Biology subjects

Starrett, G. J.

Publications and source records attributed to Starrett, G. J..

9 recordsLinked to original sources

bioRxiv2026

Subclonal IDH1/2 Mutations as a Targetable Vulnerability in Vascular Tumors

Despite extensive sequencing, the genetic etiology of sporadic angiosarcoma remains poorly defined (1-3). Maffucci syndrome, characterized by vascular tumors and elevated cancer risk, is driven by mosaic gain-of-function mutations in IDH1/2 (4,5), though these have not been reported in sporadic angiosarcoma. We identify recurrent, low-variant allele frequency hotspot mutations in IDH1/2 in over half of sporadic angiosarcomas. Mutations were validated by Sanger sequencing and immunohistochemistry. Mutant IDH1 endothelial cells promote tumorigenesis through non-cell-autonomous mechanisms, secreting 2-hydroxyglutarate (2-HG) to increase growth factor and endothelial-to-mesenchymal transition gene expression, activate pAkt/pERK signaling, induce DNA methylation changes, and promote anchorage-independent growth, which are reversed by the mutant IDH1 inhibitor ivosidenib. Patients with mosaic IDH1 mutations show reduced serum 2-HG and marked tumor regression following ivosidenib treatment. The clinical efficacy of ivosidenib in vascular tumors with subclonal IDH1 mutations suggests that low VAF IDH1/2 mutations may be a targetable vulnerability in sporadic angiosarcoma. (6,7) Statement of SignificanceWe identify recurrent, low-VAF IDH1/2 mutations in angiosarcoma and provide evidence that these subclonal mutations promote tumorigenesis through non-cell-autonomous mechanisms. Vascular tumors driven by subclonal IDH1 mutations responded dramatically to ivosidenib, thus revealing a novel treatment for a subset of vascular tumors.

cancer biology↗

bioRxiv2026

Characterization of the urinary DNA virome of hematopoietic stem cell transplant recipient and healthy cynomolgus macaques

BK polyomavirus (BKPyV) and chronic latent DNA virus infections frequently reactivate after hematopoietic stem cell transplantation (HSCT), where they contribute to major complications in humans with limited options for prevention or treatment. Mauritian cynomolgus macaques (MCM; Macaca fascicularis) serve as an important animal model for transplantation research due to their limited major histocompatibility complex (MHC) diversity. Similar viral reactivations and disease complications occur in MCMs and humans post-transplantation, including polyomavirus-associated hemorrhagic cystitis and nephropathy. To define the polyomaviruses associated with these outcomes and characterize the broader urinary DNA virome, we sequenced rolling circle-amplified urine DNA from HSCT recipient and healthy cynomolgus macaques, allowing for comprehensive genomic characterization of the detected polyomaviruses. De novo assembly and annotation identified three polyomaviruses with apparent specific host tropism to cynomolgus macaques: Macaca fascicularis polyomavirus 2 (MafaPyV2) and Macaca fascicularis polyomavirus 3 (MafaPyV3), which are closely related to human polyomaviruses, and a newly identified strain of simian virus 40 (SV40 type IIB). All three viruses were detected in both HSCT recipients and healthy animals but were shed at significantly higher relative loads in HSCT recipients. Multiple polyomaviruses were frequently detected within individual hosts, and all three were identified in HSCT recipients that developed urologic disease. Together, these findings further characterize polyomavirus diversity, shedding, and disease associations in hematopoietic stem cell-transplanted Mauritian cynomolgus macaques. ImportanceReactivation of latent viruses after hematopoietic stem cell transplantation is a major cause of illness in transplant recipients, yet options for prevention and treatment remain limited. Progress has been hindered by the lack of animal models that accurately reflect human disease. In this study, we show that Mauritian cynomolgus macaques harbor multiple polyomaviruses that reactivate at high levels following transplantation and are associated with urinary tract disease, closely paralleling complications seen in humans. We define the genetic identity of these viruses and demonstrate that immunosuppression strongly enhances viral shedding and disease severity. By establishing clear similarities between viral reactivation in macaques and humans, this work validates the Mauritian cynomolgus macaque transplantation model as a powerful platform for studying virus-driven disease mechanisms and testing antiviral therapies and vaccines relevant to human transplantation.

