Recent Genomic Discoveries Research Articles

5-mC methylation study of sORFs in 3'UTR of transcription factor JUNGBRUNNEN 1-like during leaf rust pathogenesis in wheat.

JUB1, a NAC domain containing hydrogen peroxide-induced transcription factor, plays a critical role in plant immunity. Little is known about how JUB1 responds to leaf rust disease in wheat. Recent discoveries in genomics have also unveiled a multitude of sORFs often assumed to be non-functional, to argue for the necessity of including them as potential regulatory players of translation. However, whether methylation on sORFs spanning the 3'UTR of regulatory genes like JUB1 modulate gene expression, remains unclear. In this study, we identified the methylation states of two sORFs in 3'UTR of a homologous gene of JUB1 in wheat, TaJUB1-L, at cytosine residues in CpG, CHH and CHG sites at different time points of disease progression in two near-isogenic lines of wheat (HD2329), with and without Lr24 gene during leaf rust pathogenesis. Here, we report a significant demethylation of the CpG dinucleotides occurring in the sORFs of the 3'UTR in the resistant isolines after 24h post-infection. Also, the up-regulated gene expression observed through RT-qPCR was directly proportional to the demethylation of the CpG sites in the sORFs. Our findings indicate that TaJUB1-L might be a positive regulator in providing tolerance during leaf rust pathogenesis and cytosine methylation at 3'UTR might act as a switch for its expression control. These results enrich the potential benefit of conventional methylation assay techniques for unraveling the unexplored enigma in epigenetics during plant-pathogen interaction in a cost-effective and confidentially conclusive manner.

Large-scale genomic analysis of the domestic dog informs biological discovery.

Recent advances in genomics, coupled with a unique population structure and remarkable levels of variation, have propelled the domestic dog to new levels as a system for understanding fundamental principles in mammalian biology. Central to this advance are more than 350 recognized breeds, each a closed population that has undergone selection for unique features. Genetic variation in the domestic dog is particularly well characterized compared with other domestic mammals, with almost 3000 high-coverage genomes publicly available. Importantly, as the number of sequenced genomes increases, new avenues for analysis are becoming available. Herein, we discuss recent discoveries in canine genomics regarding behavior, morphology, and disease susceptibility. We explore the limitations of current data sets for variant interpretation, tradeoffs between sequencing strategies, and the burgeoning role of long-read genomes for capturing structural variants. In addition, we consider how large-scale collections of whole-genome sequence data drive rare variant discovery and assess the geographic distribution of canine diversity, which identifies Asia as a major source of missing variation. Finally, we review recent comparative genomic analyses that will facilitate annotation of the noncoding genome in dogs.

Phylogeny and evolutionary timescales of the tribes Tagiadini and Celaenorrhinini (Hesperiidae, Pyrginae) inferred from mitochondrial genome and nuclear genes

AbstractTagiadini and Celaenorrhinini, two closely related groups of skippers in the subfamily Pyrginae, are mainly distributed across the Oriental, Palaearctic and African regions. While some efforts have been made to explore the phylogenetic relationships within Tagiadini and Celaenorrhinini, several unresolved issues still persist. In this study, we sequenced 13 complete mitochondrial genomes from Tagiadini and Celaenorrhinini. Additionally, we extracted nuclear genes CAD, EF‐1α, IDH, MDH, RPS5 and Wingless from the public database. Through comparative analysis, we gained insights into the structure of these newly sequenced mitogenomes. Furthermore, we constructed a comprehensive phylogenetic tree for Tagiadini and Celaenorrhinini, integrating the newly obtained mitochondrial genomes and nuclear genes with previously published mitogenomes and data from the sequence read archive (SRA). The total length of the mitochondrial genomes of the 13 skipper species ranged from 15,228 bp (Seseria sambara indosinica) to 15,431 bp (Pseudocoladenia festa). The newly sequenced genomes featured the standard set of 13 protein‐coding genes (PCGs), 22 transfer RNA genes (tRNAs), 2 ribosomal RNA genes (rRNAs) and a non‐coding A + T‐rich region implicated in replication initiation. The phylogenetic analysis encompassing all mitochondrial and nuclear gene data consistently upheld the monophyly of genera within the tribes Tagiadini and Celaenorrhinini. Most of the intergeneric relationships identified in our study agreed with recent genomic discoveries, showing enhanced nodal support values in some cases. Lastly, we estimated the divergence of the Tagiadini + Celaenorrhinini branch at approximately 44.06 million years ago (Ma) during the middle Eocene epoch. The crown ages of Tagiadini and Celaenorrhinini were estimated at approximately 41.69 Ma and 38.49 Ma, respectively.

