Search Results (11)

Species characterized by undetermined clade affiliations, limited research coverage, and deficient systematic investigation serve as enigmatic entities in plant and animal taxonomy, yet hold critical significance for exploring phylogenetic relationships and evolutionary trajectories. Subgenus Cyathophora (Allium, Amayllidaceae), a small taxon comprising approximately five species distributed in the Qinghai–Tibet Plateau (QTP) and adjacent regions might contain an enigmatic species that has long remained unexplored. In this study, we collected data on species from subgenus Cyathophora and its close relatives in subgenus Rhizirideum, as well as the enigmatic species Allium siphonanthum. Combining phylogenomic datasets and morphological evidence, we investigated species relationships and the underlying mechanism of phylogenetic discordance. A total of 1662 single-copy genes (SCGs) and 150 plastid loci were filtered and used for phylogenetic analyses based on concatenated and coalescent-based methods. Furthermore, to systematically evaluate phylogenetic discordance and decipher its underlying drivers, we implemented integrative analyses using multiple approaches, such as coalescent simulation, Quartet Sampling (QS), and MSCquartets. Our phylogenetic analyses robustly resolve A. siphonanthum as a member of subg. Cyathophora, forming a sister clade with A. spicatum. This relationship was further corroborated by their shared morphological characteristics. Despite the robust phylogenies inferred, extensive phylogenetic conflicts were detected not only among gene trees but also between SCGs and plastid-derived species trees. These significant phylogenetic incongruences in subg. Cyathophora predominantly stem from incomplete lineage sorting (ILS) and reticulate evolutionary processes, with historical hybridization events likely correlated with the past orogenic dynamics and paleoclimatic oscillations in the QTP and adjacent regions. Our findings not only provide new insights into the phylogeny of subg. Cyathophora but also significantly enhance our understanding of the evolution of species in this subgenus. Full article

Thyroid carcinomas are driven by diverse molecular alterations, but the tumor suppressor gene folliculin (FLCN), best known for its role in Birt–Hogg–Dubé (BHD) syndrome, has received limited attention in thyroid tumors. Here, we describe two thyroid tumors with pathogenic FLCN alterations—one germline and one somatic—and analyze the broader prevalence and significance of FLCN in thyroid carcinomas using multiple large sequencing datasets, including ORIEN-AVATAR. Patient 1, with a germline FLCN mutation and a history of BHD syndrome, presented with a well-circumscribed oncocytic adenoma. Molecular testing confirmed biallelic FLCN inactivation, but no additional mutations or aggressive features were observed, and the patient remained disease-free post-thyroidectomy. Patient 2 harbored a somatic FLCN mutation in an oncocytic poorly differentiated thyroid carcinoma, which exhibited extensive angioinvasion, high proliferative activity, and concurrent TP53 and RB1 mutations. The tumor progressed with metastatic disease despite multimodal treatment. Thyroid carcinomas revealed FLCN alterations in 1.1% of cases. Pathogenic mutations were rare but associated with oncocytic morphology, while homozygous deletions occurred more frequently in genomically unstable tumors, including anaplastic thyroid carcinoma. These findings suggest FLCN mutations may act as early oncogenic drivers in oncocytic thyroid neoplasms, while deletions represent secondary events in aggressive tumor evolution. The lack of FLCN coverage in standard thyroid molecular panels likely underestimates its clinical relevance. Including FLCN in genetic testing could improve tumor detection and characterization, particularly in BHD patients who may benefit from routine thyroid screening. Further studies are needed to clarify FLCN’s role in thyroid cancer pathogenesis. Full article

Targeted therapy indications for actionable variants in non-small-cell lung cancer (NSCLC) have primarily been studied in Caucasian populations, with limited data on Latin American patients. This study utilized a 52-genes next-generation sequencing (NGS) panel to analyze 1560 tumor biopsies from NSCLC patients in Chile, Brazil, and Peru. The RNA sequencing reads and DNA coverage were correlated to improve the detection of the actionable MET exon 14 skipping variant (METex14). The pathogenicity of MET variants of uncertain significance (VUSs) was assessed using bioinformatic methods, based on their predicted driver potential. The effects of the predicted drivers VUS T992I and H1094Y on c-MET signaling activation, proliferation, and migration were evaluated in HEK293T, BEAS-2B, and H1993 cell lines. Subsequently, c-Met inhibitors were tested in 2D and 3D cell cultures, and drug affinity was determined using 3D structure simulations. The prevalence of MET variants in the South American cohort was 8%, and RNA-based diagnosis detected 27% more cases of METex14 than DNA-based methods. Notably, 20% of METex14 cases with RNA reads below the detection threshold were confirmed using DNA analysis. The novel actionable T992I and H1094Y variants induced proliferation and migration through c-Met/Akt signaling. Both variants showed sensitivity to crizotinib and savolitinib, but the H1094Y variant exhibited reduced sensitivity to capmatinib. These findings highlight the importance of RNA-based METex14 diagnosis and reveal the drug sensitivity profiles of novel actionable MET variants from an understudied patient population. Full article

