directive on a Community framework for electronic signatures; according to the directive Member States have to ensure that "qualified" electronic signatures satisfy the legal requirements of a signature in relation to data in electronic form in the same manner as a hand-written signature satisfies those requirements in relation to paper based data and are admissible as evidence in legal proceedings.

Certification↗

PubMed1992

The pre-stenotic Doppler shift signature.

In two series of measurements the Doppler shift signatures of 10 healthy volunteers were studied at varying distances proximal to a total reflection site, in order to describe parameters which are predictive for downstream lesions. Characteristic changes both in amplitude and time parameters were found; the most marked changes being the abolishment of a DC-component for monophasic signatures, the development or the augmentation of early diastolic reverse flow amplitudes together with a highly significant reduction in the signatures' systolic deceleration time. Maximum changes however tended to be localized at 2 to 4 centimeters upstream from the reflection site. Further upstream propagation was limited. Hence the time course of a Doppler signature and particularly its systolic deceleration should be taken into account in addition to the known resistance indices, if downstream lesions shall be predicted from upstream Doppler signatures. The limited upstream propagation of pre-stenotic Doppler signature changes restricts its diagnostic value to vascular segments where the region adjacent to a lesion is routinely scanned; thus diagnostic benefit can be expected for extracranial carotid artery disease but hardly for peripheral (lower limb) lesions.

Adult↗

PubMed1998

Chromatin texture signatures in nuclei from prostate lesions.

OBJECTIVE: To characterize nuclei from prostatic lesions in a highly specific manner by developing a nuclear chromatin texture signature and to characterize lesions by means of their composition of nuclei with diverse degrees of deviation from normal. STUDY DESIGN: High-resolution digitized imagery of nuclei from normal prostates, from prostatic neoplastic lesions of low and high grade and from histologically normal appearing regions of prostates with low and high grade prostatic intraepithelial neoplasia (PIN) lesions were recorded. A set of 65 features descriptive of the spatial and statistical distribution of nuclear chromatin was computed for each nucleus. These features were arranged and processed to form a distinctive signature. A distance metric from "normal" was defined and computed for each nucleus. RESULTS: Profiles of feature values can, after suitable scaling, be presented as distinctive feature value signatures. For many practical applications, profiles based on a standardized distance from normal nuclei may be more useful. Such profiles allow the derivation of a progression curve, showing increasing distances for diagnostic groups with increasing lesion progression up to high grade PIN lesions. Within each diagnostic group different cases show distinctive distributions of nuclei with differing degrees of deviation from normal, allowing the derivation of a lesion signature. CONCLUSION: Nuclear chromatin texture signatures may be of value for the characterization of both nuclei and lesions. They are based on a more comprehensive use of information offered by the nuclear chromatin pattern than that included in classification methods. While these signatures offer a more specific characterization of a clinical sample, they also are subject to more variability within a diagnostic category. This may not be due to randomness but may reflect some actual differences between lesions.

Adenocarcinoma↗