Novel blood-based assay for detection of early stage multi-cancer.

e15035 Background: Early cancer detection has the potential to significantly improve patient outcomes and reach the Cancer Moonshot goals of reducing the death rate from cancer by at least 50 percent over the next 25 years. Harbinger Health is pioneering early cancer detection with a blood-based test that combines recent genomic and epigenomic discoveries of early cancer and biology-informed artificial intelligence. Unlike prior approaches that are purely statistical to identify informative biomarkers, Harbinger’s approach is informed by insights into specific biological events early during tumorigenesis and is therefore optimized for detecting cancer in patients with very low levels of circulating tumor DNA. Methods: Here, we present data generated using the Harbinger Health assay from 1,046 subjects, 621 with newly diagnosed, treatment-naive cancer (15 different cancer types) and 425 individuals with no history, diagnosis, or cancer symptoms. Using this sample cohort, we developed and applied a rigorous framework for training, calibration and predicting likelihood of cancer using a multi-layered logistic regression-based machine learning algorithm, generating final outputs of binary classification (cancer yes/no). Our framework involved multiple iterations of 10-fold cross-validation of the full dataset, and we report solely on samples that appear in the held-out test set in each iteration. Additionally, we developed a similar framework to predict tissue of origin (TOO) for cancer samples. Results: The overall sensitivity of cancer detection was 82% (95% confidence interval (CI): 72.7-91.0%) at 95% specificity. Notably, the sensitivity was 74% (95% CI: 54.8-92.7%) for stage 1 and 84% (95% CI: 65.3-100%) for stage 2. Furthermore, we were able to correctly predict cancer in 95% of patient samples with at least 0.037% tumor fraction. The overall sensitivity for high incident cancers were: breast (73%), prostate (82%), lung (85%), and colorectal (96%) at 95% specificity and the overall accuracy of TOO prediction was 86% when the tumor fraction was greater than 0.1% in the top 3 most prevalent cancer types (breast, colorectal and lung). Importantly, we noted that technical variability was introduced when performing assay optimization strategies, yet we observed comparable performance when assessing subsets of stably processed samples, indicating that our performance is robust. Conclusions: Overall, these results demonstrate that the Harbinger Health platform, with its biology-informed approach, has the potential for highly sensitive multi-cancer diagnostic accuracy and specifically those with early-stage cancer. The platform is now being validated in a 10,000-subject prospective clinical trial (CORE-HH/NCT05435066).

What's new in the WHO 2022 classification of kidney tumours?

The World Health Organization (WHO) 2022 classification of urinary and male genital tumours (5th edition) has significantly improved our understanding of the morphologic, immunohistochemical, and molecular characteristics of renal tumours. The aim of this review is to outline the most important changes and diagnostic updates in the WHO 2022 classification of kidney tumours. A major change in this edition is the grouping of renal tumours into broader categories that include "clear cell renal tumours", "papillary renal tumours", "oncocytic and chromophobe renal tumours", "collecting duct tumours" as well as adding two categories of "other renal tumours" and "molecularly defined renal carcinomas". Novel entities included in the WHO 2022 classification are eosinophilic solid and cystic renal cell carcinoma (ESC RCC), anaplastic lymphoma kinase (ALK)-rearranged RCC and ELOC (formerly TCEB1)-mutated RCC. The category of "other renal tumours" includes a group of diverse, unrelated renal tumours that do not fit into other categories. The group of "molecularly defined renal carcinomas" reflects recent discoveries in the renal tumour genomics. These molecularly-defined renal entities demonstrate a set of morphologic features reflecting genotype-phenotype relationships. Final diagnosis of such entities rests on phenotypic and immunohistochemical (IHC) correlation, usually associated with IHC surrogate makers that reflect specific genetic abnormalities.