microbiology↗

bioRxiv2024

Molecular patterns and mechanisms of tumorigenesis in HPV-associated and HPV-independent sinonasal squamous cell carcinoma

Mechanisms of tumorigenesis in sinonasal squamous cell carcinoma (SNSCC) remain poorly described due to its rare nature. A subset of SNSCC are associated with the human papillomavirus (HPV); however, it is unknown whether HPV is a driver of HPV-associated SNSCC tumorigenesis or merely a neutral bystander. We hypothesized that performing the first large high-throughput sequencing study of SNSCC would reveal molecular mechanisms of tumorigenesis driving HPV-associated and HPV-independent SNSCC and identify targetable pathways. High-throughput sequencing was performed on 64 patients with HPV-associated and HPV-independent sinonasal carcinomas. Mutation annotation, viral integration, copy number, and pathway-based analyses were performed. Analysis of HPV-associated SNSCC revealed similar mutational patterns observed in HPV-associated cervical and head and neck squamous cell carcinoma, including lack of TP53 mutations and the presence of known hotspot mutations in PI3K and FGFR3. Further similarities included enrichment of APOBEC mutational signature, viral integration at known hotspot locations, and frequent mutations in epigenetic regulators. HPV-associated SNSCC-specific recurrent mutations were also identified including KMT2C, UBXN11, AP3S1, MT-ND4, and MT-ND5. Mutations in KMT2D and FGFR3 were associated with decreased overall survival. We developed the first known HPV-associated SNSCC cell line and combinatorial small molecule inhibition of YAP/TAZ and PI3K pathways synergistically inhibited tumor cell clonogenicity. In conclusion, HPV-associated SNSCC and HPV-independent SNSCC are driven by molecularly distinct mechanisms of tumorigenesis. Combinatorial blockade of YAP/TAZ and vertical inhibition of the PI3K pathway may be useful in targeting HPV-associated SNSCC whereas targeting MYC and horizontal inhibition of RAS/PI3K pathways for HPV-independent SNSCC. One Sentence SummaryThis study solidifies HPV as a driver of HPV-associated SNSCC tumorigenesis, identifies molecular mechanisms distinguishing HPV-associated and HPV-independent SNSCC, and elucidates YAP/TAZ and PI3K blockade as key targets for HPV-associated SNSCC.

cancer biology↗

bioRxiv2024

Widespread Horizontal Gene Transfer Among Animal Viruses

The initial objective of this study was to shed light on the evolution of small DNA tumor viruses by analyzing de novo assemblies of publicly available deep sequencing datasets. The survey generated a searchable database of contig snapshots representing more than 100,000 Sequence Read Archive records. Using modern structure-aware search tools, we iteratively broadened the search to include an increasingly wide range of other virus families. The analysis revealed a surprisingly diverse range of chimeras involving different virus groups. In some instances, genes resembling known DNA-replication modules or known virion protein operons were paired with unrecognizable sequences that structural predictions suggest may represent previously unknown replicases and novel virion architectures. Discrete clades of an emerging group called adintoviruses were discovered in datasets representing humans and other primates. As a proof of concept, we show that the contig database is also useful for discovering RNA viruses and candidate archaeal phages. The ancillary searches revealed additional examples of chimerization between different virus groups. The observations support a gene-centric taxonomic framework that should be useful for future virus-hunting efforts.

microbiology↗

bioRxiv2021

The Transcriptome Architecture of Polyomaviruses

Polyomaviruses (PyV) are ubiquitous pathogens that can cause devastating human diseases. Due to the small size of their genomes, PyV utilize complex patterns of RNA splicing to maximize their coding capacity. Despite the importance of PyV to human disease, their transcriptome architecture is poorly characterized. Here, we compare short- and long-read RNA sequencing data from eight human and non-human PyV. We provide a detailed transcriptome atlas for BK polyomavirus (BKPyV), an important human pathogen, and the prototype PyV, simian virus 40 (SV40). We identify pervasive wraparound transcription in PyV, wherein transcription runs through the polyA site and circles the genome multiple times. Comparative analyses identify novel, conserved transcripts that increase PyV coding capacity. One of these conserved transcripts encodes superT, a T antigen containing two RB-binding LxCxE motifs. We find that superT-encoding transcripts are abundant in PyV-associated human cancers. Together, we show that comparative transcriptomic approaches can greatly expand known transcript and coding capacity in one of the simplest and most well-studied viral families.

