Explore the vast range of titles available.

PurposeEndometrial mesonephric-like adenocarcinoma (ML-AC) represents a recently recognized subtype of endometrial adenocarcinoma (AC) associated with a subtle immunophenotype with a characteristic KRAS-mutation. Detailed clinico-pathologic analyses and prognostic data on ML-AC are limited.MethodsWe report a series of four cases with histopathological, immunohistochemical, and molecular analyses. These cases as well as the data of previously published cases were reviewed for clinico-pathologic variables and clinical follow-up information.ResultsForty cases of ML-AC were identified. ML-AC represents about 1% of all endometrial carcinomas. Similar to other types of endometrial AC, vaginal bleeding was the leading presenting symptom, and the mean age was 60.0 years (range 31–91). More than a half of the patients presented with locally advanced disease (≥ FIGO stage II) at time of diagnosis, developed a recurrence or died of the disease within a mean follow-up period of 24.7 months (range 3–144.5 months). The most common site of distant disease was pulmonary involvement. Microscopically, ML-ACs present with mixed morphology and show a co-expression of so-called mesonephric and Müllerian markers, suggesting a Müllerian origin of the tumors. Immunostaining for PD-L1 was negative in all tested cases, using different antibodies against PD-L1. Retained staining for mismatch repair proteins on immunohistochemistry and a POLE-mutation suggest a copy number low phenotype within the molecular classification of endometrial carcinomas. Almost all cases showed a KRAS-mutation at codon 12 (mostly G12V).ConclusionUterine ML-AC represents a distinct subtype of invasive endometrial AC, associated with KRAS-mutations and characteristic immunohistochemical findings. Clinically, ML-AC may show an aggressive behavior with a high rate of recurrent disease and a substantial risk for distant metastatic disease, especially to the lungs.

The extinct ‘New World stilt-legged’, or NWSL, equids constitute a perplexing group of Pleistocene horses endemic to North America. Their slender distal limb bones resemble those of Asiatic asses, such as the Persian onager. Previous palaeogenetic studies, however, have suggested a closer relationship to caballine horses than to Asiatic asses. Here, we report complete mitochondrial and partial nuclear genomes from NWSL equids from across their geographic range. Although multiple NWSL equid species have been named, our palaeogenomic and morphometric analyses support the idea that there was only a single species of middle to late Pleistocene NWSL equid, and demonstrate that it falls outside of crown group Equus. We therefore propose a new genus, Haringtonhippus, for the sole species H. francisci. Our combined genomic and phenomic approach to resolving the systematics of extinct megafauna will allow for an improved understanding of the full extent of the terminal Pleistocene extinction event. The horse family – which also includes zebras, donkeys and asses – is often featured on the pages of textbooks about evolution. All living horses belong to a group, or genus, called Equus. The fossil record shows how the ancestors of these animals evolved from dog-sized, three-toed browsers to larger, one-toed grazers. This process took around 55 million years, and many members of the horse family tree went extinct along the way. Nevertheless, the details of the horse family tree over the past 2.5 million years remain poorly understood. In North America, horses from this period – which is referred to as the Pleistocene – have been classed into two major groups: stout-legged horses and stilt-legged horses. Both groups became extinct near the end of the Pleistocene in North America, and it was not clear how they relate to one another. Based on their anatomy, many scientists suggested that stilt-legged horses were most closely related to modern-day asses living in Asia. Yet, other studies using ancient DNA placed the stilt-legged horses closer to the stout-legged horses. Heintzman et al. set out to resolve where the stilt-legged horses sit within the horse family tree by examining more ancient DNA than the previous studies. The analyses showed that the stilt-legged horses were much more distinct than previously thought. In fact, contrary to all previous findings, these animals actually belonged outside of the genus Equus. Heintzman et al. named the new genus for the stilt-legged horses Haringtonhippus, and showed that all stilt-legged horses belonged to a single species within this genus, Haringtonhippus francisci. Together these new findings provide a benchmark for reclassifying problematic fossil groups across the tree of life. A similar approach could be used to resolve the relationships in other problematic groups of Pleistocene animals, such as mammoths and bison. This would give scientists a more nuanced understanding of evolution and extinction during this period.

