Citations

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Abstract Objective To measure the relative levels of signal and noise in expert diagnosis of epilepsy. Methods Twenty multinational epileptologists independently reviewed 50 vignettes of adult and pediatric patients presenting with suspected seizure(s) on two separate occasions with a ≥30‐day washout period. Experts provided a diagnosis of epilepsy or non‐epilepsy based on clinical information and, if requested, routine EEG and neuroimaging data. Cases had an established clinical diagnosis of epilepsy or non‐epilepsy based on capture of habitual paroxysmal events on video‐EEG or long‐term clinical follow‐up. Experts' judgments were analyzed to decompose variability into different sources: signal (objective differences between cases), level noise (experts' bias toward over/under‐diagnosis), pattern noise (experts' idiosyncratic reactions to specific case features), and occasion noise (inconsistency across occasions). Results The probability of an expert making a different diagnosis for a given case on two different occasions was 16%. The probability of two different experts making a different diagnosis for the same case was 26%. Signal (case “difficulty”) accounted for 66–69% of total variation, with 31–34% attributable to noise. Level noise was the largest contributor in the absence of EEG/neuroimaging results (23%), while pattern noise dominated when test results were available (24%). Occasion noise contributed relatively little (1%) but was still sufficient to cause diagnostic reversals in 16–22% between occasions. Significance The degree of noise in expert diagnosis of epilepsy is substantial, stemming primarily from physicians' idiosyncratic interpretations of case features and variable dispositions toward over‐ or under‐diagnosis. Strategies to improve reliability are needed, including standardized data collection protocols and structured decision algorithms. For “difficult cases,” where expert reliability and accuracy are lowest, our findings support current clinical practice which favors early referral for video‐EEG monitoring over reliance on diagnostic anchoring. This diagnostic pathway may become more accessible with advances in EEG technology (e.g., wearable devices) and artificial intelligence.

Abstract Understanding tumor cell dynamics can improve prognosis and treatment but remains limited for lung adenocarcinoma in people who have never smoked (NS-LUAD). With RNA sequencing data from 684 NS-LUAD cases and validation in an independent dataset, we identified three subtypes with distinct phenotypic traits and cell compositions. Additional genomic and histologic data further characterized the subtypes. “Steady,” marked by low proliferation, high alveolar cell fraction, moderate-to-well differentiation, and fewer driver gene alterations, is linked to prolonged survival and low immune evasion. “Proliferative” shows high proliferation markers, TP53 mutations, and gene fusions. “Chaotic,” with high epithelial-to-mesenchymal transition markers, has the worst prognosis, even within stage I tumors. Lacking known molecular or histologic characteristics, this aggressive subtype is solely identified by transcriptomic data. A 60-gene signature recapitulates the classification and predicts survival even within subgroups based on tumor stage or known genomic features, emphasizing its potential for improving early-stage NS-LUAD prognostication in clinical settings. Significance: The transcriptome of 684 NS-LUAD identifies three subtypes with different cellular dynamics and genomic and morphologic features. A 60-gene signature accurately stratifies subjects for mortality risk, even in stage I, offering a potential clinically applicable tool for treatment decision-making in patients with NS-LUAD. See related commentary by Azizi et al., p. 423

ABSTRACT Understanding lung cancer evolution can identify tools for intercepting its growth. In a landscape analysis of 1024 lung adenocarcinomas (LUAD) with deep whole-genome sequencing integrated with multiomic data, we identified 542 LUAD that displayed diverse clonal architecture. In this group, we observed an interplay between mobile elements, endogenous and exogenous mutational processes, distinct driver genes, and epidemiological features. Our results revealed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry, and sex. LUAD from smokers showed an abundance of tobacco-related C:G>A:T driver mutations in KRAS plus short subclonal diversification. LUAD in never smokers showed early occurrence of copy number alterations and EGFR mutations associated with SBS5 and SBS40a mutational signatures. Tumors harboring EGFR mutations exhibited long latency, particularly in females of European-ancestry (EU_N). In EU_N, EGFR mutations preceded the occurrence of other driver genes, including TP53 and RBM10. Tumors from Asian never smokers showed a short clonal evolution and presented with heterogeneous repetitive patterns for the inferred mutational order. Importantly, we found that the mutational signature ID2 is a marker of a previously unrecognized mechanism for LUAD evolution. Tumors with ID2 showed short latency and high L1 retrotransposon activity linked to L1 promoter demethylation. These tumors exhibited an aggressive phenotype, characterized by increased genomic instability, elevated hypoxia scores, low burden of neoantigens, propensity to develop metastasis, and poor overall survival. Re-activated L1 retrotransposition-induced mutagenesis can contribute to the origin of the mutational signature ID2, including through the regulation of the transcriptional factor ZNF695 , a member of the KZFP family. The complex nature of LUAD evolution creates both challenges and opportunities for screening and treatment plans.

