Refinement of a Published Gene-Physical Activity Interaction Impacting HDL-Cholesterol: Role of Sex and Lipoprotein Subfractions.

Large-scale gene-environment interaction (GxE) discovery efforts often involve analytical compromises for the sake of data harmonization and statistical power. Refinement of exposures, covariates, outcomes, and population subsets may be helpful to establish often-elusive replication and evaluate potential clinical utility. Here, we used additional datasets, an expanded set of statistical models, and interrogation of lipoprotein metabolism via nuclear magnetic resonance (NMR)-based lipoprotein subfractions to refine a previously discovered GxE modifying the relationship between physical activity (PA) and HDL-cholesterol (HDL-C).

Prediction of checkpoint inhibitor immunotherapy efficacy for cancer using routine blood tests and clinical data.

Predicting whether a patient with cancer will benefit from immune checkpoint inhibitors (ICIs) without resorting to advanced genomic or immunologic assays is an important clinical need. To address this, we developed and evaluated SCORPIO, a machine learning system that utilizes routine blood tests (complete blood count and comprehensive metabolic profile) alongside clinical characteristics from 9,745 ICI-treated patients across 21 cancer types. SCORPIO was trained on data from 1,628 patients across 17 cancer types from Memorial Sloan Kettering Cancer Center.

Adolescents and Young Adults with Germline CDH1 Variants and the Risk of Overtreatment.

Background: Adolescents and young adults (AYA) with germline CDH1 variants are at risk of overtreatment when precancer lesions are detected with endoscopic screening. We characterize diffuse-type gastric cancer prevalence and survival in AYA managed with prophylactic total gastrectomy (PTG) or endoscopic surveillance.

Methods: Prospective cohort study of 188 individuals aged 39 and younger enrolled from January 27, 2017, to May 1, 2023.

Racial/ethnic differences in trends of testicular germ cell tumor incidence in the United States, 1992-2021.

Background: Testicular germ cell tumors (TGCTs) are the most common cancers among young men in the United States. Incidence rates among non-Hispanic White (NHW) men historically have been much higher than the rates among other men. To study whether this pattern had changed, the authors examined trends in TGCT incidence for the years 1992-2021.

Changing Treatment and Metastatic Disease Patterns in Patients with EGFR Mutated NSCLC: An Academic Thoracic Medical Investigator's Consortium Registry Analysis.

Introduction: Osimertinib is now a standard first-line (1L) therapy for EGFR-mutated (EGFRm) advanced NSCLC. We aimed to characterize patterns of therapy and longitudinal risk of brain and liver metastasis in a cohort of EGFRm NSCLC.

Methods: Patients with metastatic EGFRm NSCLC who received 1L systemic therapy at sites within the Academic Thoracic Medical Investigator's Consortium were included; demographic and clinical data including treatment patterns were described.

Study Protocol of the Korean EGFR Registry: A Multicenter Prospective and Retrospective Cohort Study in Nonsmall Cell Lung Cancer Patients With EGFR Mutation.

Introduction: The provision of treatment for epidermal growth factor receptor (EGFR)-mutated nonsmall cell lung cancer (NSCLC) patients has increased in Korea. However, multicenter studies on the clinicopathologic dataset and treatment outcomes, using a large-scale dataset, have not been conducted. The current study is a prospective and retrospective multicenter observational cohort study that registers all stages of EGFR-mutated NSCLC patients.

Pulmonary neuroendocrine neoplasms: the molecular landscape, therapeutic challenges, and diagnosis and management strategies.

Lung neuroendocrine neoplasms are a group of diverse, heterogeneous tumours that range from well-differentiated, low-grade neuroendocrine tumours-such as typical and atypical carcinoids-to high-grade, poorly differentiated aggressive malignancies, such as large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC). While the incidence of SCLC has decreased, the worldwide incidence of other pulmonary neuroendocrine neoplasms has been increasing over the past decades. In addition to the standard histopathological classification of lung neuroendocrine neoplasms, the introduction of molecular and sequencing techniques has led to new advances in understanding the biology of these diseases and might influence future classifications and staging that can subsequently improve management guidelines in the adjuvant or metastatic settings.

Imagine, Discover, Inspire: Proceedings of the 4th International Conference of the Trisomy 21 Research Society.

