Biomedical subjects

Michael Dean

Publications and source records attributed to Michael Dean.

6 recordsLinked to original sources

PubMed2026

Longitudinal analysis of high-risk HPV infections reveals within-host viral genome changes over time.

Persistent infection with high-risk (HR)-HPV causes cervical cancer, however, it is unclear why most infections resolve while a minority progress. We deep sequenced the HPV genomes of 1,228 HR-HPV-positive serial samples from 351 women with persistent infections (2-10 serial samples per woman over 1-8 years), including 279 controls and 72 precancer/cancer cases, to assess HR-HPV genome changes during infection and relation to infection outcomes. Seventy-seven percent of persistent infections (45-97% by HPV type) were infections with the same exact viral genome isolate; for HPV16, only 52% were persistent with the same isolate. This may suggest some infections include a type-specific isolate switch or new isolate infection during persistence. We additionally observed within-host change to the HPV genome estimated as gradual changes to intrahost single nucleotide variant (iSNV) frequency, and changes varied by HPV type, with HPV33 infections showing the most iSNV changes. Cases exhibited fewer viral genome changes during infection compared to controls (OR = 0.31, 95% CI = 0.1 - 0.86, p = 0.019), suggesting a more stable and clonal viral genome in cases. By viral gene, E7 had fewer nonsynonymous mutations in the cases compared to controls that cleared within 2 years of infection (p = 0.012), which confirms the importance of E7 conservation and suggests mutations to E7 reduce persistence associated with progression. There was a similar pattern in E4 (p = 0.013), while E5 had more changes in the cases (p = 0.008). A subset of 28 infections had an intervening HPV-negative sample between HPV-positive visits; 93% of these infections had the same exact viral genome isolate in the samples before and after the negative, consistent with subclinical persistence and subsequent re-detection. Our data suggests that HR-HPV type-persistence can include a collection of viral isolates, and viral mutations during infection, particularly in E7, reduce HR-HPV persistence and thus carcinogenic potential.

Humans↗

PubMed2026

TriosCompass: a snakemake workflow for integrated detection of SNVs, indels, STRs, and structural de novo variants in parent-child trios.

MOTIVATION: The accurate and sensitive identification of de novo variants, which are unique to an individual and not found in the parents' germlines, is critical for understanding the genetic basis of rare diseases, developmental disorders, and evolutionary processes. Existing de novo variant detection pipelines often lack the flexibility to handle multiple variant types, struggle with speed and reproducibility across computational environments, demand extensive manual configuration, or require bioinformatics expertise for downstream curation and analysis, limiting their scalability and usability for large genomic studies. Accordingly, there is a pressing need to better address these challenges. RESULTS: We introduce TriosCompass, an open-source Snakemake workflow that addresses these challenges by providing a modular, accelerated, and environmentally-configurable end-to-end solution for comprehensive de novo variant discovery. It integrates state-of-the-art tools into a reproducible framework, empowering researchers to discover novel genetic insights with greater efficiency and reliability. AVAILABILITY: TriosCompass is implemented as a Snakemake workflow and is freely available at https://github.com/NCI-CGR/TriosCompass_v2 or on Zenodo (10.5281/zenodo.17981062). SUPPLEMENTARY INFORMATION: Supplementary data is available on GitHub at https://github.com/NCI-CGR/TriosCompass_v2/tree/manuscript/report_dashboards. Supplementary methods on DeepTrio benchmark runs can be viewed at: https://github.com/NCI-CGR/TriosCompass_v2/blob/manuscript/TriosCompass_Supp_Methods_deeptrio_benchmark.md.

Software↗

PubMed2026

STK11 Mutations and Deletions Define an Aggressive Molecular Subgroup of Cervical Adenocarcinoma.

