Biology subjects

Hooper, W. F.

Publications and source records attributed to Hooper, W. F..

5 recordsLinked to original sources

bioRxiv2026

Comprehensive Molecular Characterization of High-Grade Endometrial Cancer in an Ancestrally-Diverse Cohort

Endometrial cancer (EC) exhibits one of the most striking racial disparities in oncology with black women disproportionately affected by aggressive high-grade subtypes that have poorer outcomes. While social and environmental factors undoubtedly contribute, the molecular underpinnings of these disparities remain critically understudied. To bridge this knowledge gap, we performed matched tumor-normal whole-genome sequencing and tumor transcriptome sequencing on 71 predominantly high-grade EC patient samples from an ancestrally diverse cohort of women recruited at a large hospital system in the New York metropolitan area. Our analysis characterized the germline and somatic mutation landscape, identifying ancestry-associated molecular differences. Notably, focal amplification of the EVI1 transcription factor (encoded at the MECOM locus) was significantly more frequent in African ancestry patients and associated with poorer clinical outcomes in an external validation cohort. Additionally transcriptome analysis revealed decreased CD8+ T cell infiltration with increasing African ancestry, suggesting tumor immune microenvironment differences with potential therapeutic implications. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/721962v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@12125b9org.highwire.dtl.DTLVardef@133c787org.highwire.dtl.DTLVardef@707af0org.highwire.dtl.DTLVardef@97615c_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThis study represents the most ancestrally diverse whole-genome sequencing characterization of high-grade endometrial cancer, with 62% of patients of African ancestry. C_LIO_LIMECOM focal amplification preferentially targets the oncogenic short isoform (EVI1) and is more frequent in patients of African ancestry. C_LIO_LIAfrican ancestry is associated with reduced CD8+ T cell infiltration and differential activation of immune and metabolic pathways in copy-number high endometrial tumors. C_LI

cancer biology↗

bioRxiv2026

An explainable boosting machine model for identifying artifacts caused by formalin-fixed paraffin embedding

BackgroundFormalin-fixed paraffin-embedding (FFPE) is a widely used, cost-effective method for long-term storage of clinical samples. However, fixation is known to introduce damage to nucleic acids that can present as artifactual bases in sequencing otherwise absent from higher fidelity storage methods such as fresh freezing (FF). Various machine learning methods exist for filtering these variant artifacts, but benchmarking performance can be difficult without reliable truth sets. In this study, we employ a collection of 90 paired fresh-frozen and formalin-fixed paraffin embedded samples from the same tumor to robustly define real and FFPE-derived, artifactual variation and enable objective evaluation of filtering methods. To address existing shortcomings, we propose a novel explainable boosting machine (EBM) model that improves performance, can be easily updated with new data, requires modest computational resources, and is analysis pipeline agnostic, making it broadly accessible. ResultsWe evaluated several methods for limiting FFPE-derived variant artifacts using cohorts of B-cell lymphoma samples. We found capturing local context around variants to be a highly informative, under-utilized feature set not commonly incorporated into many existing machine learning methods. Consequently, we developed a novel algorithm, FIFA, for filtering FFPE artifacts, which uses an EBM model, an interpretable decision-tree-based learning algorithm, to address some of the existing shortcomings. We used four independent cohorts composed of paired lymphoma and cervical cancer samples and a breast cancer cell line with both FF and FFPE samples to define clearly annotated training and test sets and demonstrated improved performance over existing methods. Additionally, FIFA filtering increased relevant biological signals in FFPE breast cancer datasets distinct from the training and testing sets. The EBM framework employed by FIFA is computationally efficient and easily amenable to incorporation of additional datasets due to its generalized additive modeling of features making it straightforward to incorporate new data into existing models dynamically over time. ConclusionsOur novel FFPE variant artifact filtering tool, FIFA, is a marked improvement over existing methods. It can be easily implemented, post hoc, to supplement existing somatic calling pipelines, training and inference can be run quickly across most compute environments, and it can be easily updated online as new training data becomes available. Accordingly, FIFA represents an important advance in retrospective cancer genomics research by further enhancing access to the vast stores of FFPE-archived tumor samples currently in existence.

