Genetic Pathology Research Articles

Cancer genomes and clinical care

Stratifying individual patients for specific therapies based on the clinical stage and morphological features (phenotype) of their disease is the basis of modern clinical oncology. Appropriate therapeutic regimens are selected in light of the characteristics of an individual’s cancer based on imaging and histopathology, which are indirect ‘surrogate’ measures of disease biology. Advances in molecular pathology and our understanding of cancer biology have led to refinement of existing clinico-pathological phenotypes, and in some cases such as leukaemia and breast cancer, a new molecular taxonomy has emerged which is integral to the modern management of these diseases. Increasingly, the development of a novel targeted therapy involves defining drug-diagnostic combinations where the presence of a molecular marker identifies patients who are most likely to respond to treatment. This model of developing treatment and diagnostic/companion biomarker combinations in order to target patient populations with a greater chance of benefiting from treatment is the emerging paradigm for new drug and diagnostic development. This strategy is facilitating significant advances in some cancer types, with one of the more recent examples being the successful use of the BRAF inhibitor PLX4032, which targets a specific mutation (V600E) in melanoma. The number of target-drug combinations with efficacy is growing, and some are suggesting that the era of personal genomic cancer therapy is already here. This emerging paradigm is changing the focus from therapeutic strategy development to diagnostics and will create significant challenges in the development and delivery of personalised medicine strategies. The Australian Pancreatic Cancer Genome Initiative, a part of the International Cancer Genome Consortium, aims to define, interpret and apply cancer genomic data. Direct potential clinical applications include the delineation of phenotypes based on patterns of genomic aberrations co-segregating with clinico-pathological endpoints and identifying druggable mutations. In addition, other approaches such as the detection of tumour specific genomic abnormalities in blood would have applications in early detection of recurrence and surrogate markers of therapeutic responsiveness. These advances are rapidly altering diagnostic and therapeutic strategies for cancer, and potentially other diseases, paving the way to genomic health. These advances in genetic pathology have the potential to refine, and possibly replace current morphology based diagnostic approaches.

“A decision meaning a new foundation…”: From the Kaiser Wilhelm Institute for Anthropology, Human Genetics and Eugenics to the Max Planck Institute for Molecular Genetics

The Max Planck Institute for Molecular Genetics (MPIMG) in Berlin-Dahlem dates its establishment to 1964. Its homepage makes no mention of its predecessor institutes, the Kaiser Wilhelm Institute for Anthropology, Human Genetics and Eugenics (KWIA) and the subsequent MPI for Comparative Genetics and Hereditary Pathology (MPIVEE). This article traces the two critical phases of transition regarding the constellations of academic staff, institutional and epistemic ruptures and continuities specific to the era. Only one of the five department heads from the final war years, Hans Nachtsheim, remained a researcher within the Max Planck Society (MPG); he nevertheless continued to advocate the pre-war and wartime eugenic agenda in the life sciences and social policy. The generational change of 1959/60 became a massive struggle within the institute, in which microbial genetics (with Fritz Kaudewitz) was pitted against human genetics (with Friedrich Vogel) and managed to establish itself after a fresh change in personnel in 1964/65. For the Dahlem institute, this involved a far-reaching reorientation of its research, but for the genetically oriented life sciences in the Max Planck Society as a whole it only meant that molecular biology, which was already being pursued in the West German institutes, gained an additional facility. With this realignment of research traditions, the Society was able to draw a line under the Nazi past without having to address it head-on.

Major Depressive Disorder With Subthreshold Bipolarity: Exploring and Managing New Diagnoses

Major Depressive Disorder With Subthreshold Bipolarity: Exploring and Managing New Diagnoses

Transmissible Genes Induced Chromosome-type Aberrations in the Lymphocytes of Multiple Endocrine Neoplasia Type 1 and Type 2A (MEN1 and MEN2A) Patients

Multiple endocrine neoplasia (MEN1& MEN2) are autosomal dominant disorders presenting tumors in two or more organs such as parathyroid tumors and anterior pituitary glands so on. Lymphocyte chromosomes from a MEN1patient with an anterior pituitary tumor including her sisters and children and 5 MEN2A patients with medullary thyroid carcinoma were studied for the genetic instability. Chromosome type aberrations such as dicentrics, rings, minutes, translocations and deletions were found in 20% of the observed cells of the MEN1patient. Three of the 5 patients showed a slight increase in this type of aberrations in 6.4, 4.3 and 1.1% of observed cells. Contrarily, frequencies of spontaneous chromatid type aberration in both MEN1and MEN2A patients were not significantly higher than of controls. There were no increase in the MTX-induced chromatid breaks and no unique fragile sites were observed in all MEN2A patients. High incidence of chromosome instability (only chromosome type aberrations) in the lymphocytes of MEN1 and MEN2A patients presents an interesting observation to understand the genetic pathology prone to the hereditary type tumor development of acquisition of more advance stage tumors and the mechanisms for how transmissible genes induce chromosome type aberrations alone.

