Recent Molecular Genetic Findings Research Articles

Uncommon Morphologic Types of Endometrial Cancer and Their Mimickers: How Much Does Molecular Classification Improve the Practice for Challenging Cases?

The previous endometrial cancer (EC) FIGO staging primarily relied on the extent of the disease spread into the anatomical sites at diagnosis. The most recent one (2023) incorporates clinicopathological features such as histological subtype, tumor grade, the extent of lymphovascular space invasion (LVI), and, when available, molecular subtypes of EC. The emphasis on accurate histological typing, tumor grading, and the molecular features of the cancer is stronger than ever. This review addresses challenging diagnostic patterns in the histologic subtyping and grading EC under five categories: 1. EC with spindle cells, 2. EC with clear cells, 3. EC with a papillary architecture, 4. EC with a biphasic morphology, and 5. EC with a microglandular architecture. The morphological features differentiating low- and high-grade cancers are discussed, along with relevant clinical work-ups. Recent molecular genetic findings regarding the diagnosis and prognosis of the disease and the results of related clinical trials are summarized. The potential challenges in the evaluation of LVI follow these sections. The final section of the review includes an overview of the literature on incorporating molecular subtypes of EC into clinical practice.

Longitudinal Factor Structure of the Brief Psychiatric Rating Scale Among Incident Cases of Schizophrenia Attending a Nigerian Hospital.

Schizophrenia, from its early conceptualization, has been described in distinct clinical subtypes. However, these categories were found not to be stable phenotypes over time, hence the dimensional option, whereas at cross-sectional level, the dimensions of psychopathology have been replicated across studies; there is dearth of data on the longitudinal stability of the factor structure of the symptoms of schizophrenia in African populations. This study examined the longitudinal stability of the factor structure of the 18-item Brief Psychiatric Rating Scale (BPRS) across intervals of 16-week naturalistic treatment follow-up. Consecutive incident cases that fulfilled the criteria for schizophrenia were recruited into the study. After a baseline assessment, 160 incident cases of schizophrenia were followed up 4 weekly for indicators of symptomatic outcome for 16 weeks. The Brief Psychiatric Rating Scale (BPRS) assessments were conducted in clinical interviews and with the Scale for Assessment of Negative Symptoms (SANS). Five BPRS assessments were made across the monthly intervals of follow-up. Exploratory factor analyses (EFA) using maximum likelihood extraction and varimax rotation with Kaiser normalization was used to extract the factors. A four-factor structure was found at baseline, namely negative, positive, depressive/anxiety, and manic symptom dimensions. From week 4, the manic and anxiety/depression dimensions remained invariant over time, while negative and positive symptoms merged into a psychosis dimension that was invariant. The persistence of the mood dimensions supports the DSM-5 recommendation to include these dimensions in the assessment of schizophrenia psychopathology. The longitudinal emergence and invariance of the psychosis factor echo the idea of unitary psychosis and, along with the prominence of mood dimensions over time, reflect recent molecular genetic findings about the sharing of genes by schizophrenia and mood disorders.

The molecular genetic basis of creativity: a mini review and perspectives.

Although creativity is one of the defining features of human species, it is just the beginning of an ambitious attempt for psychologists to understand its genetic basis. With ongoing efforts, great progress has been achieved in molecular genetic studies of creativity. In this mini review, we highlighted recent molecular genetic findings for both domain-general and domain-specific creativity, and provided some perspectives for future studies. It is expected that this work will provide an update on the knowledge regarding the molecular genetic basis of creativity, and contribute to the further development of this field.

Assortative mating biases marker-based heritability estimators

Many traits are subject to assortative mating, with recent molecular genetic findings confirming longstanding theoretical predictions that assortative mating induces long range dependence across causal variants. However, all marker-based heritability estimators implicitly assume mating is random. We provide mathematical and simulation-based evidence demonstrating that both method-of-moments and likelihood-based estimators are biased in the presence of assortative mating and derive corrected heritability estimators for traits subject to assortment. Finally, we demonstrate that the empirical patterns of estimates across methods and sample sizes for real traits subject to assortative mating are congruent with expected assortative mating-induced biases. For example, marker-based heritability estimates for height are 14% – 23% higher than corrected estimates using UK Biobank data.