Down syndrome (DS) or trisomy 21 (T21) is present in a significant number of children and adults around the world and is associated with cognitive and medical challenges. Through research, the T21 Research Society (T21RS), established in 2014, unites a worldwide community dedicated to understanding the impact of T21 on biological systems and improving the quality of life of people with DS across the lifespan. T21RS hosts an international conference every two years to support collaboration, dissemination, and information sharing for this goal.

Genomic and phenotypic stability of fusion-driven pediatric sarcoma cell lines.

Human cancer cell lines are the mainstay of cancer research. Recent reports showed that highly mutated adult carcinoma cell lines (mainly HeLa and MCF-7) present striking diversity across laboratories and that long-term continuous culturing results in genomic/transcriptomic heterogeneity with strong phenotypical implications. Here, we hypothesize that oligomutated pediatric sarcoma cell lines mainly driven by a fusion transcription factor, such as Ewing sarcoma (EwS), are genetically and phenotypically more stable than the previously investigated adult carcinoma cell lines.

Screening Criteria Evaluation for Expansion in Pulmonary Neoplasias (SCREEN) II.

Background: There is a need to expand eligibility criteria for lung cancer screening beyond age and smoking history. In this study, we sought to assess whether light-or-never-smokers and heavy smokers differ in molecular and immunologic markers based on conventional lung cancer screening criteria.

Methods: We conducted a retrospective review of lung cancer cases from 2005 to 2018 at a tertiary Canadian institution.

Mitochondrial DNA lineages determine tumor progression through T cell reactive oxygen signaling.

Mitochondrial DNA (mtDNA) is highly polymorphic, and host mtDNA variation has been associated with altered cancer severity. To determine the basis of this mtDNA-cancer association, we analyzed conplastic mice with the C57BL/6J (B6) nucleus but two naturally occurring mtDNA lineages, and , where mitochondria generate more oxidative phosphorylation (OXPHOS)-derived reactive oxygen species (mROS). In a cardiac transplant model, Foxp3+ T regulatory (Treg) cells supported long-term allograft survival, whereas Treg cells failed to suppress host T effector (Teff) cells, leading to acute rejection.

Social Risks and Nonadherence to Recommended Cancer Screening Among US Adults.

Importance: Research indicates that social drivers of health are associated with cancer screening adherence, although the exact magnitude of these associations remains unclear.

Objective: To investigate the associations between individual-level social risks and nonadherence to guideline-recommended cancer screenings.

Design, Setting, And Participants: This cross-sectional study used 2022 Behavioral Risk Factor Surveillance System data from 39 US states and Washington, DC.

SARS-CoV-2 Diversity and Transmission on a University Campus across Two Academic Years during the Pandemic.

Background: Institutions of higher education (IHE) have been a focus of SARS-CoV-2 transmission studies but there is limited information on how viral diversity and transmission at IHE changed as the pandemic progressed.

Methods: Here we analyze 3606 viral genomes from unique COVID-19 episodes collected at a public university in Seattle, Washington from September 2020 to September 2022.

Results: Across the study period, we found evidence of frequent viral transmission among university affiliates with 60% (n = 2153) of viral genomes from campus specimens genetically identical to at least one other campus specimen.

RNA-Based Next-Generation Sequencing in Non-Small Cell Lung Cancer patients: data from Campania, Italy.

Objective: ALK, ROS1, NTRK, and RET gene fusions and MET exon 14 skipping alterations represent fundamental predictive biomarkers for advanced non-small cell lung cancer (NSCLC) patients to ensure the best treatment choice. In this scenario, RNA-based NGS approach has emerged as an extremely useful tool for detecting these alterations. In this study, we report our NGS molecular records on ALK, ROS1, NTRK, and RET gene fusions and MET exon 14 skipping alterations detected by using a narrow RNA-based NGS panel, namely SiRe fusion.

BRCA testing in metastatic castration-resistant prostate cancer: successes and troubles in a real world setting. An Italian Multicentric study.

Objective: Prostate cancer (PCa) is the most common cause of cancer-related deaths in men worldwide. BRCA1/2 genes are reported altered in approximately 1% and 8% of PCa cases, respectively. To date, formalin-fixed paraffin-embedded (FFPE) tissues have a consolidate use in the clinical practice, but with a significant drawback related to DNA/RNA degradation during the pre-analytical process.