Goals and guidelines for residency training in cytopathology

The time available to train residents in cytopathology has been impacted by the contraction of the training period, in the face of growing expectations for training in other facets of anatomic pathology and laboratory medicine (i.e. molecular genetic pathology, laboratory management and administration). Guidelines for appropriate levels of achievement in cytopathology have been proposed by those within the field, under the guidance of the Accreditation Council for Graduate Medical Education (ACGME). Presented here is a discussion of recommendations for training programs, in order to effectively train residents to an acceptable level of competence in cytopathology, within the training time allotted.

Sturge-Weber Syndrome With Congenital Glaucoma and Cytochrome P450 (CYP1B1) Gene Mutations

Sturge-Weber syndrome (SWS) is a progressive condition of mesodermal phakomatosis. This preliminary study is the first report of CYP1B1 mutation analysis in SWS with congenital glaucoma. Mutations in CYP1B1 gene are the major cause of congenital glaucoma. CYP1B1 is involved in metabolism of melatonin, retinol, and other endogenous/exogenous substrates. Mutations in CYP1B1 adversely affect signal transduction pathways and thus impair development/differentiation of anterior segment structures. This results in impaired aqueous outflow. CYP1B1 has higher expression in fetal eyes and plays major role in morphogenesis of iris, ciliary body, and anterior chamber angle. Hence, we decided to evaluate SWS cases with buphthalmos for 6 most prevalent CYP1B1 mutations by polymerase chain reaction-restriction-fragment length polymorphism followed by sequencing. Trabecular meshwork was studied for morphological alterations by scanning electron microscopy. All patients had normal 46, XY karyotype. Polymerase chain reaction-restriction-fragment length polymorphism showed CYP1B1 mutations in 2 of 5 SWS cases. Scanning electron microscopy findings were suggestive of trabecular dysgenesis. No CYP1B1 mutation has been reported in any SWS case till date because syndromic cases were not analyzed for mutations in earlier studies. Earlier studies have reported that onset of glaucoma in SWS shows a bimodal pattern. The results from this pilot study show that SWS cases with gyral calcification, buphthalmos, and early onset glaucoma should be analyzed for CYP1B1 mutations. The effect of vascular malformation-induced venous engorgement and raised intraocular pressure may only be additive and may result in a much more severe phenotype. SWS with buphthalmos and gyral calcification should undergo CYP1B1 mutation analysis to identify an underlying genetic pathology for glaucoma. This will aid in determining the prognosis and management and will also help to provide comprehensive counseling in such cases.

Genetics and developmental pathology of twinning

Twin pregnancy is associated with a high risk of congenital malformations. This review covers the risk of such anomalies in both dizygotic and monozygotic twin pregnancies, and discusses current insights into the associations relating to zygosity, chorionicity and genetic factors. The pathological basis of specific malformations unique to the monochorionic twinning process, including conjoined twinning and twin reversed arterial perfusion (TRAP) sequence, is discussed in more detail, and factors contributing to the higher perinatal mortality rate in multiple pregnancies are addressed.

Nonalcoholic, Nonbiliary Pancreatitis: Cross-Sectional Imaging Spectrum

The purpose of this review is to describe the epidemiologic, etiopathogenetic, clinical, and imaging characteristics of various nonalcoholic, nonbiliary pancreatitis syndromes. The spectrum of nonalcoholic, nonbiliary pancreatitis includes autoimmune pancreatitis, groove pancreatitis, hereditary pancreatitis, tropical pancreatitis, tuberculous pancreatitis, and metabolic pancreatitis. Advances in genetics and molecular pathology have shed new light on the etiopathogenesis and course of these syndromes. Accurate diagnosis aided by imaging findings allows optimal management.