The Origin and Pathogenesis of Endometriosis.

Recent molecular genetic findings on endometriosis and normal endometrium suggest a modified model in which circulating epithelial progenitor or stem cells intended to regenerate uterine endometrium after menstruation may become overreactive and trapped outside the uterus. These trapped epithelium-committed progenitor cells form nascent glands through clonal expansion and recruit polyclonal stromal cells, leading to the establishment of deep infiltrating endometriosis. Once formed, the ectopic tissue becomes subject to immune surveillance, resulting in chronic inflammation. The inflammatory response orchestrated by nuclear factor-κB signaling is exacerbated by aberrations in the estrogen receptor-β and progesterone receptor pathways, which are also affected by local inflammation, forming a dysregulated inflammation-hormonal loop. Glandular epithelium within endometriotic tissue harbors cancer-associated mutations that are frequently detected in endometriosis-related ovarian cancers. In this review, we summarize recent advances that have illuminated the origin and pathogenesis of endometriosis and have provided new avenues for research that promise to improve the early diagnosis and management of endometriosis.

Maple syrup urine disease mutation spectrum in a cohort of 40 consanguineous patients and insilico analysis of novel mutations.

Maple syrup urine disease is the primary aminoacidopathy affecting branched-chain amino acid (BCAA) metabolism. The disease is mainly caused by the deficiency of an enzyme named branched-chained α-keto acid dehydrogenase (BCKD), which consist of four subunits (E1α, E1β, E2, and E3), and encoded by BCKDHA, BCKDHB, DBT, and DLD gene respectively. BCKD is the main enzyme in the catabolism pathway of BCAAs. Hight rate of autosomal recessive disorders is expected from consanguineous populations like Iran. In this study, we selected two sets of STR markers linked to the four genes, that mutation in which can result in MSUD disease. The patients who had a homozygous haplotype for selected markers of the genes were sequenced. In current survey, we summarized our recent molecular genetic findings to illustrate the mutation spectrum of MSUD in our country. Ten novel mutations including c.484 A > G, c.834_836dup CAC, c.357del T, and c. (343 + 1_344-1) _ (742 + 1_743-1)del in BCKDHB, c.355-356 ins 7nt ACAAGGA, and c.703del T in BCKDHA, and c.363delCT/c.1238T > C, c. (433 + 1_434-1) _ (939 + 1_940-1)del, c.1174 A > C, and c.85_86ins AACG have been found in DBT gene. Additionally, structural models of MSUD mutations have been performed to predict the pathogenicity of the newly identified variants.

Mass Migration and the Polynesian Settlement of New Zealand

This paper reintroduces the concept of mass migration into debates concerning the timing and nature of New Zealand’s settlement by Polynesians. Upward revisions of New Zealand’s chronology show that the appearance of humans on the landscape occurred extremely rapidly, and that within decades settlements had been established across the full range of climatic zones. We show that the rapid appearance of a strong archaeological signature in the early 14th century AD is the result of a mass migration event, not the consequence of gradual demographic growth out of a currently unidentified earlier phase of settlement. Mass migration is not only consistent with the archaeological record but is supported by recent findings in molecular biology and genetics. It also opens the door to a new phase of engagement between archaeological method and indigenous Maori and Polynesian oral history and tradition.

The Current Status of Solitary Fibrous Tumor: Diagnostic Features, Variants, and Genetics.