Circulating resistin levels and mutation burden of the RETN gene variants predict long-term mortality in a Taiwanese population.

Human resistin is a proinflammatory cytokine involving the development and progression of cancer and cardiovascular diseases. However, prediction of long-term outcome using circulating resistin level and its genetic determinants in a population-based study remain to be explored. After genome-wide association study (GWAS), DNA methylation (DNAm) analysis and functional assays of a RETN rs370006313 variant, we tested whether resistin level and its genetic determinants can be used to determine the long-term outcomes of 5678 Taiwan Biobank (TWB) participants.

Cooperative integration of spatially resolved multi-omics data with COSMOS.

Recent advancements in biological technologies have enabled the measurement of spatially resolved multi-omics data, yet computational algorithms for this purpose are scarce. Existing tools target either single omics or lack spatial integration. We generate a graph neural network algorithm named COSMOS to address this gap and demonstrated the superior performance of COSMOS in domain segmentation, visualization, and spatiotemporal map for spatially resolved multi-omics data integration tasks.

Rare germline structural variants increase risk for pediatric solid tumors.

Pediatric solid tumors are a leading cause of childhood disease mortality. In this work, we examined germline structural variants (SVs) as risk factors for pediatric extracranial solid tumors using germline genome sequencing of 1765 affected children, their 943 unaffected parents, and 6665 adult controls. We discovered a sex-biased association between very large (>1 megabase) germline chromosomal abnormalities and increased risk of solid tumors in male children.

Double CHEK2 Pathogenic and Low-Risk Variants and Associated Cancer Phenotypes.

Importance: CHEK2 pathogenic and likely pathogenic variants (PVs) are common, and low-risk (LR) variants, p.I157T, p.S428F, and p.

Whole-exome sequencing association study reveals genetic effects on tumor microenvironment components in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) presents a substantial clinical challenge due to the limited understanding of its genetic underpinnings. Here we conduct the largest scale whole-exome sequencing association study of NPC to date, encompassing 6,969 NPC cases and 7,100 controls. We unveil 3 germline genetic variants linked to NPC susceptibility: a common rs2276868 in RPL14, a rare rs5361 in SELE, and a common rs1050462 in HLA-B.

Nutritional characterization of patients with oropharyngeal cancers: impact of human papillomavirus status.

Background: Oropharyngeal squamous cell carcinoma (OPSCC) of human papillomavirus (HPV)-positive status is increasing relative to HPV-negative disease. Nutritional features of OPSCC patients according to HPV status is unclear.

Subjects/methods: Canadian and Spanish patients with OPSCC were assessed for body mass index (BMI), weight loss grade (WLG), and computed tomography-defined skeletal muscle index (SMI).

Evaluation of methotrexate Pharmacogenomic variation to predict acute neurotoxicity in children with acute lymphoblastic leukemia.

Background: Methotrexate is an important component of curative therapy in childhood acute lymphoblastic leukemia (ALL), but the role of genetic variation influencing methotrexate clearance and transport in toxicity susceptibility in children with ALL is not well established. Therefore, we evaluated the association between suspected methotrexate pharmacogenomic variants and methotrexate-related neurotoxicity.

Methods: This study included children (aged 2-20 years) diagnosed with ALL (2005-2019) at six treatment centers in the southwest United States.

Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction.

Background: The 313-variant polygenic risk score (PRS) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS across different European populations which could influence risk estimation has not been performed.

Methods: We explored the distribution of PRS across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank.

Evaluating the Use of Environmental and Polygenic Risk Scores to Inform Colorectal Cancer Risk-Based Surveillance Intervals.

Introduction: United States Multi-Society Task Force colonoscopy surveillance intervals are based solely on adenoma characteristics, without accounting for other risk factors. We investigated whether a risk model including demographic, environmental, and genetic risk factors could individualize surveillance intervals under an "equal management of equal risks" framework.

Methods: Using 14,069 individuals from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who had a diagnostic colonoscopy following an abnormal flexible sigmoidoscopy, we modeled the risk of colorectal cancer, considering the diagnostic colonoscopy finding, baseline risk factors (e.