bioinformatics↗

bioRxiv2023

The Interplay between Mutagenesis and Extrachromosomal DNA Shapes Urothelial Cancer Evolution

Advanced urothelial cancer is a frequently lethal disease characterized by marked genetic heterogeneity. In this study, we investigate the evolution of the genomic signatures caused by endogenous and external mutagenic stimuli and their interplay with complex structural variants. We superimposed mutational signatures and phylogenetic analyses of matched serial tumors from patients with urothelial cancer to define the evolutionary patterns of these processes. We show that APOBEC3-induced mutations are clonal and early, whereas mutational bursts comprising hundreds of late subclonal mutations are induced by chemotherapy. Using a novel genome graph computational paradigm, we observed frequent circular high copy-number amplicons characteristic of extrachromosomal DNA (ecDNA) involving double-minutes, breakage-fusion-bridge, and tyfonas events. We characterized the distinct temporal patterns of APOBEC3 mutations and chemotherapy-induced mutations within ecDNA, gaining new insights into the timing of these events relative to ecDNA biogenesis. Finally, we discovered that most CCND1 amplifications in urothelial cancer arise within circular ecDNA amplicons. These CCND1 ecDNA amplification events persisted and increased in complexity incorporating additional DNA segments potentially contributing selective fitness advantage to the evolution of treatment resistance. Our findings define fundamental mechanisms driving urothelial cancer evolution and have therapeutic implications for treating this disease.

genomics↗

bioRxiv2022

Whole genome error-corrected sequencing for sensitive circulating tumor DNA cancer monitoring

Circulating cell-free DNA (ccfDNA) sequencing for low-burden cancer monitoring is limited by sparsity of circulating tumor DNA (ctDNA), the abundance of genomic material within a plasma sample, and pre-analytical error rates due to library preparation, and sequencing errors. Sequencing costs have historically favored the development of deep targeted sequencing approaches for overcoming sparsity in ctDNA detection, but these techniques are limited by the abundance of ccfDNA in samples, which imposes a ceiling on the maximal depth of coverage in targeted panels. Whole genome sequencing (WGS) is an orthogonal approach to ctDNA detection that can overcome the low abundance of ccfDNA by supplanting sequencing depth with breadth, integrating signal across the entire tumor mutation landscape. However, the higher cost of WGS limits the practical depth of coverage and hinders broad adoption. Lower sequencing costs may thus allow for enhanced ctDNA cancer monitoring via WGS. We therefore applied emerging lower-cost WGS (Ultima Genomics, 1USD/Gb) to plasma samples at [~]120x coverage. Copy number and single nucleotide variation profiles were comparable between matched Ultima and Illumina datasets, and the deeper WGS coverage enabled ctDNA detection at the parts per million range. We further harnessed these lower sequencing costs to implement duplex error-corrected sequencing at the scale of the entire genome, demonstrating a [~]1,500x decrease in errors in the plasma of patient-derived xenograft mouse models, and error rates of [~]10-7 in patient plasma samples. We leveraged this highly de-noised plasma WGS to undertake cancer monitoring in the more challenging context of resectable melanoma without matched tumor sequencing. In this context, duplex-corrected WGS allowed us to harness known mutational signature patterns for disease monitoring without matched tumors, paving the way for de novo cancer monitoring.

genomics↗

bioRxiv2021

Failure to detect mutations U2AF1 due to changes in the GRCh38 reference sequence

The U2AF1 gene is a core part of mRNA splicing machinery and frequently contains somatic mutations that contribute to oncogenesis in MDS, AML, and other cancers. A change introduced in the GRCh38 version of the human reference build prevents mutations in this gene from being detected by many variant calling pipelines. We describe the problem in detail and show that a modified GRCh38 reference build with unchanged coordinates can be used to ameliorate the issue. This reference is available at https://zenodo.org/record/4684553 (doi:10.5281/zenodo.4684553)

genomics↗