Solitary fibrous tumor (SFT) is a fibroblastic mesenchymal tumor originally described in the pleura but now shown at almost every anatomic site. Histopathologically, SFT is characteristically a circumscribed neoplasm composed of variably cellular and patternless distributions of bland spindle and ovoid cells within prominent collagenous stroma and shows diffuse expression of CD34, but it has a broad spectrum of both morphology and of biologic behavior. Many different names (particularly hemangiopericytoma) were previously used in the course of our understanding of this neoplasm but are now subsumed under the term "SFT," and the putative cell of origin was debated. However, it is now recognized that SFT is a translocation-associated neoplasm, consistently associated with NAB2-STAT6 gene fusions arising from recurrent intrachromosomal rearrangements on chromosome 12q, and this translocation is a likely major contributor to its pathogenesis. While most SFT with classical morphologic features behave in an indolent manner and those with overtly malignant histologic features tend to be aggressive neoplasms that behave as high-grade sarcomas, the behavior of SFT is unpredictable, and it is important to be aware of the propensity for aggressive behavior in a minority of histologically classical SFT and to ensure adequate clinical follow-up. Surgical excision remains the treatment gold standard; while radiotherapy and conventional chemotherapeutic agents have only shown limited efficacy, further understanding of the molecular events underlying tumorigenesis may allow the development of novel targeted treatments. We review SFT, discussing the morphologic spectrum and variants, including malignant and dedifferentiated subtypes, clinicopathological aspects, recent molecular genetic findings, and the differential diagnosis.

Ossifying fibromyxoid tumor: morphology, genetics, and differential diagnosis.

Ossifying fibromyxoid tumor (OFMT) is a soft tissue neoplasm of uncertain differentiation and intermediate (rarely metastasizing) biologic potential, with typical morphologic features, of an encapsulated, lobulated tumor comprising uniform polygonal cells within fibromyxoid stroma, which is surrounded by or contains metaplastic bone, classically as a peripheral rim of lamellar bone. Ossifying fibromyxoid tumor can arise at almost any site, although most frequently occurs within the extremities and trunk. Although most behave in a benign fashion, tumors can rarely show atypical or malignant features. It is now established that OFMTs represent translocation-associated tumors, with up to 85% associated with recurrent gene rearrangements, mostly involving the PHF1 gene (including in typical, atypical, and malignant neoplasms), with EP400-PHF1 in approximately 40% of tumors, and ZC3H7B-BCOR, MEAF6-PHF1, and EPC1-PHF1 fusions also described. Correct diagnosis is clinically important to ensure correct treatment and prognostication, both to avoid overdiagnosing OFMT as a malignant neoplasm such as osteosarcoma and also because of the propensity for aggressive behavior in a small number of OFMT. We review OFMT, with emphasis on the morphologic spectrum, recent molecular genetic findings, and the differential diagnosis.

An update on gnathic pathology.

An update on gnathic pathology.

Janus Molecule I: Dichotomous Effects of COMT in Neuropathic vs Nociceptive Pain Modalities

The enzyme catechol-O-methyltransferase (COMT) has been shown to play a critical role in pain perception by regulating levels of epinephrine (Epi) and norepinephrine (NE). Although the key contribution of catecholamines to the perception of pain has been recognized for a long time, there is a clear dichotomy of observations. More than a century of research has demonstrated that increasing adrenergic transmission in the spinal cord decreases pain sensitivity in animals. Equally abundant evidence demonstrates the opposite effect of adrenergic signaling in the peripheral nervous system, where adrenergic signaling increases pain sensitivity. Viewing pain processing within spinal and peripheral compartments and determining the directionality of adrenergic signaling helps clarify the seemingly contradictory findings of the pain modulatory properties of adrenergic receptor agonists and antagonists presented in other reviews. Available evidence suggests that adrenergic signaling contributes to pain phenotypes through α(1/2) and β(2/3) receptors. While stimulation of α(2) adrenergic receptors seems to uniformly produce analgesia, stimulation of α(1) or β receptors produces either analgesic or hyperalgesic effects. Establishing the directionality of adrenergic receptor modulation of pain processing, and related COMT activity in different pain models are needed to bring meaning to recent human molecular genetic findings. This will enable the translation of current findings into meaningful clinical applications such as diagnostic markers and novel therapeutic targets for complex human pain conditions.