Activating mutations and fusions of the ALK oncogene have been identified as drivers in a number of malignancies. Crizotinib and subsequent ALK tyrosine kinase inhibitors have improved treatment outcomes for these patients. In this paper, we discuss the case of an adolescent patient with acute myeloid leukemia, who was identified to have an activating ALK fusion, which is a rare finding and has never been reported in cases of AML without monosomy 7. Crizotinib was added to this patient’s frontline therapy and was well tolerated. In cases of more common gene alterations, existing data supports the use of targeted agents as post-HSCT maintenance therapy; however, crizotinib was not able to be used post-HSCT for this patient due to the inability to obtain insurance coverage. Full article

Identifying the driver genes of cancer progression is of great significance in improving our understanding of the causes of cancer and promoting the development of personalized treatment. In this paper, we identify the driver genes at the pathway level via an existing intelligent optimization algorithm, named the Mouth Brooding Fish (MBF) algorithm. Many methods based on the maximum weight submatrix model to identify driver pathways attach equal importance to coverage and exclusivity and assign them equal weight, but those methods ignore the impact of mutational heterogeneity. Here, we use principal component analysis (PCA) to incorporate covariate data to reduce the complexity of the algorithm and construct a maximum weight submatrix model considering different weights of coverage and exclusivity. Using this strategy, the unfavorable effect of mutational heterogeneity is overcome to some extent. Data involving lung adenocarcinoma and glioblastoma multiforme were tested with this method and the results compared with the MDPFinder, Dendrix, and Mutex methods. When the driver pathway size was 10, the recognition accuracy of the MBF method reached 80% in both datasets, and the weight values of the submatrix were 1.7 and 1.89, respectively, which are better than those of the compared methods. At the same time, in the signal pathway enrichment analysis, the important role of the driver genes identified by our MBF method in the cancer signaling pathway is revealed, and the validity of these driver genes is demonstrated from the perspective of their biological effects. Full article

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and is the leading cause of cancer-related death. Despite advances in chemotherapy and immunotherapy, the prognosis for advanced patients remains poor. The discovery of oncogenic driver mutations, such as anaplastic lymphoma kinase (ALK) mutations, means that a subset of patients has opportunities for targeted therapy. With the improvement of genetic testing coverage, more and more ALK fusion subtypes and ALK partners have been discovered, and more than 90 rare ALK fusion subtypes have been found in NSCLC. However, unlike the common fusion, echinoderm microtubule-associated protein-like 4 (EML4)-ALK, some rare ALK fusions such as striatin (STRN)-ALK and huntingtin interacting protein 1 (HIP1)-ALK, etc., the large-scale clinical data related to its efficacy are still immature. The clinical application of ALK-tyrosine kinase inhibitors (ALK-TKIs) mainly depends on the positivity of the ALK gene, regardless of the molecular characteristics of the fusion partner. Recent clinical studies in the ALK-positive NSCLC population have demonstrated differences in progression-free survival (PFS) among patients based on different ALK fusion subtypes. This article will introduce the biological characteristics of ALK fusion kinase and common detection methods of ALK fusion and focus on summarizing the differential responses of several rare ALK fusions to ALK-TKIs, and propose corresponding treatment strategies, so as to better guide the application of ALK-TKIs in rare ALK fusion population. Full article

Universal antiretroviral therapy (ART, “treat all”) was recommended by the World Health Organization in 2015; however, HIV-1 transmission is still ongoing. This study characterizes the drivers of HIV transmission in the “treat all” era. Demographic and clinical information and HIV pol gene were collected from all newly diagnosed cases in Shenyang, the largest city in Northeast China, during 2016 to 2019. Molecular networks were constructed based on genetic distance and logistic regression analysis was used to assess potential transmission source characteristics. The cumulative ART coverage in Shenyang increased significantly from 77.0% (485/630) in 2016 to 93.0% (2598/2794) in 2019 (p < 0.001). Molecular networks showed that recent HIV infections linked to untreated individuals decreased from 61.6% in 2017 to 28.9% in 2019, while linking to individuals with viral suppression (VS) increased from 9.0% to 49.0% during the same time frame (p < 0.001). Undiagnosed people living with HIV (PLWH) hidden behind the links between index cases and individuals with VS were likely to be male, younger than 25 years of age, with Manchu nationality (p < 0.05). HIV transmission has declined significantly in the era of “treat all”. Undiagnosed PLWH may drive HIV transmission and should be the target for early detection and intervention. Full article