ImportanceThe fecal immunochemical test (FIT) is widely used for colorectal cancer (CRC) screening, but evidence of its effectiveness is limited.ObjectiveTo evaluate whether FIT screening is associated with a lower risk of dying from CRC overall, according to cancer location, and within demographic groups.Design, Setting, and ParticipantsThis nested case-control study in a cohort of screening-eligible people was conducted in 2 large, integrated health systems of racially, ethnically, and socioeconomically diverse members with long-term programs of mailed FIT screening outreach. Eligible participants included people aged 52 to 85 years who died from colorectal adenocarcinoma between 2011 and 2017 (cases); cases were matched in a 1:8 ratio based on age, sex, health-plan membership duration, and geographic area to randomly selected persons who were alive and CRC-free on case’s diagnosis date (controls). Data analysis was conducted from January 2002 to December 2017.ExposuresCompleting 1 or more FIT screenings in the 5-year period prior to the CRC diagnosis date among cases or the corresponding date among controls; in secondary analyses, 2- to 10-year intervals were evaluated.Main Outcomes and MeasuresThe primary study outcome was CRC death overall and by tumor location. Secondary analyses were performed to assess CRC death by race and ethnicity.ResultsFrom a cohort of 2 127 128 people, a total of 10 711 participants (3529 aged 60-69 years [32.9%]; 5587 male [52.1%] and 5124 female [47.8%]; 1254 non-Hispanic Asian [11.7%]; 973 non-Hispanic Black [9.1%]; 1929 Hispanic or Latino [18.0%]; 6345 non-Hispanic White [59.2%]) was identified, including 1103 cases and 9608 controls. Among controls during the 10-year period prior to the reference date, 6101 (63.5%) completed 1 or more FITs with a cumulative 12.6% positivity rate (768 controls), of whom 610 (79.4%) had a colonoscopy within 1 year. During the 5-year period, 494 cases (44.8%) and 5345 controls (55.6%) completed 1 or more FITs. In regression analysis, completing 1 or more FIT screening was associated with a 33% lower risk of death from CRC (adjusted odds ratio [aOR], 0.67; 95% CI, 0.59-0.76) and 42% lower risk in the left colon and rectum (aOR, 0.58; 95% CI, 0.48-0.71). There was no association with right colon cancers (aOR, 0.83; 95% CI, 0.69-1.01) but the difference in the estimates between the right colon and left colon or rectum was statistically significant (P = .01). FIT screening was associated with lower CRC mortality risk among non-Hispanic Asian (aOR, 0.37; 95% CI, 0.23-0.59), non-Hispanic Black (aOR, 0.58; 95% CI, 0.39-0.85) and non-Hispanic White individuals (aOR, 0.70; 95% CI, 0.57-0.86) (P for homogeneity = .04 for homogeneity).Conclusions and RelevanceIn this nested case-control study, completing FIT was associated with a lower risk of overall death from CRC, particularly in the left colon, and the associations were observed across racial and ethnic groups. These findings support the use of FIT in population-based screening strategies.