microbiology↗

bioRxiv2019

Identification of \"Missing Link\" Families of Small DNA Tumor Viruses

Polintons (also known as Mavericks) were initially identified as a widespread class of eukaryotic transposons named for their hallmark type B DNA polymerase and retrovirus-like integrase genes. It has since been recognized that many polintons encode possible capsid proteins and viral genome-packaging ATPases similar to those of a diverse range of double-stranded DNA (dsDNA) viruses. This supports the inference that at least some polintons are viruses that remain capable of cell-to-cell spread. At present, there are no polinton-associated capsid protein genes annotated in public sequence databases. To rectify this deficiency, we used a data-mining approach to investigate the distribution and gene content of polinton-like elements and related DNA viruses in animal genomic and metagenomic sequence datasets. The results define a discrete family-like clade of animal-specific viruses with two genus-level divisions. We suggest the family name Adintoviridae, connoting similarities to adenovirus virion proteins and the presence of a retrovirus-like integrase gene. Although adintovirus-class PolB sequences were detected in datasets for fungi and various unicellular eukaryotes, sequences resembling adintovirus virion proteins and accessory genes appear to be restricted to animals. Degraded adintovirus sequences are endogenized into the germlines of a wide range of animals, including humans.

microbiology↗

bioRxiv2019

Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin mediated by the integration of Merkel cell polyomavirus (MCPyV) and expression of viral T antigens or by ultraviolet induced damage to the tumor genome from excessive sunlight exposure. An increasing number of deep sequencing studies of MCC have identified significant differences between the number and types of point mutations, copy number alterations, and structural variants between virus-positive and virus-negative tumors. In this study, we assembled a cohort of 71 MCC patients and performed deep sequencing with OncoPanel, a next-generation sequencing assay targeting over 400 cancer-associated genes. To improve the accuracy and sensitivity for virus detection compared to traditional PCR and IHC methods, we developed a hybrid capture baitset against the entire MCPyV genome. The viral baitset identified integration junctions in the tumor genome and generated assemblies that strongly support a model of a hybrid, virus-host, circular DNA intermediate during integration that promotes focal amplification of host DNA. Using the clear delineation between virus-positive and virus-negative tumors from this method, we identified recurrent somatic alterations common across MCC and alterations specific to each class of tumor, associated with differences in overall survival. Comparing the molecular and clinical data from these patients revealed a surprising association of immunosuppression with virus-negative MCC and significantly shortened overall survival. These results demonstrate the value of high-confidence virus detection for identifying clinically important features in MCC that impact patient outcome.

cancer biology↗

bioRxiv2019

Mash Screen: High-throughput sequence containment estimation for genome discovery

The MinHash algorithm has proven effective for rapidly estimating the resemblance of two genomes or metagenomes. However, this method cannot reliably estimate the containment of a genome within a metagenome. Here we describe an online algorithm capable of measuring the containment of genomes and proteomes within either assembled or unassembled sequencing read sets. We describe several use cases, including contamination screening and retrospective analysis of metagenomes for novel genome discovery. Using this tool, we provide containment estimates for every NCBI RefSeq genome within every SRA metagenome, and demonstrate the identification of a novel polyomavirus species from a public metagenome.

bioinformatics↗

bioRxiv2019

Discovery of several thousand highly diverse circular DNA viruses

Although it is suspected that there are millions of distinct viral species, fewer than 9,000 are catalogued in GenBanks RefSeq database. We selectively enriched for and amplified the genomes of circular DNA viruses in over 70 animal samples, ranging from cultured soil nematodes to human tissue specimens. A bioinformatics pipeline, Cenote-Taker, was developed to automatically annotate over 2,500 circular genomes in a GenBank-compliant format. The new genomes belong to dozens of established and emerging viral families. Some appear to be the result of previously undescribed recombination events between ssDNA viruses and ssRNA viruses. In addition, hundreds of circular DNA elements that do not encode any discernable similarities to previously characterized sequences were identified. To characterize these "dark matter" sequences, we used an artificial neural network to identify candidate viral capsid proteins, several of which formed virus-like particles when expressed in culture. These data further the understanding of viral sequence diversity and allow for high throughput documentation of the virosphere.

microbiology↗