Profile of Jeffery L. Dangl

If you make the mistake, as some do, of calling Jeff Dangl a botanist, his embarrassment is palpable. Trained as a mouse immunologist, he admits to a “certain lack” of botanical knowledge. The John N. Couch distinguished professor of biology and adjunct professor of microbiology and immunology at the University of North Carolina, Chapel Hill, will, however, give you an earful about the lack of respect, and with it, funding, historically given to the plant sciences compared with his former field of immunology. Jeffery L. Dangl. He studies Arabidopsis thaliana , a fast-growing, weedy plant known as thale cress, which has become the Drosophila of plant-based molecular biology. Long before it became the first plant to have its entire genome sequenced, Dangl was among a handful of researchers who pioneered its use as a model system for studying plant disease resistance, not solely as botanists but using all of the powerful tools of molecular biology, genetics, and plant pathology combined. He was at the cutting edge of what he calls a mini-revolution that not only showed that plants have an immune system, but that, at the genetic and molecular levels, the system shares basic organizational traits with mammals. For his work in deciphering how plants interact, at the molecular level, with pathogens to fight off disease, Dangl was elected into the National Academy of Sciences in 2007. In his Inaugural Article (1), Dangl, his graduate/postdoctoral student David Hubert, and colleagues build on that work using genetics techniques to show how three chaperone molecules interact to control the levels of nucleotide-binding domain and leucine-rich repeat (NB-LRR) proteins—critical intracellular receptors for proper immune function in plants. Dangl grew up in Redding, northern California, surrounded by mountains, lakes, and streams and close enough to the ocean for frequent visits. His mother, a teacher …

Out of a Cell into This Darkened Space

Out of a Cell into This Darkened Space

Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research

25–30% of families fulfilling the criteria for hereditary diffuse gastric cancer have germline mutations of the CDH1 (E-cadherin) gene. In light of new data and advancement of technologies, a multidisciplinary...

Early Pharmacotherapy Restores Neurogenesis and Cognitive Performance in the Ts65Dn Mouse Model for Down Syndrome

Down syndrome (DS) is a genetic pathology characterized by intellectual disability and brain hypotrophy. Widespread neurogenesis impairment characterizes the fetal and neonatal DS brain, strongly suggesting that this defect may be a major determinant of mental retardation. Our goal was to establish, in a mouse model for DS, whether early pharmacotherapy improves neurogenesis and cognitive behavior. Neonate Ts65Dn mice were treated from postnatal day (P) 3 to P15 with fluoxetine, an antidepressant that inhibits serotonin (5-HT) reuptake and increases proliferation in the adult Ts65Dn mouse (Clark et al., 2006). On P15, they received a BrdU injection and were killed after either 2 h or 1 month. Results showed that P15 Ts65Dn mice had notably defective proliferation in the hippocampal dentate gyrus, subventricular zone, striatum, and neocortex and that proliferation was completely rescued by fluoxetine. In the hippocampus of untreated P15 Ts65Dn mice, we found normal 5-HT levels but a lower expression of 5-HT1A receptors and brain-derived neurotrophic factor (BDNF). In Ts65Dn mice, fluoxetine treatment restored the expression of 5-HT1A receptors and BDNF. One month after cessation of treatment, there were more surviving cells in the dentate gyrus of Ts65Dn mice, more cells with a neuronal phenotype, more proliferating precursors, and more granule cells. These animals were tested for contextual fear conditioning, a hippocampus-dependent memory task, and exhibited a complete recovery of memory performance. Results show that early pharmacotherapy with a drug usable by humans can correct neurogenesis and behavioral impairment in a model for DS.

Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and management.

Frontotemporal lobar degeneration (FTLD) is a clinically and pathologically heterogeneous syndrome, characterized by progressive decline in behaviour or language associated with degeneration of the frontal and anterior temporal lobes. While the seminal cases were described at the turn of the 20th century, FTLD has only recently been appreciated as a leading cause of dementia, particularly in patients presenting before the age of 65 years. Three distinct clinical variants of FTLD have been described: (i) behavioural-variant frontotemporal dementia, characterized by changes in behaviour and personality in association with frontal-predominant cortical degeneration; (ii) semantic dementia, a syndrome of progressive loss of knowledge about words and objects associated with anterior temporal neuronal loss; and (iii) progressive nonfluent aphasia, characterized by effortful language output, loss of grammar and motor speech deficits in the setting of left perisylvian cortical atrophy. The majority of pathologies associated with FTLD clinical syndromes include either tau-positive (FTLD-TAU) or TAR DNA-binding protein 43 (TDP-43)-positive (FTLD-TDP) inclusion bodies. FTLD overlaps clinically and pathologically with the atypical parkinsonian disorders corticobasal degeneration and progressive supranuclear palsy, and with amyotrophic lateral sclerosis. The majority of familial FTLD cases are caused by mutations in the genes encoding microtubule-associated protein tau (leading to FTLD-TAU) or progranulin (leading to FTLD-TDP). The clinical and pathological heterogeneity of FTLD poses a significant diagnostic challenge, and in vivo prediction of underlying histopathology can be significantly improved by supplementing the clinical evaluation with genetic tests and emerging biological markers. Current pharmacotherapy for FTLD focuses on manipulating serotonergic or dopaminergic neurotransmitter systems to ameliorate behavioural or motor symptoms. However, recent advances in FTLD genetics and molecular pathology make the prospect of biologically driven, disease-specific therapies for FTLD seem closer than ever.