Genetic diagnostics of neurodevelopmental disorders with epilepsy (NDDE) are predominantly applied in children, thus limited information is available regarding adults or elderly. We investigated 150 adult/elderly individuals with NDDE by conventional karyotyping, FMR1 testing, chromosomal microarray, panel sequencing, and for unresolved cases, also by exome sequencing (nsingle = 71, ntrios = 24). We identified (likely) pathogenic variants in 71 cases (47.3%) comprising fragile X syndrome (n = 1), disease-causing copy number (n = 23), and single-nucleotide variants (n = 49). Seven individuals displayed multiple independent genetic diagnoses. The diagnostic yield correlated with the severity of intellectual disability. Individuals with anecdotal evidence of exogenic early-life events (e.g., nuchal cord, complications at delivery) with alleged/unproven association to the disorder had a particularly high yield of 58.3%. Screening for disease-specific comorbidities was indicated in 45.1% and direct treatment consequences arose in 11.8% of diagnosed individuals. Panel/exome sequencing displayed the highest yield and should be considered as first-tier diagnostics in NDDE. This high yield and the numerous indications for additional screening or treatment modifications arising from genetic diagnoses indicate a current medical undersupply of genetically undiagnosed adult/elderly individuals with NDDE. Moreover, knowledge of the course of elderly individuals will ultimately help in counseling newly diagnosed individuals with NDDE.

Telomerase reverse transcriptase ( TERT ) promoter mutations occur frequently in cancer, have been associated with increased TERT expression and cell proliferation, and could potentially influence therapeutic regimens for melanoma. As the role of TERT expression in malignant melanoma and the non-canonical functions of TERT remain understudied, we aimed to extend the current knowledge on the impact of TERT promoter mutations and expression alterations in tumor progression by analyzing several highly annotated melanoma cohorts. Using multivariate models, we found no consistent association for TERT promoter mutations or TERT expression with the survival rate in melanoma cohorts under immune checkpoint inhibition. However, the presence of CD4+ T cells increased with TERT expression and correlated with the expression of exhaustion markers. While the frequency of promoter mutations did not change with Breslow thickness, TERT expression was increased in metastases arising from thinner primaries. As single-cell RNA-sequencing (RNA-seq) showed that TERT expression was associated with genes involved in cell migration and dynamics of the extracellular matrix, this suggests a role of TERT during invasion and metastasis. Co-regulated genes found in several bulk tumors and single-cell RNA-seq cohorts also indicated non-canonical functions of TERT related to mitochondrial DNA stability and nuclear DNA repair. This pattern was also evident in glioblastoma and across other entities. Hence, our study adds to the role of TERT expression in cancer metastasis and potentially also immune resistance.

The straight-tusked elephants Palaeoloxodon spp. were widespread across Eurasia during the Pleistocene. Phylogenetic reconstructions using morphological traits have grouped them with Asian elephants (Elephas maximus), and many paleontologists place Palaeoloxodon within Elephas. Here, we report the recovery of full mitochondrial genomes from four and partial nuclear genomes from two P. antiquus fossils. These fossils were collected at two sites in Germany, Neumark-Nord and Weimar-Ehringsdorf, and likely date to interglacial periods ~120 and ~244 thousand years ago, respectively. Unexpectedly, nuclear and mitochondrial DNA analyses suggest that P. antiquus was a close relative of extant African forest elephants (Loxodonta cyclotis). Species previously referred to Palaeoloxodon are thus most parsimoniously explained as having diverged from the lineage of Loxodonta, indicating that Loxodonta has not been constrained to Africa. Our results demonstrate that the current picture of elephant evolution is in need of substantial revision. Understanding how extinct species are related to each other or to their living relatives is often a difficult task. Many extinct species have been identified only from incomplete fragments of some of their bones. However, even if complete skeletons have been found, determining the relationships between species can be tricky because researchers often have to rely solely on the shapes of the bones. It is sometimes possible to retrieve DNA sequences from fossil bones. This is easier with younger fossils and those that have been recovered from cold environments. Ancient DNA sequences have been retrieved from only a few fossils older than 100,000 years, but such DNA sequences can be tremendously useful in determining how different species are related to each other. Today there are three living elephant species: the African forest elephant, the African savanna elephant and the Asian elephant. However, there are many extinct elephant species. For example, the European straight-tusked elephant went extinct at least 30,000 years ago, although most of the fossils that have been discovered are at least 100,000 years old. Straight-tusked elephants are generally assumed to be closely related to the Asian elephant, but this conclusion had been based solely on reconstructing skeletons. Meyer et al. have now obtained DNA sequences from fossils of four straight-tusked elephants ranging from around 120,000 to 240,000 years in age. These sequences were analysed to determine how straight-tusked elephants are related to the three living elephant species and the extinct mammoth, the DNA sequences for which can be found in public databases. The analyses revealed that straight-tusked elephants are in fact most closely related to the African forest elephant, not the Asian elephant as previously thought. This result completely changes our picture of elephant evolution and suggests that it is extremely difficult to determine elephant relationships based on the shape of their skeleton alone. It also shows that the African elephant lineage was not restricted to the African continent (the place where all elephant lineages originated), but that it also left Africa. Overall, the results presented by Meyer et al. confirm that DNA sequences are of critical importance for understanding the evolution of animals. Future research should include obtaining DNA sequences from additional extinct elephant species as well as careful re-evaluation of skeletal measurements for reconstructing elephant evolution.

