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PubMed2005

Ruling in and ruling out: implications of molecular genetic diagnoses for disease classification.

We report on a qualitative analysis of interviews with 14 genetic counsellors in Ontario, Canada about the implications of developments in molecular genetic knowledge for disease definition and classification. Genetic counsellors express a restrained set of hopes and expectations about the utility of genetic diagnoses. They identify several limitations faced by available genetic tests, limitations that constrain the significance of genetic information in disease identification and clinical management. Yet they also emphasize the fundamental nature of genetic information, its decisive role in specifying disease causation, and its significance for disease classification. The decisive nature of genetic information means that, in some cases, genetic tests foster change in disease categories. Diseases are redefined by the "ruling in" of atypical cases demonstrating a broader spectrum of clinical effects, or the "ruling out" of typical cases with classic clinical presentations that are better assigned to other (or no) causes. These redefinitions can be profoundly consequential, producing several kinds of uncertainty: What do we call this state of being? How do we manage it clinically? And, what are the social entitlements of individuals in this state? Though limited today, such complex effects can be expected to increase, alongside the growing diagnostic power of molecular genetics.

Clinical Competence↗
PubMedDate not supplied

News of TNM and its use for classification of gastric cancer.

Tumor classification is associated with two inherent problems: (1) to find a compromise between the simplicity needed for a wide application by the medical community and sufficient differentiation and specification required for the presently high differentiation in treatment options and for detailed analysis of treatment results; and (2) to achieve an agreement between the stability necessary for data collection over long periods and the needed continuous inclusion of new proposals that arise by advances in diagnostic and therapeutic methods and the increasing knowledge of prognostic factors. The aim of this report is to inform on the changes and expansions of the international classification of gastric carcinoma during the last few years, to refer to new developments, to point out the relations between established classifications and molecular biology, and to show the future trend in tumor classification.

Carcinoma↗
PubMed2002

[WHO classification of Hodgkin's lymphoma and its molecular pathological relevance].

The current WHO classification of Hodgkin's lymphoma (HL) generally distinguishes the relatively rare variant (approximately 5% of all cases of HL) of nodular lymphocyte predominant type from a second group, which comprises classical HL and is separated into four subtypes: lymphocyte rich type, nodular sclerosis type, mixed cellularity type and lymphocyte depleted type. The classical lymphocyte rich subtype is a new entity and based on the typical morphology, can be recognized by definition only by the immunohistochemical characteristics of the Hodgkin and Reed/Sternberg cells (HRS) (CD30+, CD15+, CD20-). Molecular single cell studies are consistent with the dichotomy of HL in nodular lymphocyte predominant and classical types and stress the exceptional position of the former, which shows similarities with non-Hodgkin's lymphomas in several aspects. On the molecular biology level the tumor cells of all kinds of HL turn out to be clonal B cells derived from germinal center cells. However, tumor cells of nodular lymphocyte predominant HL differ from those of classical HL by the pattern of somatic mutations. Considering the inability of HRS cells of classical HL to express a B cell receptor, they should perish under normal conditions. However, they escape from apoptosis by mechanisms so far only partially understood, such as genomic mutations of the l-kappa B gene and the fas receptor gene or probably by down-regulation of B cell markers. In rare cases, HRS cells of HL can also be derived from T cells, as could be demonstrated by single cell analysis. Also, it could be shown by single cell PCR that HL and non-Hodgkin's lymphoma of both B and T cell types can arise from a common precursor. These results suggest that future classifications of HL will not only take into account the morphological and phenotypical profile, but also mechanisms of transformation yet to be discovered.

Biomarkers, Tumor↗
PubMed1999

Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects.