Cervical adenocarcinoma accounts for 15%-20% of cervical cancers and is associated with poorer survival and reduced response to screening and immunotherapy compared with squamous cell carcinoma (SCC). The genomic drivers underlying this molecular subgroup remain incompletely characterized. Whole-exome sequencing was performed on 302 invasive cervical cancers from Guatemala and Venezuela. Structural variation analysis was conducted using SNP-array and whole-genome sequencing data. Findings were replicated in more than 4600 additional cervical cancer samples from TCGA, AACR Project GENIE, MSKCC, and Caris datasets. TP53 mutations were more frequent in adenocarcinoma than SCC, particularly in HPV-negative tumors. STK11 alterations, including mutations and focal deletions, were significantly enriched in HPV-positive adenocarcinomas compared with SCC and affected 23% of adenocarcinomas overall. Whole-genome analyses identified recurrent focal deletions, inversions, chromosomal rearrangements, and breakage-fusion-bridge events involving chromosome 19p and STK11 that were not detected by exome sequencing alone. STK11 alterations were associated with younger age at diagnosis, poorer overall survival, and inferior outcomes following immune checkpoint inhibitor (ICI) therapy. STK11 alterations significantly co-occurred with YAP1 amplification but were largely mutually exclusive with PIK3CA mutation. Cervical adenocarcinomas also demonstrated significantly lower CD274 (PD-L1) expression than SCC. STK11 alterations define a distinct molecular subgroup of cervical adenocarcinoma characterized by structural disruption of chromosome 19p, younger age at onset, and poorer clinical outcomes. These findings have implications for molecular classification and future targeted therapeutic approaches in cervical cancer.

Humans↗

PubMed2025

Severus detects somatic structural variation and complex rearrangements in cancer genomes using long-read sequencing.

For the detection of somatic structural variation (SV) in cancer genomes, long-read sequencing is advantageous over short-read sequencing with respect to mappability and variant phasing. However, most current long-read SV detection methods are not developed for the analysis of tumor genomes characterized by complex rearrangements and heterogeneity. Here, we present Severus, a breakpoint graph-based algorithm for somatic SV calling from long-read cancer sequencing. Severus works with matching normal samples, supports unbalanced cancer karyotypes, can characterize complex multibreak SV patterns and produces haplotype-specific calls. On a comprehensive multitechnology cell line panel, Severus consistently outperforms other long-read and short-read methods in terms of SV detection F1 score (harmonic mean of the precision and recall). We also illustrate that compared to long-read methods, short-read sequencing systematically misses certain classes of somatic SVs, such as insertions or clustered rearrangements. We apply Severus to several clinical cases of pediatric leukemia/lymphoma, revealing clinically relevant cryptic rearrangements missed by standard genomic panels.

Humans↗

PubMed2024

Genetics of Latin American Diversity Project: Insights into population genetics and association studies in admixed groups in the Americas.

Latin Americans are underrepresented in genetic studies, increasing disparities in personalized genomic medicine. Despite available genetic data from thousands of Latin Americans, accessing and navigating the bureaucratic hurdles for consent or access remains challenging. To address this, we introduce the Genetics of Latin American Diversity (GLAD) Project, compiling genome-wide information from 53,738 Latin Americans across 39 studies representing 46 geographical regions. Through GLAD, we identified heterogeneous ancestry composition and recent gene flow across the Americas. Additionally, we developed GLAD-match, a simulated annealing-based algorithm, to match the genetic background of external samples to our database, sharing summary statistics (i.e., allele and haplotype frequencies) without transferring individual-level genotypes. Finally, we demonstrate the potential of GLAD as a critical resource for evaluating statistical genetic software in the presence of admixture. By providing this resource, we promote genomic research in Latin Americans and contribute to the promises of personalized medicine to more people.

Humans↗

PubMed2021

Dissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma.

Little is known about the transcriptomic plasticity and adaptive mechanisms of circulating tumor cells (CTCs) during hematogeneous dissemination. Here we interrogate the transcriptome of 113 single CTCs from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) using single-cell full-length RNA sequencing in hepatocellular carcinoma (HCC) patients. We reveal that the transcriptional dynamics of CTCs were associated with stress response, cell cycle and immune-evasion signaling during hematogeneous transportation. Besides, we identify chemokine CCL5 as an important mediator for CTC immune evasion. Mechanistically, overexpression of CCL5 in CTCs is transcriptionally regulated by p38-MAX signaling, which recruites regulatory T cells (Tregs) to facilitate immune escape and metastatic seeding of CTCs. Collectively, our results reveal a previously unappreciated spatial heterogeneity and an immune-escape mechanism of CTC, which may aid in designing new anti-metastasis therapeutic strategies in HCC.

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