Introduction: PET/CT is the standard-of-care for staging and therapy response assessment in lymphoma. Fluorodeoxyglucose (FDG)-avidity in extranodal marginal zone lymphoma (EMZL) remains controversial with some variability by extranodal location. The current Lugano classification recommends the use of CT scans only in staging and follow-up for EMZL. However, emerging data from small studies have challenged this suggestion. In this study we aimed to determine the ability of PET/CT to detect FDG-avid EMZL during staging work-up. Methods: First, we retrospectively analyzed the University of Miami (UM) MZL database (period 2/2016-1/2023) searching for patients who underwent staging PET/CT. Images were reviewed by expert radiologists to ascertain avidity of tumor and not surrounding tissue, with specific attention to ocular and GI locations; if scans were not available (n=15), we retrieved data from reports (results presented in part at ICML2023). Next, we aimed to validate the initial UM results additionally analyzing data from imaging reports for patients prospectively enrolled in the Lymphoma Epidemiology of Outcomes (LEO) MZL cohort (period 7/2015-5/2020), excluding LEO patients from Miami to avoid overlap. Patients with high-grade transformation at diagnosis were excluded. For patients with >1 extranodal site, each location was counted independently. We considered FDG-avid disease if SUVmax was ≥2 as this value is commonly observed between mediastinal blood pool (BP) and liver background. To normalize data, we calculated ratios of lymphoma SUVmax versus both BP and liver background, as available. Patients without measurable disease were excluded from analysis. Results: Among 210 patients with EMZL in the UM cohort, 152 had staging PET/CT and were analyzed. Twenty-two patients demonstrated >1 extranodal site providing a total of 187 locations. The LEO cohort included 411 patients from 7 centers, with 235 having available imaging reports. Fifty-two patients in this cohort demonstrated >1 extranodal site providing a total of 306 locations. Disease distribution is depicted in Table 1. Among 187 EMZL locations in the UM cohort, the most common were gastric (n=33, 17.6%), ocular (n=31, 16.6%), lung (n=30, 16%), skin and soft tissue (n=16, 8.6%, each). Similarly, lung (n=63; 20.6%), soft tissue (n=46; 15%), gastric and ocular (n=34 each; 11%) were common locations in the LEO cohort. EMZL demonstrated FDG-avidity (SUVmax ≥2) across all locations with identical values in both cohorts (UM= 78.1% & LEO= 76.5%). FDG-avidity by location is shown in Table 1A & B with salivary gland (100% & 100%), lung (93.3% & 95.2%), soft tissue (93.8% & 100%), and airways (90.9% & 100%) demonstrating high avidity in both cohorts. Contrarily, skin was commonly non-FDG avid (93.8% & 81%). The median size of FDG-avid lesions was 2.4cm (range, 0.7-17.4) in UM and 2.9cm (range, 0.1-12) in LEO cohorts. In patients with >1 extranodal site FDG-avidity was nearly universal across sites (UM=93% & LEO=100%). We observed a significant correlation between lymphoma size and FDG-avidity for UM (r=0.33; P=0.001), and for LEO (r=0.55; P<0.0001). In patients with background FDG-avidity data in the UM cohort (n=150), a BP index and liver index ≥1 detected lymphoma in 79.3% & 71.5% cases, respectively. We were unable to calculate indexes in LEO cohort since only limited data on BP (n=26) and liver (n=19) background was available in imaging reports. Conclusions: This study represents the largest analysis evaluating accuracy of PET/CT to determine initial tumor burden in 387 patients with EMZL. We demonstrate that EMZL is largely an FDG-avid disease across two cohorts, and PET/CT should be included in the staging of these patients while acknowledging possible limited sensitivity in GI locations due to physiologic uptake. Furthermore, we observed that patients with multiple extranodal locations demonstrate uniform FDG-avidity across all sites except for skin involvement. Based on our results we recommend the incorporation of PET/CT into standard staging of EMZL in planned revised Lugano classification guidelines. In those demonstrating initial FDG-avidity, a lower SUVmax threshold of SUVmax ≥2, comparison to mediastinal BP rather than to liver background activity and evaluating for resolution of focal FDG-avidity should be considered to assess treatment response in routine care and clinical trials.

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross‐sectional and prospective association analyses of blood‐derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole‐genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1‐SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04–1.12; P <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; P =0.11) or in the reverse direction (β=−0.012; P =0.076). Additional bidirectional Mendelian randomization analyses revealed that low‐density lipoprotein cholesterol had a causal effect on mtDNA CN (β=−0.084; P <0.001), but the reverse direction was not significant ( P =0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low‐density lipoprotein cholesterol level ( P =0.52), whereas there was a strong direct causal effect of higher low‐density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=−0.092; P <0.001). Conclusions Our findings indicate that high low‐density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.