Inducible Positive Mutant Screening System to Unveil the Signaling Pathway of Late Blight Resistance

Late blight is the most devastating potato disease and it also causes serious yield loss in tomato. Several disease resistance genes (R genes) to late blight have been cloned from potato in the past decade. However, the resistance mechanisms remain elusive. Tomato and potato belong to the botanical family Solanaceace and share remarkably conserved genome structure. Since tomato is a model system in genetic and plant pathology research, we used tomato to develop a powerful mutant screening system that will greatly facilitate the analysis of the signaling pathway of resistance to Phytophthora infestans. First we proved that the R3a transgenic tomatoes developed specific hypersensitive cell death response (HR) to P. infestans strains carrying the corresponding avirulence gene Avr3a, indicating that the signaling pathway from the R3a-Avr3a recognition to HR is conserved between potato and tomato. Second, we generated transgenic tomatoes carrying both R3a and Avr3a genes, with the latter under the control of a glucocorticiod-inducible promoter. Dexamethasone induced expression of Avr3a and resulted in localized HR. This versatile system can be used to construct a mutant library to screen surviving mutants whose resistance signal transduction was interrupted, providing the basis to identify key genes involved in the resistance to late blight in Solanaceae.

Automated segmentation of tissue images for computerized IHC analysis

This paper presents two automated methods for the segmentation of immunohistochemical tissue images that overcome the limitations of the manual approach as well as of the existing computerized techniques. The first independent method, based on unsupervised color clustering, recognizes automatically the target cancerous areas in the specimen and disregards the stroma; the second method, based on colors separation and morphological processing, exploits automated segmentation of the nuclear membranes of the cancerous cells. Extensive experimental results on real tissue images demonstrate the accuracy of our techniques compared to manual segmentations; additional experiments show that our techniques are more effective in immunohistochemical images than popular approaches based on supervised learning or active contours. The proposed procedure can be exploited for any applications that require tissues and cells exploration and to perform reliable and standardized measures of the activity of specific proteins involved in multi-factorial genetic pathologies.

The Impact of Advances in Molecular Genetic Pathology on the Classification, Diagnosis and Treatment of Selected Soft Tissue Tumors of the Head and Neck

Recent advances in molecular pathology have had a significant impact on the diagnosis, classification, and treatment of soft tissue tumors. The practical application of these discoveries promises to assist greatly in the evaluation and treatment of soft tissue neoplasms in the head and neck region-an area characterized by exceedingly complex anatomy that often restricts the ample sampling of lesions and complete surgical resection. This reviews details some ways in which molecular techniques have strengthened conventional diagnostic and management approaches to low-grade fibromyxoid sarcoma, angiomatoid (malignant) fibrous histiocytoma, and dermatofibrosarcoma protuberans, all of which may involve the head and neck region.