EBV-associated NK and T-cell lymphoid neoplasms.

Epstein-Barr virus (EBV)-associated neoplasms derived from natural killer (NK) or T cells comprise a group of clinically and biologically heterogenous disorders affecting children and adults, which are overall rare but more prevalent in Asia and South America. This review focuses on neoplasms presenting in the adulthood, addressing recent genomic discoveries as well as therapeutic developments in these highly aggressive disorders. Distinct molecular subtypes of extranodal NK/T-cell lymphomas (ENKTCLs) have been described, with differences in cell of origin, EBV pattern, genomic alterations, clinical characteristics, response to asparaginase-based therapies and to more recent approaches targeting molecular aberrations of the lymphoma. For the last two decades, progress in the clinical management of ENKTCL was based on L-asapraginase containing combinations and the incoroperation of radiotherapy. A subset of cases with PDL1-2 structural alterations may be more responsive to treatment with immune checkpoint inhibitors. Primary nodal EBV+ lymphomas derived from T or NK cells have distinctive features separating them from both peripheral T-cell lymphoma not otherwise specified and ENKTCL. Treatment algorithms correspond to those for advanced ENKTCL. With better understanding of lymphomagenesis, genomic landscape and immunologic aspects of the diseases, future treatment options will include targeted therapies including immune checkpoint inhibitors and novel antibodies.

Pancreatic Ductal Adenocarcinoma Cortical Mechanics and Clinical Implications.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers due to low therapeutic response rates and poor prognoses. Majority of patients present with symptoms post metastatic spread, which contributes to its overall lethality as the 4th leading cause of cancer-related deaths. Therapeutic approaches thus far target only one or two of the cancer specific hallmarks, such as high proliferation rate, apoptotic evasion, or immune evasion. Recent genomic discoveries reveal that genetic heterogeneity, early micrometastases, and an immunosuppressive tumor microenvironment contribute to the inefficacy of current standard treatments and specific molecular-targeted therapies. To effectively combat cancers like PDAC, we need an innovative approach that can simultaneously impact the multiple hallmarks driving cancer progression. Here, we present the mechanical properties generated by the cell’s cortical cytoskeleton, with a spotlight on PDAC, as an ideal therapeutic target that can concurrently attack multiple systems driving cancer. We start with an introduction to cancer cell mechanics and PDAC followed by a compilation of studies connecting the cortical cytoskeleton and mechanical properties to proliferation, metastasis, immune cell interactions, cancer cell stemness, and/or metabolism. We further elaborate on the implications of these findings in disease progression, therapeutic resistance, and clinical relapse. Manipulation of the cancer cell’s mechanical system has already been shown to prevent metastasis in preclinical models, but it has greater potential for target exploration since it is a foundational property of the cell that regulates various oncogenic behaviors.

A Summary of the Inaugural WHO Classification of Pediatric Tumors: Transitioning from the Optical into the Molecular Era.

Pediatric tumors are uncommon, yet are the leading cause of cancer-related death in childhood. Tumor types, molecular characteristics, and pathogenesis are unique, often originating from a single genetic driver event. The specific diagnostic challenges of childhood tumors led to the development of the first World Health Organization (WHO) Classification of Pediatric Tumors. The classification is rooted in a multilayered approach, incorporating morphology, IHC, and molecular characteristics. The volume is organized according to organ sites and provides a single, state-of-the-art compendium of pediatric tumor types. A special emphasis was placed on "blastomas," which variably recapitulate the morphologic maturation of organs from which they originate. SIGNIFICANCE: In this review, we briefly summarize the main features and updates of each chapter of the inaugural WHO Classification of Pediatric Tumors, including its rapid transition from a mostly microscopic into a molecularly driven classification systematically taking recent discoveries in pediatric tumor genomics into account.