The oculo-auriculo-fronto-nasal syndrome (OAFNS) – Description of a rare and complex craniofacial deformity and its interdisciplinary management before school age

Craniofacial clefts are certainly among the most challenging congenital malformations with respect to functional, aesthetic and psychosocial consequences. The aetiology is still under discussion, recent molecular genetic findings suggest defects in the ciliary function of neural crest cells during facial development. The severity of craniofacial clefting is known to be extremely variable. Different classifications have been proposed however nomenclature is not uniform. If vertical, median craniofacial clefting of fronto-naso-maxillary structures is accompanied by auriculo-mandibular malformations the term oculo-auriculo-fronto-nasal syndrome (OAFNS) has been proposed. Extreme craniofacial abnormalities have to be expected in this rare disorder. Adequate correction is a surgical challenge and interventions have to be adapted individually to patient's needs with respect to general condition, age and growth. This case report describes both the underlying pathology as well as the interdisciplinary management of a female patient from birth to 6years of age affected by this rare combination of vertical craniofacial clefting and bilateral auriculo-mandibular dysplasia.

Molecular genetics and the relationship between epilepsy and psychosis

We read with interest the paper by Adachi et al1 in which they conclude that early development of interictal psychosis in people with epilepsy may reflect individual vulnerabilities to psychosis, including genetic, rather than being driven by epilepsy-related damage. As they point out, their conclusion challenges traditional assumptions about the relationship between epilepsy and psychosis, many of which have been based on relatively sparse data. It is of interest that recent molecular genetic findings in psychosis suggest that the comorbidity of psychotic symptoms and epilepsy is a product of shared underlying biological mechanisms. For example, specific genomic structural variants (copy number variants) have been described that predispose to schizophrenia, epilepsy, as well as some other ‘neurodevelopmental’ phenotypes such as autism and intellectual disability.2 Individuals with such structural variants do not typically have both schizophrenia and epilepsy, but rather some with a variant have schizophrenia, others have epilepsy, and others have a different phenotype or are unaffected. This means that the relationship cannot be caused simply by ‘ toxic’ effects of epileptic seizures on the brain. Rather the finding strongly suggests that one or more genes, the function of which is disturbed by the structural variant, play(s) a role in the pathogenesis of both epilepsy and psychosis. A second recent observation of potential interest concerns genes encoding ion channels. Ion channelopathies are known to underlie some epilepsies, so it is of great interest that variation within the gene CACNA1C (encoding a subunit of the L-type voltage-dependent calcium channel) is associated with schizophrenia as well as recurrent depression and bipolar disorder.3,4 This suggests that ion channel dysfunction may be also be involved in mood and psychotic illness. Again, this provides support for the possibility that some individuals might experience both psychosis and epilepsy at least in part because of an underlying vulnerability to both. It is likely that as the understanding of brain function increases we will move closer to understanding the complexities, multiple associations and comorbidities that commonly occur in psychiatric illness. A sufficient number of adequately trained psychiatrists working within appropriate services will be vital for translating this knowledge into benefits for patients

The origins of early breast carcinoma

Assessing the distribution of the in situ and invasive components of breast carcinomas and the extent of the disease represent an integrated part of our diagnostic routine. In this article, we summarize findings from 792 consecutive breast carcinoma cases, each documented in large-format histology slides. Selected cases were also analyzed in thick, large sections. Of these, 35.0% (42/120) of the purely in situ carcinomas were diffuse and occupied mostly larger ducts, whereas 37.5% (45/120) were multifocal and involved several distant terminal ductal-lobular units (TDLUs). The proportion of unifocal in situ cases involving a single TDLU or several neighboring TDLUs was 27.5% (33/120). Forty-one percent (136/332) of early (< 15 mm) invasive carcinomas and 40.0% (136/340) of larger invasive tumors contained only a single invasive focus, with or without an in situ component within it. The remaining tumors were nonunifocal because of multiple invasive or multiple in situ foci or both. The proportion of extensive nonunifocal cases within purely in situ, early invasive, and more advanced invasive cases were 45.0% (54/120), 42.5% (141/332), and 42.4% (144/340), respectively. The results are discussed in the context of recent molecular genetic findings and the sick lobe theory. Elements that are congruent with the classical views of Professor Azzopardi expressed over 3 decades ago will be pointed out. Breast carcinoma seems to develop within a field of genetic alterations, often at multiple sites, and a considerable proportion of the cases comprise extensive lesions occupying a tissue space > or = 40 mm in all tumor size categories.