Biological invasions are considered one of the main extinction drivers of native species worldwide. Invasive species have detrimental effects on local ecosystems by means of competition, predation, habitat modification and nutrient cycling, as well as disease spreading. Along with ecological impacts, there are socio-economic consequences to human populations dependent on the services provided by these ecosystems. One of the most fundamental steps towards understanding the influence of invasive species is to determine their role on the local food web. The Mozambique tilapia (Oreochromis mossambicus) is an extremely aggressive opportunistic feeder that has a high biological and ecological plasticity, including flexible reproductive strategies (including mouthbrooding) and tolerance to a wide range of temperature, salinity and dissolved oxygen conditions. Its biological traits coupled with being used in aquaculture have made it a successful invader, widely distributed outside its native range. Yet, its populations have rarely been studied in the wild; hence, its potential impacts remain largely unknown. In this study, we investigate the diet of the invasive Mozambique tilapia in two mangroves of the oceanic island of São Tomé. We applied metabarcoding to simultaneously identify multiple taxa in tilapia gut content samples, using high-throughput sequencing. To achieve a greater taxonomic coverage, we combined the use of two barcodes, the 18S ribosomal RNA and the cytochrome C oxidase subunit I genes, to target phytoplankton and animal species, respectively. We found a total of 251 amplicon sequence variants belonging to 96 taxa. The results revealed diet differences between specimens from the two mangrove locations, not only regarding the level of biodiversity, but also in the frequencies of the occurrence of certain functional groups. Some taxa, such as diatoms, green algae and rotifers were found in the gut contents at both mangroves, whereas others, such as arthropods and mollusks, were almost exclusive to one of them. These findings provide useful insights into the ecological implications of the biological invasion of vulnerable island ecosystems, offering some specific guidance on how to minimize the impact of tilapia on the mangroves of the São Tomé Island. Full article

Metastatic renal cell carcinoma (RCC) exhibits poor prognosis. Better knowledge of distant metastases is crucial to foster personalized treatment strategies. Here, we aimed to investigate the genetic landscape of metastases, including synchronous and/or recurrent metastases to elucidate potential drug target genes and clinically relevant mutations in a real-world setting of patients. We assessed 81 metastases from 56 RCC patients, including synchronous and/or recurrent metastases of 19 patients. Samples were analysed through next-generation sequencing with a high coverage (~1000× mean coverage). We therefore established a novel sequencing panel comprising 32 genes with impact on RCC development. We observed a high frequency of mutations in known RCC driver genes (e.g., >40% carriers of VHL and PBRM1 mutations) in metastases irrespective of the metastatic site. The somatic mutational composition was significantly associated with cancer-specific survival (p(logrank) = 0.03). Moreover, we identified in 34 patients at least one drug target gene as well as clinically relevant mutations listed in the VICC Meta-Knowledgebase in 7%. In addition to significantly higher mutational burden in recurrent metastases compared to earlier ones, synchronous and/or recurrent metastases of individual patients, even after a time-period >2 yrs, shared a high proportion of somatic events. Our data demonstrate the importance of somatic profiling in metastases for precision medicine in RCC. Full article

Biomarker discovery would be an important tool in advancing and utilizing the concept of precision and personalized medicine in the clinic. Discovery of novel variants in local population provides confident targets for developing biomarkers for personalized medicine. We identified the need to generate high-quality sequencing data from local colorectal cancer patients and understand the pattern of occurrence of variants. In this report, we used archived samples from Saudi Arabia and used the AmpliSeq comprehensive cancer panel to identify novel somatic variants. We report a comprehensive analysis of next-generation sequencing results with a coverage of >300X. We identified 466 novel variants which were previously unreported in COSMIC and ICGC databases. We analyzed the genes associated with these variants in terms of their frequency of occurrence, probable pathogenicity, and clinicopathological features. Among pathogenic somatic variants, 174 were identified for the first time in the large intestine. APC, RET, and EGFR genes were most frequently mutated. A higher number of variants were identified in the left colon. Occurrence of variants in ERBB2 was significantly correlated with those of EGFR and ATR genes. Network analyses of the identified genes provide functional perspective of the identified genes and suggest affected pathways and probable biomarker candidates. This report lays the ground work for biomarker discovery and identification of driver gene mutations in local population. Full article

Among the different components that can be analyzed in liquid biopsy, the utility of exosomes is particularly promising because of their presence in all biological fluids and their potential for multicomponent analyses. Exosomes are extracellular vesicles with an average size of ~100 nm in diameter with an endosomal origin. All eukaryotic cells release exosomes as part of their active physiology. In an oncologic patient, up to 10% of all the circulating exosomes are estimated to be tumor-derived exosomes. Exosome content mirrors the features of its cell of origin in terms of DNA, RNA, lipids, metabolites, and cytosolic/cell-surface proteins. Due to their multifactorial content, exosomes constitute a unique tool to capture the complexity and enormous heterogeneity of cancer in a longitudinal manner. Due to molecular features such as high nucleic acid concentrations and elevated coverage of genomic driver gene sequences, exosomes will probably become the “gold standard” liquid biopsy analyte in the near future. Full article