Significance Knowledge of ancient viruses is limited due to their low concentration and poor preservation in ancient specimens. Using a viral particle-associated nucleic acid enrichment approach, we genetically characterized one complete DNA and one partial RNA viral genome from a 700-y-old fecal sample preserved in ice. Using reverse genetics, we reconstituted the DNA virus, which replicated and systemically spread in a model plant species. Under constant freezing conditions, encapsidated viral nucleic acids may therefore be preserved for centuries. Our finding indicates that cryogenically preserved materials can be repositories of ancient viral nucleic acids, which in turn allow molecular genetics to regenerate viruses to study their biology. Viruses preserved in ancient materials provide snapshots of past viral diversity and a means to trace viral evolution through time. Here, we use a metagenomics approach to identify filterable and nuclease-resistant nucleic acids preserved in 700-y-old caribou feces frozen in a permanent ice patch. We were able to recover and characterize two viruses in replicated experiments performed in two different laboratories: a small circular DNA viral genome (ancient caribou feces associated virus, or aCFV) and a partial RNA viral genome (Ancient Northwest Territories cripavirus, or aNCV). Phylogenetic analysis identifies aCFV as distantly related to the plant-infecting geminiviruses and the fungi-infecting Sclerotinia sclerotiorum hypovirulence-associated DNA virus 1 and aNCV as within the insect-infecting Cripavirus genus. We hypothesize that these viruses originate from plant material ingested by caribou or from flying insects and that their preservation can be attributed to protection within viral capsids maintained at cold temperatures. To investigate the tropism of aCFV, we used the geminiviral reverse genetic system and introduced a multimeric clone into the laboratory model plant Nicotiana benthamiana . Evidence for infectivity came from the detection of viral DNA in newly emerged leaves and the precise excision of the viral genome from the multimeric clones in inoculated leaves. Our findings indicate that viral genomes may in some circumstances be protected from degradation for centuries.

Despite extensive genetic analysis, the evolutionary relationship between polar bears (Ursus maritimus) and brown bears (U. arctos) remains unclear. The two most recent comprehensive reports indicate a recent divergence with little subsequent admixture or a much more ancient divergence followed by extensive admixture. At the center of this controversy are the Alaskan ABC Islands brown bears that show evidence of shared ancestry with polar bears. We present an analysis of genome-wide sequence data for seven polar bears, one ABC Islands brown bear, one mainland Alaskan brown bear, and a black bear (U. americanus), plus recently published datasets from other bears. Surprisingly, we find clear evidence for gene flow from polar bears into ABC Islands brown bears but no evidence of gene flow from brown bears into polar bears. Importantly, while polar bears contributed <1% of the autosomal genome of the ABC Islands brown bear, they contributed 6.5% of the X chromosome. The magnitude of sex-biased polar bear ancestry and the clear direction of gene flow suggest a model wherein the enigmatic ABC Island brown bears are the descendants of a polar bear population that was gradually converted into brown bears via male-dominated brown bear admixture. We present a model that reconciles heretofore conflicting genetic observations. We posit that the enigmatic ABC Islands brown bears derive from a population of polar bears likely stranded by the receding ice at the end of the last glacial period. Since then, male brown bear migration onto the island has gradually converted these bears into an admixed population whose phenotype and genotype are principally brown bear, except at mtDNA and X-linked loci. This process of genome erosion and conversion may be a common outcome when climate change or other forces cause a population to become isolated and then overrun by species with which it can hybridize.