Phenotypic heterogeneity in sporadic Creutzfeldt-Jakob disease (sCJD) is well documented, but there is not yet a systematic classification of the disease variants. In a previous study, we showed that the polymorphic codon 129 of the prion protein gene (PRNP), and two types of protease-resistant prion protein (PrP(Sc)) with distinct physicochemical properties, are major determinants of these variants. To define the full spectrum of variants, we have examined a series of 300 sCJD patients. Clinical features, PRNP genotype, and PrP(Sc) properties were determined in all subjects. In 187, we also studied neuropathological features and immunohistochemical pattern of PrP(Sc) deposition. Seventy percent of subjects showed the classic CJD phenotype, PrP(Sc) type 1, and at least one methionine allele at codon 129; 25% of cases displayed the ataxic and kuru-plaque variants, associated to PrP(Sc) type 2, and valine homozygosity or heterozygosity at codon 129, respectively. Two additional variants, which included a thalamic form of CJD and a phenotype characterized by prominent dementia and cortical pathology, were linked to PrP(Sc) type 2 and methionine homozygosity. Finally, a rare phenotype characterized by progressive dementia was linked to PrP(Sc) type 1 and valine homozygosity. The present data demonstrate the existence of six phenotypic variants of sCJD. The physicochemical properties of PrP(Sc) in conjunction with the PRNP codon 129 genotype largely determine this phenotypic variability, and allow a molecular classification of the disease variants.

Adult↗
PubMed1999

Inherited prion disease with an alanine to valine mutation at codon 117 in the prion protein gene.

A large English family with autosomal dominant segregation of presenile dementia, ataxia and other neuropsychiatric features is described. Diagnoses of demyelinating disease, Alzheimer's disease, Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker syndrome have been attributed to particular individuals at different times. An Irish family, likely to be part of the same kindred, is also described, in which diagnoses of multiple sclerosis, dementia, corticobasal degeneration and new variant CJD have been considered in affected individuals. Molecular genetic studies have enabled the classification of this disease at the molecular level as one of the group of inherited prion diseases, with the substitution of valine for alanine at codon 117 of the prion protein gene (PRNP). Only three other kindreds have been described world-wide with this mutation and only limited phenotypic information has been reported. Here we describe the phenotypic spectrum of inherited prion disease (PrPA117V). The diversity of phenotypic expression seen in this kindred emphasizes the logic of molecular classification of the inherited prion diseases rather than classification by specific clinicopathological syndrome. Indeed, inherited prion disease should be excluded by PRNP analysis in any individual presenting with atypical presenile dementia or neuropsychiatric features and ataxia, including suspected cases of new variant CJD.

Adult↗
PubMed2006

[Molecular imaging and molecular guided therapy].

AIM AND METHOD: Scientific publications in the journal of Nuklearmedizin Molecular Imaging and Therapy during 2004/2005 were retrospectively examined for their potential classification to molecular imaging or molecular guided therapy, functional imaging and therapy, and were compared to earlier analyses. RESULTS: Of the 57 original papers examined, 36 (63%) were assigned to the category of molecular imaging/molecular guided therapy. Within this category, the number of original papers on molecular guided therapy increased by 19% compared to preceding periods. There was a general overall increase in the proportion of experimental papers and more frequent inclusion of basic background subjects. CONCLUSION: The development of molecular imaging as a direct instrument in therapy planning leads to further promotion of molecular guided therapy. The structural advantage of nuclear medicine, uniting method-lead diagnosis and therapy within one specialist subject, predestines it to advance molecular imaging and molecular guided therapy.

Humans↗
PubMed2005

Behavioral and molecular genetic contributions to a dimensional classification of personality disorder.

This article examines the possible contribution of behavioral and molecular genetic research to the development of a dimensional classification of personality disorder. It is argued that the results of molecular studies are too preliminary to have immediate nosological significance. However, behavioral genetic methods could play a useful role in constructing a classification that reflects the genetic architecture of personality disorder. It is also argued that the best approach to constructing a valid classification would be to integrate behavioral genetic methods with the construct validation framework used in test construction. An integrative approach is proposed that seeks to combine constructs from alternative dimensional models. It is suggested that strong evidence of a four-dimensional structure to personality disorder provides a way to organize a preliminary model. An initial set of primary traits to define these secondary domains would then be compiled from existing models and refined using a combination of traditional psychometric analyses and behavioral genetic methods. It is concluded that an etiologically based classification is feasible for the DSM-V.