Genetics and molecular pathology of Stargardt-like macular degeneration

Stargardt-like macular degeneration (STGD3) is an early onset, autosomal dominant macular degeneration. STGD3 is characterized by a progressive pathology, the loss of central vision, atrophy of the retinal pigment epithelium, and accumulation of lipofuscin, clinical features that are also characteristic of age-related macular degeneration. The onset of clinical symptoms in STGD3, however, is typically observed within the second or third decade of life (i.e., starting in the teenage years). The clinical profile at any given age among STGD3 patients can be variable suggesting that, although STGD3 is a single gene defect, other genetic or environmental factors may play a role in moderating the final disease phenotype. Genetic studies localized the STGD3 disease locus to a small region on the short arm of human chromosome 6, and application of a positional candidate gene approach identified protein truncating mutations in the elongation of very long chain fatty acids-4 gene (ELOVL4) in patients with this disease. The ELOVL4 gene encodes a protein homologous to the ELO group of proteins that participate in fatty acid elongation in yeast. Pathogenic mutations found in the ELOVL4 gene result in altered trafficking of the protein and behave with a dominant negative effect. Mice carrying an Elovl4 mutation developed photoreceptor degeneration and depletion of very long chain fatty acids (VLCFA). ELOVL4 protein participates in the synthesis of fatty acids with chain length longer than 26 carbons. Studies on ELOVL4 indicate that VLCFA may be necessary for normal function of the retina, and the defective protein trafficking and/or altered VLCFA elongation underlies the pathology associated with STGD3. Determining the role of VLCFA in the retina and discerning the implications of abnormal trafficking of mutant ELOVL4 and depleted VLCFA content in the pathology of STGD3 will provide valuable insight in understanding the retinal structure, function, and pathology underlying STGD3 and may lead to a better understanding of the process of macular disease in general.

Intérêt des modèles animaux pour l'étude des pathologies humaines : exemple d'un modèle de souris pour la trisomie 21

Animal models provide a simplified representation of biological systems impossible to study directly in the human being. Regarding genetic pathologies, mouse models are the most studied since they enable to reproduce in animals the mutation of the gene or genes responsible for the disease and to study the phenotypic consequences. Down syndrome is a genetic disorder arising from the presence of a third copy of the human chromosome 21 (Hsa21) and is characterized by different degrees of phenotypic alterations including morphological, cardiac, muscular, cerebral, motor and intellectual changes. This high phenotypic heterogeneity involves genetic and environmental effects, which are impossible to dissect out in human beings. Various models in mice have been developed in order to identify the genetic and neurobiological mechanisms responsible for Down syndrome. The Tc1 mouse is the most complete genetic animal model currently available to study Down syndrome, since it carries an almost complete Hsa 21. The behavioural and electrophysiological studies of this model reveal a great similarity between the animal phenotype and the Down syndrome symptomatology, consequently this model represents a powerful genetic tool with a potential to unravel the mechanisms underlying the deficiencies array characteristic of this human condition. In the long term, Tc1 mice will contribute to the development and the screening of new therapeutics, with the goal of improving all the impairments reported in Down syndrome.

Websites of note

Websites of note

Mitochondrial pathogenic mutations are population-specific

BackgroundSurveying deleterious variation in human populations is crucial for our understanding, diagnosis and potential treatment of human genetic pathologies. A number of recent genome-wide analyses focused on the prevalence of segregating deleterious alleles in the nuclear genome. However, such studies have not been conducted for the mitochondrial genome.ResultsWe present a systematic survey of polymorphisms in the human mitochondrial genome, including those predicted to be deleterious and those that correspond to known pathogenic mutations. Analyzing 4458 completely sequenced mitochondrial genomes we characterize the genetic diversity of different types of single nucleotide polymorphisms (SNPs) in African (L haplotypes) and non-African (M and N haplotypes) populations. We find that the overall level of polymorphism is higher in the mitochondrial compared to the nuclear genome, although the mitochondrial genome appears to be under stronger selection as indicated by proportionally fewer nonsynonymous than synonymous substitutions. The African mitochondrial genomes show higher heterozygosity, a greater number of polymorphic sites and higher frequencies of polymorphisms for synonymous, benign and damaging polymorphism than non-African genomes. However, African genomes carry significantly fewer SNPs that have been previously characterized as pathogenic compared to non-African genomes.ConclusionsFinding SNPs classified as pathogenic to be the only category of polymorphisms that are more abundant in non-African genomes is best explained by a systematic ascertainment bias that favours the discovery of pathogenic polymorphisms segregating in non-African populations. This further suggests that, contrary to the common disease-common variant hypothesis, pathogenic mutations are largely population-specific and different SNPs may be associated with the same disease in different populations. Therefore, to obtain a comprehensive picture of the deleterious variability in the human population, as well as to improve the diagnostics of individuals carrying African mitochondrial haplotypes, it is necessary to survey different populations independently.ReviewersThis article was reviewed by Dr Mikhail Gelfand, Dr Vasily Ramensky (nominated by Dr Eugene Koonin) and Dr David Rand (nominated by Dr Laurence Hurst).