Biological nitrification inhibition in the rhizosphere: determining interactions and impact on microbially mediated processes and potential applications

Nitrification is the microbial conversion of reduced forms of nitrogen (N) to nitrate (NO3-), and in fertilized soils it can lead to substantial N losses via NO3- leaching or nitrous oxide (N2O) production. To limitsuch problems, synthetic nitrification inhibitors have been applied but their performance differs between soils. In recent years, there has been an increasing interest in the occurrence of biological nitrification inhibition (BNI), a natural phenomenon according to which certain plants can inhibit nitrification through the release of active compounds in root exudates. Here, we synthesize the current state of research but also unravel knowledge gaps in the field. The nitrification process is discussed considering recent discoveries in genomics, biochemistry and ecology of nitrifiers. Secondly, we focus on the 'where' and 'how' of BNI. The N transformations and their interconnections as they occur in, and are affected by, the rhizosphere, are also discussed. The NH4+ and NO3- retention pathways alternative to BNI are reviewed as well. We also provide hypotheses on how plant compounds with putative BNI ability can reach their targets inside the cell and inhibit ammonia oxidation. Finally, we discuss a set of techniques that can be successfully applied to solve unresearched questions in BNI studies.

Molecular Pathways and Targeted Therapies for Malignant Ovarian Germ Cell Tumors and Sex Cord–Stromal Tumors: A Contemporary Review

Non-epithelial ovarian tumors are heterogeneous and account for approximately 10% of ovarian malignancies. The most common subtypes of non-epithelial ovarian tumors arise from germ cells or sex cord and stromal cells of the gonads. These tumors are usually detected at an early stage, and management includes surgical staging and debulking. When indicated for advanced disease, most respond to chemotherapy; however, options for patients with refractory disease are limited, and regimens can be associated with significant toxicities, including permanent organ dysfunction, secondary malignancies, and death. Targeted therapies that potentially decrease chemotherapy-related adverse effects and improve outcomes for patients with chemotherapy-refractory disease are needed. Here, we review the molecular landscape of non-epithelial ovarian tumors for the purpose of informing rational clinical trial design. Recent genomic discoveries have uncovered recurring somatic alterations and germline mutations in subtypes of non-epithelial ovarian tumors. Though there is a paucity of efficacy data on targeted therapies, such as kinase inhibitors, antibody–drug conjugates, immunotherapy, and hormonal therapy, exceptional responses to some compounds have been reported. The rarity and complexity of non-epithelial ovarian tumors warrant collaboration and efficient clinical trial design, including high-quality molecular characterization, to guide future efforts.

Genomics and metagenomics of colorectal cancer

Colorectal cancer (CRC) is a common cancer globally. It is a complex disease influenced by genetic and environmental factors. Early studies on familial cases have identified major genes involved in CRC, such as proto-oncogenes KRAS, PIK3CA and BRAF, and tumour-suppressor genes APC and TP53. These genes have provided valuable insight into the molecular pathogenesis of CRC, and some have made ways to clinical utility to help diagnose cancer syndromes, prognosticate oncological outcomes and predict treatment responses. While these genetic factors are important, recent studies have suggested contribution of microorganisms to colorectal carcinogenesis. Observational studies, animal experiments and translational works have identified several microorganisms as potential carcinogenic bacteria, such as Fusobacterium nucleatum and Peptostreptococcus anaerobius. With the advent of sequencing technology and bioinformatics, more genomic and metagenomic factors are being uncovered as important players in CRC carcinogenesis. This article aims to review recent genomic and metagenomic discoveries relating to CRC.

Genetics of testicular germ cell tumors.

Understanding the molecular basis underlying testicular germ cell tumors (TGCTs) may help improve patient outcomes, particularly for patients with poorer risk or chemoresistant disease. Here, we review the major contemporary advances in elucidating TGCT genetics by discussing patterns of TGCT inheritance, recent genomic and transcriptomic discoveries in TGCT, and the role of genetics in predicting therapeutic resistance and in guiding treatment. In the absence of a major high-penetrance TGCT susceptibility gene, inheritance is likely driven by a complex polygenic model with considerable variation. The most common genomic alterations found in TGCTs include gains in chromosome 12p and mutations in KIT, KRAS, and NRAS, particularly in seminomas. Sensitivity to cisplatin-based chemotherapy likely relies on intact TP53, reciprocal loss of heterozygosity, and high mitochondrial priming. Targetable mutations are uncommon in TGCTs, however, posing a challenge for the development of effective personalized therapies. Consistent with the characteristically low tumor mutational burden, immune checkpoint inhibitors do not appear to be effective for most TGCTs. Refinements in next-generation sequencing techniques over the last few years have enabled considerable advances in elucidating the genomic, transcriptomic, and epigenetic landscape of TGCTs. Future efforts focused on developing novel treatment modalities are needed.