Genetics, Behavioral↗
PubMed2004

The classification of cortical dysplasias through molecular genetics.

Recent genetic insight into the mechanisms of human brain malformation have allowed one to consider a classification of these disorders by the genetic disruption. In this article an attempt is made to classify human cortical dysplasias by the known genetic disruptions or insults that lead to them. The discussion of malformation is within the context of the embryologic processes that have thought to have gone awry. Human disorders of segmentation, cell proliferation, telencephalic cleavage, differentiation, and neuronal migration are discussed. As this is a rapidly changing area, the reader is encouraged to check online databases for updates on the genetic insights that have been gained since the publication of this article.

Body Patterning↗
PubMed1999

Nearest neighbor classification in 3D protein databases.

In molecular databases, structural classification is a basic task that can be successfully approached by nearest neighbor methods. The underlying similarity models consider spatial properties such as shape and extension as well as thematic attributes. We introduce 3D shape histograms as an intuitive and powerful approach to model similarity for solid objects such as molecules. Errors of measurement, sampling, and numerical rounding may result in small displacements of atomic coordinates. These effects may be handled by using quadratic form distance functions. An efficient processing of similarity queries based on quadratic forms is supported by a filter-refinement architecture. Experiments on our 3D protein database demonstrate the high classification accuracy of more than 90% and the good performance of the technique.

Algorithms↗
PubMed1994

Analyses of monoclonal antibodies reactive with porcine CD6.

Amongst the monoclonal antibodies (mAbs) submitted to the first porcine CD workshop, two mAbs (workshop numbers 055 and 120) could be identified to recognize the porcine CD6 analogue. Both mAbs seemed to be highly T-cell specific and showed neither reactivity with cells of the myeloic lineage nor with B lymphocytes. The observed molecular mass of the antigen precipitated by mAb 120 of 110 kDa confirmed this classification. Without molecular analyses of the antigen recognized by mAb 055, but similar staining pattern in FCM compared with 120, mAb 055 was allocated to the wCD6 subcluster.

Animals↗
PubMed2001

Cytochemical and molecular biological aspects of the pituitary and pituitary adenomas--cell differentiation and transcription factors.

The anterior pituitary is composed of several cell types, each responsible for the production of specific hormones. Each hormone secreting cells is defined by the activation of its respective hormone genes in a temporally and spatially regulated manner. Recent development in cytochemistry and molecular biology have provided various aspects of human pituitary adenomas, i.e., functional differentiation and classification. The molecular factors that determine hormone production have now been identified as transcription factors. Many novel transcription factors that play a role in anterior pituitary development are implicated. In this review, we focus on the transcriptional factors roles on functional differentiation of the pituitary cells and adenomas and the contribution of cytochemistry and recent development in molecular biological techniques.

Adenoma↗
PubMed2001

Transcriptional profiling in cancer: the path to clinical pharmacogenomics.

Cancer is a major source of morbidity and mortality, second only to heart disease as the leading cause of death in most developed countries. Our ability to treat the disease depends heavily on our understanding its aetiology. Different types of cancer often respond best to different courses of treatment, yet our understanding of cancer classification remains imperfect. Novel expression-monitoring technology provides unique opportunities to learn more about cancer at the molecular level, to improve classification methods, and to progress towards personalised cancer treatment. This review describes the techniques that make such advances possible, summarises recent work in the area, and discusses future developments needed to realise the potential of a thorough molecular classification of cancer.

Animals↗
PubMed2006

The dominantly inherited motor and sensory neuropathies: clinical and molecular advances.