Molecular genetics of congenital atrial septal defects.

Congenital heart defects (CHD) are the most common developmental errors in humans, affecting 8 out of 1,000 newborns. Clinical diagnosis and treatment of CHD has dramatically improved in the last decades. Hence, the majority of CHD patients are now reaching reproductive age. While the risk of familial recurrence has been evaluated in various population studies, little is known about the genetic pathogenesis of CHD. In recent years significant progress has been made in uncovering genetic processes during cardiac development. Data from human genetic studies in CHD patients indicate that the genetic aetiology was presumably underestimated in the past. Inherited mutations in genes encoding cardiac transcription factors and sarcomeric proteins were found as an underlying cause for familial recurrence of non-syndromic CHD in humans, in particular cardiac septal defects. Notably, the cardiac phenotypes most frequently seen in mutation carriers are ostium secundum atrial septal defects (ASDII). This review outlines experimental approaches employed for the detection of CHD-related genes in humans and summarizes recent findings in molecular genetics of congenital cardiac septal defects with an emphasis on ASDII.

Flat Ductal Intraepithelial Neoplasia of the Breast: A Review of Diagnostic Criteria, Differential Diagnoses, Molecular-Genetic Findings, and Clinical Relevance—It Is Time to Appreciate the Azzopardi Concept!

More than 25 years ago, John G. Azzopardi described a distinctive intraepithelial neoplastic breast lesion, which he designated "clinging carcinoma in situ"; he considered it as another variant of ductal carcinoma in situ, an early lesion that can easily be missed because the changes are mainly cytologic rather than architectural. The lesion remained widely unrecognized and/or ignored until recent years when its neoplastic nature was confirmed at the molecular-genetic level. To deal with historical aspects of the evolving concept of "clinging" and to focus on several important issues such as characteristic morphologic features with particular attention to the diagnostic criteria and differential diagnoses, recent molecular-genetic findings, appropriate terminology and classification, as well as the significance of this type of lesion for both surgical pathologists and clinicians. A thorough search of the literature was performed and publications using a variety of designations including "clinging carcinoma in situ," "flat epithelial atypia," "ductal intraepithelial neoplasia-flat type," "atypical cystic lobules," "columnar cell change with atypia," "columnar cell hyperplasia with or without atypia," "columnar alteration with prominent apical snouts and secretion," and so forth were reviewed. This distinctive lesion represents one of the earliest morphologically recognizable neoplastic alterations of the breast that is commonly associated with mammographically suspicious microcalcifications. It is characterized by mildly to severely atypical cells simply replacing the single layer of native epithelial cells in a flat fashion without appreciable proliferation; tufting, intraluminal bridging, micropapillary structures, and so forth are typically absent or very focal and minimal, if present at all. Based on the degree of cytologic atypia, low- and high-grade flat ductal intraepithelial neoplasia need to be separated. Although additional studies are needed to better understand the clinical significance of flat ductal intraepithelial neoplasia, several lines of evidence strongly support the concept of clinging. Indeed, as pointed out by Azzopardi, surgical pathologists need to pay more attention to the cytologic alterations of the breast lesions by analyzing the involved cell populations using high-power magnification.

