Charles Lee

Background: This study explored employees' decision‐making processes and perspectives on workplace genetic testing (wGT), comparing those who had not participated (Non‐Testers) with those who had participated (Testers) in wGT. Methods: Employees at a large US healthcare system offering wGT were recruited via email and onsite advertising and surveyed. The web survey assessed respondent demographics, information‐seeking activities, and perceived benefits and risks of wGT. Descriptive statistics, Chi‐square analyses, and multivariable logistic regression compared the similarities and differences between Non‐Testers and Testers on key study outcomes. Results: Survey respondents included 358 Non‐Testers (80.7% female; 69.8% White, non‐Hispanic) and 418 Testers (88.3% female; 80.6% White, non‐Hispanic). Demographics associated with lower odds of being a Tester included self‐reporting as Black, non‐Hispanic ( p = 0.001), male ( p = 0.004), and less than one year of employment ( p < 0.001). Non‐Testers endorsed more perceived risks regarding wGT (e.g., privacy, discrimination) than Testers, while Testers more commonly endorsed perceived benefits, including lack of cost and potential healthcare benefits. Non‐Testers engaged in fewer information‐seeking activities than Testers. Non‐Testers' most common decision‐making activity was talking with family (28.9%), and Testers' most common activity was engaging with the testing company's information (50.0%). Conclusion: This is the first study to examine wGT decision‐making in a real‐world setting. To address the perceived risks of Non‐Testers and ensure equitable access, it may be necessary to develop educational materials that review current legal protections and limitations, as well as potential health benefits of genetic testing. Outreach strategies providing such education must address different types of information seeking to ensure perceived risks are addressed.

Metastasis remains the major cause of mortality in triple-negative breast cancer (TNBC) ^1,2 , yet the metastatic potential of primary tumors is difficult to predict at diagnosis ^3,4 . Here, we leveraged patient-derived xenograft (PDX) models as a functional readout of primary tumor metastatic propensity. We first performed integrated genomic and transcriptomic profiling of 57 primary breast tumors and their matched PDX models and found that key driver mutations, recurrent copy number alterations, and molecular subtype features were largely conserved between patient tumors and xenografts. These findings support the utility of matched PDX models as clinically relevant platforms for studying tumor-intrinsic features associated with breast cancer progression. We classified the 38 TNBC PDX models based on their reproducible in vivo metastasis capacity and the clinical outcomes of the corresponding patients. Non-metastatic PDX models were characterized by the lack of distant metastasis development in either mouse experiments or clinical follow-up data (n = 4). PDX models were defined as metastatic models when they developed distant metastasis in both mice and humans (n = 4). Single-cell transcriptomic profiling of these tumors revealed that metastatic samples were characterized by hypoxia-associated metabolic reprogramming, with coordinated activation of hypoxia and glycolysis pathways. Network-based prioritization identified adenylate kinase 1 (AK1) as a candidate regulator of this metastatic program. Functionally, AK1 promoted metastatic potential in primary tumor by supporting glycolytic ATP production, resistance to hypoxic and oxidative stress, and promoting trans-endothelial migration. Together, our findings establish primary tumor–matched PDX models as a clinically relevant discovery platform for metastatic potential. Using reproducible PDX metastasis as a functional readout, we identify AK1 as a key regulator underlying metastatic potential in primary TNBC.

The human Y chromosome is among the most structurally dynamic chromosomes in the human genome, yet much of its diversity remains unresolved because of extensive palindromes, ampliconic gene families, satellite-rich heterochromatin and large segmental duplications. What remained unclear was how these diverse forms of variation fit together across the full chromosome, how often similar structures recur in different lineages, and which aspects of organization remain constrained despite rapid sequence turnover. Here, we generated and analyzed 142 nearly complete human Y chromosome assemblies from 17 major haplogroups spanning approximately 180,000 years of evolution, creating a population-scale resource for studying Y chromosome biology and diversity. These assemblies show that structural change on the Y chromosome is recurrent but constrained, even in its most repetitive regions. In the fertility-associated azoospermia factor c (AZFc) region, recurrent inversions, deletions, and complex rearrangements generate a limited repertoire of structural haplotypes. Multicopy ampliconic gene families follow distinct evolutionary paths: DAZ paralogues differ in structural constraint, RBMY evolves within a modular array, and TSPY copy number varies mainly through local expansion and contraction. The centromere and Yq12 heterochromatin vary greatly in size but retain a stable higher-order organization, including a single hypomethylated centromeric core and conserved Yq12 repeat composition and orientation. Methylation across palindromic and ampliconic regions is likewise structured by repeat class, copy order and local architecture. Together, these results provide a population-scale resource for the human Y chromosome and show that its rapid structural evolution is repeatedly funneled into a limited set of architectural outcomes.

Modern humans inherited DNA from Neanderthals and Denisovans, but the contribution of introgressed structural variants (SVs) to present-day human phenotypes and adaptation remains poorly understood. Here, we used a graph-genome approach to genotype 96,277 SVs in 3,332 present-day humans and three high-coverage archaic hominin genomes, identifying 153 candidate introgressed SVs. These SVs are enriched for signatures of local adaptation compared to non-introgressed SVs ( p-value = 3.04 × 10 ^-7 ). Among these, we focused on a Denisovan-derived Alu insertion located in intron 18 of OCA2 , a gene central to pigmentation. This introgressed Alu insertion is most frequently observed (> 60%) in Indigenous people from Bougainville Island of Melanesia, and is significantly associated with increased skin pigmentation in this region. To assess its functional impact, the Alu insertion was introduced into human induced pluripotent stem cells (iPSCs), which were subsequently differentiated into melanocytes. Melanocytes harboring the Alu insertion demonstrated elevated OCA2 expression, increased pigmentation, and higher levels of enhancer activity compared to controls. Collectively, these findings highlight introgressed SVs as a significant source of adaptive and phenotypic diversity in modern humans and implicate the Denisovan-derived Alu insertion in OCA2 in pigmentation variation among present-day Melanesian populations.

Classification of thymic epithelial tumors into three subgroups using PCA, k-means clustering, and NMF, along with correlations between non-tumor cell proportions and T cell markers

Characteristics of 137 thymic epithelial tumors, including clinical data, genomic alterations, and transcriptional signatures

Differential expression of lipid metabolism genes between GTF2I-type and CN-type thymomas is shown through box plots and scatter plots, revealing consistent expression differences not biased by tumor cell fraction and indicating that these transcripts originate mainly from tumor cells

IRS4's high expression in certain thymoma types, its tissue distribution, cellular expression patterns, regulatory associations, prognostic significance, and the presence of a cryptic exon influencing IRS4 transcripts

Validation of thymic epithelial tumor subgroups using single-cell RNA-seq data, including UMAP projections, gene expression heatmaps, inferred copy-number alterations, and mapping onto the normal TECs

List of gene sets used in immune component analysis