The rapid advances in the molecular genetics and cell biology of hereditary neuropathy have revealed great genetic complexity. It is a challenge for physicians and laboratories to keep pace with new discoveries. Classification of hereditary neuropathies has evolved from a simple clinical to a detailed molecular classification. However, the molecular classification is not simple to use, as different mutations of the same gene produce a range of phenotypes. The logistics of testing for multiple gene mutations are considerable. This review gives a clinical overview of molecular and clinical advances in the dominant hereditary motor and sensory neuropathies [HMSNs, Charcot-Marie-Tooth (CMT) neuropathy], which account for some 60%-70% of families with CMT. The dominant forms of CMT have cellular mechanisms different from those of recessive forms and are a separate diagnostic challenge, so they are not included in this review. Diagnostic testing requires accurate clinical information and a selective approach to gene screening until the cost of multiple gene mutation screening falls. Accurate molecular diagnosis is critical to genetic counseling. This review concentrates on how molecular information can be used clinically, on how physicians can keep pace with new developments, and on the relevance of this new knowledge to patients.

Animals↗
PubMed2002

Fundamentals of prion biology and diseases.

One of the most remarkable changes in medicine during the last 20 years of the 20th century was the shift from the clinical-neuropathological classification of Creutzfeldt-Jakob disease (CJD) and related disorders as 'transmissible spongiform encephalopathies' to a molecular-etiologic classification as 'prion diseases'. We now know that these diseases are caused by abnormalities of the prion protein (PrP). Specifically, CJD is caused by the conversion of the normal, protease-sensitive PrP isoform, designated PrP(C), to a protease resistant isoform, designated PrP(Sc). PrP(Sc) forms into an infectious particle, named a 'prion', that can transmit the disease. Accumulation of PrP(Sc) in the brain causes neurodegeneration. The main goals of this review are to summarize our understanding of the attributes of the PrP molecule that give it the properties of an infectious agent and to describe how different alterations of the PrP molecule cause the multiple known prion disease variants. Finally, the emergence of a new variant of CJD in Great Britain and to a lesser extent in Europe and its relationship to the emergence of a particularly virulent form of bovine spongiform encephalopathy will be discussed.

Animals↗
PubMed2003

Analyzing tumor gene expression profiles.

A brief introduction to high throughput technologies for measuring and analyzing gene expression is given. Various supervised and unsupervised data mining methods for analyzing the produced high-dimensional data are discussed. The main emphasis is on supervised machine learning methods for classification and prediction of tumor gene expression profiles. Furthermore, methods to rank the genes according to their importance for the classification are explored. The approaches are illustrated by exploratory studies using two examples of retrospective clinical data from routine tests; diagnostic prediction of small round blue cell tumors (SRBCT) of childhood and determining the estrogen receptor (ER) status of sporadic breast cancer. The classification performance is gauged using blind tests. These studies demonstrate the feasibility of machine learning-based molecular cancer classification.

Adult↗
PubMed2000

[Current concepts of metastasis classification].

New findings of molecular pathology provide better insight in the process of metastasis. Single findings in few patients are, however, useful in being taken as parameters which signalize the individual risk of a metastasis not detectable by clinical methods. In addition they cannot be used as prognostic factors. On the other hand, there are important data which indicate a prognostic significance of so called isolated tumour cells, which can be detected by cytological or molecular methods. Current and proposed classifications of metastasis reflect the necessity, to better describe the situation of an individual patient to design an optimal therapy. Such more exact classifications will form the basis of a more differentiated therapy and will give more exact data to estimate prognosis.

Humans↗
PubMed2000

Contribution of molecular genetic data to the classification of sarcomas.

Many sarcomas are characterized by specific recurrent chromosomal translocations which provide powerful diagnostic tumor markers. Since 1992, the genes involved by almost all of these translocations have been cloned, inaugurating a new era in the study of sarcomas. At the biological level, these chromosomal translocations produce highly specific gene fusions, usually encoding aberrant chimeric transcription factors. Clinically, the correlation of these translocation-derived genetic markers and discrete histopathologic entities has been remarkable. Fusion gene detection has confirmed and refined the nosology of several sarcoma groups. The overall effect has been to strengthen certain pathological concepts rather than to revolutionize. The focus of this brief review is the recent impact that the cytogenetic and molecular detection of these translocations has had on sarcoma diagnosis and classification.

Artificial Gene Fusion↗