Viviparity‐driven Conflict

Equipped with Mendel's laws and only rudimentary knowledge of genes and genomes, the architects of the Modern Synthesis provided key insights into the dynamics of gene frequency change within populations. Extension of population genetic models to speciation identified Dobzhansky-Muller incompatibilities (negative epistatic interactions between genes from isolated populations) as the primary cause of hybrid inviability and sterility, a view consistent with empirical findings on the genetics of reproductive isolation in Drosophila. Although speciation models have become increasingly mathematically sophisticated, many remain based on an overly static concept of the genome, grounded in Mendelian genetics and devoid of potentially important biological details. A unifying theory of speciation therefore remains elusive, with debate over the relative importance of natural selection, sexual selection, sexual conflict, genetic drift, and selfish genetic elements in the evolution of reproductive isolation. Drawing on recent findings in molecular genetics and comparative genomics, we revisit, update, and extend the theory that reproductive mode plays a crucial role in shaping the speciation process. By providing a direct conduit for manipulation of the mother's physiology by genes expressed in the embryo, viviparity creates a postfertilization arena for genomic conflicts absent in species that lay eggs. In polyandrous species, viviparity-driven conflict (VDC) is likely to generate perpetual antagonistic coevolution between genes expressed during embryonic development and those involved in maternal reproductive physiology, thereby accelerating the rate at which postzygotic isolation evolves between populations. Moreover, in mammals and flowering plants, VDC has favored the evolution of genomic imprinting and a central role for epigenetic mechanisms in the regulation of antagonistic patterns of gene expression by maternally and paternally inherited genomes. VDC can account for the rapid rate at which mammals and viviparous fishes lose their ability to hybridize; the key role of the triploid endosperm in postzygotic reproductive isolation in flowering plants; and the kinds of traits, genes, and gene regulatory systems most critical to the evolution of postzygotic reproductive isolation in live-bearing species.

How to combine the molecular profile with the clinicopathological profile of urothelial neoplastic lesions

The current World Health Organization (WHO) 2004 classification of urothelial neoplasms was based on an attempt to reconcile molecular-genetic and pathology findings. This article provides an overview of the more recent molecular-genetic findings in the field and critically appraises their relationship with each of the WHO 2004 disease categories. Most of the WHO 2004 categories were successfully distinguished by means of expression and genome profiling and by distinct genetic alterations. Regarding urothelial papilloma, clinical and limited molecular-genetic data seem to suggest that they may not represent a precursor lesion for bladder cancer. It is more likely that urothelial papilloma is a benign neoplasm sharing mutations in the fibroblast growth factor-3 gene with seborrhoeic keratosis, allegedly its epidermal counterpart. Genetic alterations in papillary urothelial neoplasia of low malignant potential are identical to those found in non-invasive low-grade papillary urothelial carcinoma, implying that they are within a spectrum of the same neoplasm. Expression profiling data corroborate the view that (secondary) carcinoma in situ may act not only as a precursor lesion for invasive non-papillary urothelial carcinoma, but also as a precursor for non-muscle-invasive papillary urothelial carcinoma. Given the significant molecular genetic differences between non-invasive and invasive papillary urothelial carcinomas and their analogy with exophytic neoplastic precursor lesions in other organ systems, an alternative nomenclature is proposed, replacing papillary urothelial carcinoma with papillary intraurothelial neoplasm for the non-invasive (pTa) papillary carcinomas.

The genetics of depression and related traits

There is considerable evidence that genetic factors play a major role in the etiology of unipolar depression. Investigations into vulnerability genes for unipolar depression are underway and for more broadly defined depression-related traits, such as anxiety, neuroticism, and harm avoidance. This review discusses some of the core issues related to study design and molecular genetic methodology, followed by an overview of recent molecular genetic findings for unipolar depression. The research to date has identified regions within certain chromosomes that may contain risk genes. Improved study design and the use of new molecular techniques hold promise for the identification of more specific vulnerability genes for unipolar depression.

Genetics of anxiety disorders.

There is considerable evidence that genetic determinants play a major role in the etiology of anxiety. Investigations into susceptibility genes for anxiety are well underway, particularly for panic disorder and obsessive-compulsive disorder and more broadly defined anxiety-related traits, such as neuroticism and harm avoidance. This review will discuss some of the core issues related to diagnosis and molecular genetic methodology, followed by a review of recent molecular genetic findings for anxiety. The authors will attempt to highlight the numerous convergent and exciting findings. Given the rapid acceleration in knowledge of the human genome, a more definitive understanding of the genetic roots of these complex conditions may be anticipated in the relatively near future.