Imaging of Histiocytosis in the Era of Genomic Medicine.

Histiocytosis describes a group of diseases that have long been considered enigmatic in the history of medicine. Recently, novel genomic analyses have identified somatic oncogenic driver mutations responsible for the pathogenesis of these entities. These discoveries have led to the recharacterization of histiocytoses as neoplastic diseases and have opened a new era of precision medicine approaches for treatment. The histiocytic disorders demonstrate a variety of imaging manifestations involving multiple organ systems, and radiologists play a major role in diagnosis and monitoring. An up-to-date knowledge of the novel genomic discoveries and their implications is essential for radiologists to understand the new approaches to treating histiocytic disorders and to contribute as key members of the multidisciplinary treatment team. This article provides a cutting-edge review of the novel concepts in histiocytosis, with a focus on recent genomic discoveries and precision medicine approaches to treating the disease, and describes imaging manifestations with correlative histologic and genomic findings, with an emphasis on adult-onset cases and uncommon subtypes. ©RSNA, 2018.

Ethical conundrums in pediatric genomics.

Recent genomic discoveries have improved our understanding of many hematologic diseases and led to novel therapeutic options for many patients. The rapid decrease in the cost of genomic testing has enabled widespread use of clinical genomic testing. However, these advances are accompanied by concomitant challenging ethical concerns. In pediatrics, issues of informed consent for genomic testing, assent, and permission vary significantly by patient age and comprehension. Broader testing strategies, such as whole-exome or whole-genome sequencing, are more likely to yield incidental findings unrelated to the reason for the initial test, and plans to deal with these results when they occur are increasingly important. The lines of clinical care and research are becoming more blurry in the era of precision medicine in which approaches to individual genetic mutations (as opposed to disease phenotypes) occur with increased frequency. Finally, because justice is a fundamental ethical consideration, access to genomic testing and a rigorous approach to utility are critical to individual patients and the field of hematology. In this review, we use 3 cases of genomic testing in pediatric hematology to illustrate core ethical concerns and explore potential solutions.

DNA damage pathways and B-cell lymphomagenesis.

Recent lymphoma genome sequencing projects have shed light on the genomic landscape of indolent and aggressive lymphomas, as well as some of the molecular mechanisms underlying recurrent mutations and translocations in these entities. Here, we review these recent genomic discoveries, focusing on acquired DNA repair defects in lymphoma. In addition, we highlight recently identified actionable molecular vulnerabilities associated with recurrent mutations in chronic lymphocytic leukemia (CLL), which serves as a model entity. The results of several large lymphoma genome sequencing projects have recently been reported, including CLL, T-PLL and DLBCL. We align these discoveries with proposed mechanisms of mutation acquisition in B-cell lymphomas. Moreover, novel autochthonous mouse models of CLL have recently been generated and we discuss how these models serve as preclinical tools to drive the development of novel targeted therapeutic interventions. Lastly, we highlight the results of early clinical data on novel compounds targeting defects in the DNA damage response of CLL with a particular focus on deleterious ATM mutations. Defects in DNA repair pathways are selected events in cancer, including lymphomas. Specifically, ATM deficiency is associated with PARP1- and DNA-PKcs inhibitor sensitivity in vitro and in vivo.

Recent Advances in the Biology and Treatment of T Cell Acute Lymphoblastic Leukemia.

This article provides an overview of the current knowledge regarding the biology and treatment of T cell acute lymphoblastic leukemia (T-ALL) and highlights the most recent findings in this field over the past 5years. Remarkable progress has been made in the genomic landscape of T-ALL over the past few years. The discovery of activating mutations of NOTCH1 and FBXW7 in a majority of patients has been a seminal observation, with several early phase clinical trials currently exploring these as potential therapeutic targets. Characterization of early T cell precursor ALL, incorporation of minimal residual disease assessment into therapeutic protocols, and use of pediatric-intensive regimens along with judicious use of allogeneic HCT have significantly improved risk stratification and treatment outcomes. Improved risk stratification and the use of novel targeted therapies based on recent genomic discoveries are expected to change the therapeutic landscape of T-ALL and hopefully improve the outcomes of this historically poor prognosis disease.