The genus Equus is richly represented in the fossil record, yet our understanding of taxonomic relationships within this genus remains limited. To estimate the phylogenetic relationships among modern horses, zebras, asses and donkeys, we generated the first data set including complete mitochondrial sequences from all seven extant lineages within the genus Equus. Bayesian and Maximum Likelihood phylogenetic inference confirms that zebras are monophyletic within the genus, and the Plains and Grevy's zebras form a well-supported monophyletic group. Using ancient DNA techniques, we further characterize the complete mitochondrial genomes of three extinct equid lineages (the New World stilt-legged horses, NWSLH; the subgenus Sussemionus; and the Quagga, Equus quagga quagga). Comparisons with extant taxa confirm the NWSLH as being part of the caballines, and the Quagga and Plains zebras as being conspecific. However, the evolutionary relationships among the non-caballine lineages, including the now-extinct subgenus Sussemionus, remain unresolved, most likely due to extremely rapid radiation within this group. The closest living outgroups (rhinos and tapirs) were found to be too phylogenetically distant to calibrate reliable molecular clocks. Additional mitochondrial genome sequence data, including radiocarbon dated ancient equids, will be required before revisiting the exact timing of the lineage radiation leading up to modern equids, which for now were found to have possibly shared a common ancestor as far as up to 4 Million years ago (Mya).

Glioneural tumors are primary brain tumors that consist of both neural and glial neoplastic cells, often presenting with seizures and primarily affecting children and young adults. Specifically, gangliogliomas are composed of neoplastic ganglion and glial cells, accompanied by other characteristic histological features such as lymphoid cuffing, eosinophilic granular bodies, and Rosenthal fibers. Oncogenic driver mutations and gene fusions have been shown to be of prognostic significance in gangliogliomas and can offer potential therapeutic targets. Typical molecular alterations are mitogen-activated protein kinase (MAPK) pathway activations with BRAF p.V600E being the most frequent one. Here, we report for the first time a gene fusion between epidermal growth factor receptor ( EGFR ) and vesicular, overexpressed in cancer, prosurvival protein 1 ( VOPP1) as a potential oncogenic driver in a glioneuronal tumor morphologically resembling ganglioglioma. VOPP1::EGFR fusion associated with the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling. Furthermore, we provide histological and epigenetic findings and clinical outcome. The case expands the known molecular spectrum of oncogenic drivers in glioneuronal tumors and provides a link to potentially prognostic and therapeutically relevant alterations.

Pathogenic variants in TP53 have been classically thought to cause Li-Fraumeni syndrome (LFS), a cancer predisposition with high risks for various childhood- and adult-onset malignancies. However, increased genetic testing has lately revealed, that pathogenic variant carriers exhibit a broader range of phenotypes and that penetrance may be dependent both on variant type and modifiers. Using next generation sequencing and short tandem repeat analysis, we identified germline pathogenic variants in TP53 and RAD51C located in cis on chromosome 17 in a 43-year-old male, who has developed a rare sebaceous gland carcinoma (SGC) but so far no tumors of the LFS spectrum. This course mirrors a Trp53-Rad51c-double-mutant cis mouse-model, which similarly develops SGC, while the characteristic Trp53-associated tumor spectrum occurs with significantly lower frequency. Therefore, we propose that co-occurent pathogenic variants in RAD51C and TP53 may predispose to SGC, reminiscent of Muir-Torre syndrome. Further, this report supports the diversity of clinical presentations associated with germline TP53 alterations, and thus, the proposed expansion of LFS to heritable TP53-related cancer syndrome.