Classification and risk assessment in AML: integrating cytogenetics and molecular profiling.

In recent years, the composite molecular architecture in acute myeloid leukemia (AML) has been mapped out. We now have a clearer understanding of the key genetic determinants, the major genetic interactions, and the broad order in which these mutations occur. The next impending challenge is to discern how these recent genomic discoveries define disease biology as well as how to use molecular markers to deliver patient-tailored clinical decision support.

Clarifying sub-genomic positions of QTLs for flowering habit and fruit quality in U.S. strawberry (Fragaria\xd7ananassa) breeding populations using pedigree-based QTL analysis

The cultivated strawberry (Fragaria×ananassa) is consumed worldwide for its flavor and nutritional benefits. Genetic analysis of commercially important traits in strawberry are important for the development of breeding methods and tools for this species. Although several quantitative trait loci (QTL) have been previously detected for fruit quality and flowering traits using low-density genetic maps, clarity on the sub-genomic locations of these QTLs was missing. Recent discoveries in allo-octoploid strawberry genomics led to the development of the IStraw90 single-nucleotide polymorphism (SNP) array, enabling high-density genetic maps and finer resolution QTL analysis. In this study, breeder-specified traits were evaluated in the Eastern (Michigan) and Western (Oregon) United States for a common set of breeding populations during 2 years. Several QTLs were validated for soluble solids content (SSC), fruit weight (FWT), pH and titratable acidity (TA) using a pedigree-based QTL analysis approach. For fruit quality, a QTL for SSC on linkage group (LG) 6A, a QTL for FWT on LG 2BII, a QTL for pH on LG 4CII and two QTLs for TA on LGs 2A and 5B were detected. In addition, a large-effect QTL for flowering was detected at the distal end of LG 4A, coinciding with the FaPFRU locus. Marker haplotype analysis in the FaPFRU region indicated that the homozygous recessive genotype was highly predictive of seasonal flowering. SNP probes in the FaPFRU region may help facilitate marker-assisted selection for this trait.

Molecular pathogenesis and therapeutic implications in pediatric high-grade gliomas.

High-grade gliomas (HGG) are the most common malignant brain tumors in the pediatric population and account for a large subset of all pediatric central nervous system neoplasms. The management of pediatric HGG continues to be challenging, with poor outcome in many cases despite aggressive treatments. Consequently, parallel research efforts have been focused on identifying the underlying genetic and biological basis of pediatric HGG in order to more clearly define prognostic subgroups for treatment stratification as well as identify new treatment targets. These cutting-edge advances have revolutionized pediatric neuro-oncology and have revealed novel oncogenic vulnerabilities that are being therapeutically leveraged. Promising treatments - including pathway-targeting small molecules as well as epigenetic therapy - are being evaluated in clinical trials, and recent genomic discoveries in rare glioma subgroups have led to the identification of additional new potentially-actionable alterations. This review summarizes the current state of knowledge about the molecular characterization of pediatric HGG in correlation to the revised World Health Organization (WHO) classification, as well as provides an overview of some targeted treatment approaches in the modern clinical management of high-grade gliomas.

The Roles of Chromatin Remodeling Genes in Pancreatic-Biliary Malignancies.

Recent studies have definitively established that chromatin remodeling is a crucial epigenetic mechanism not only in physiological conditions but also in influencing cancer biology. It is a dynamic process in which the chromatin, the functional entity of DNA, can undergo specific modifications by obtaining transcriptional activation or transcriptional silencing. One of the most important recent discoveries in cancer genetics and genomics is that the genes involved in the establishment of chromatin structure, the so called chromatin remodelers, are frequently mutated in different types of human cancer. This review aims to summarize the main novelties related to this topic, describing also the contribution of such genes during oncogenesis. Particularly, we focus on the switch/sucrose non-fermentable complexes and on three of the most important chromatin remodeling genes in biliary and pancreatic cancer: ARID1A, PBRM1, and BAP1.