Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: r(g) = 0.098, p = 2.3 x 10(-8)) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: r(g) = 0.137, p = 2.0 x 10(-12)). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis

Assessing Lung Cancer Absolute Risk Trajectory Based on a Polygenic Risk Model

Lung cancer is the leading cause of cancer death globally. An improved risk stratification strategy can increase efficiency of low-dose computed tomography (LDCT) screening. Here we assessed whether individual’s genetic background has clinical utility for risk stratification in the context of LDCT screening. Based on 13,119 lung cancer patients and 10,008 controls with European ancestry in the International Lung Cancer Consortium, we constructed a polygenic risk score (PRS) via 10-fold cross-validation with regularized penalized regression. The performance of risk model integrating PRS, including calibration and ability to discriminate, was assessed using UK biobank data (N=335,931). Absolute risk was estimated based on age-specific lung cancer incidence and all-cause mortality as competing risk. To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial (N=50,772 participants). The lung cancer odds ratio (ORs) for individuals at the top decile of the PRS distribution versus those at bottom 10% was 2.39 (95%CI=1.92–3.00, P=1.80×10(−14)) in the validation set (trend p-value of 5.26 × 10(−20)). The OR per standard deviation of PRS increase was 1.26 (95%CI=1.20–1.32, P=9.69×10(−23)) for overall lung cancer risk in the validation set. When considering absolute risks, individuals at different PRS deciles showed differential trajectories of 5-year and cumulative absolute risk. The age reaching the LDCT screening recommendation threshold can vary by 4 to 8 years, depending on the individual’s genetic background, smoking status and family history. Collectively, these results suggest that individual’s genetic background may inform the optimal lung cancer LDCT screening strategy

Lifetimes and spatio-temporal response of protein crystals in intense X-ray microbeams

Serial synchrotron-based crystallography using intense microfocused X-ray beams, fast-framing detectors and protein microcrystals held at 300 K promises to expand the range of accessible structural targets and to increase overall structure-pipeline throughputs. To explore the nature and consequences of X-ray radiation damage under microbeam illumination, the time-, dose- and temperature-dependent evolution of crystal diffraction have been measured with maximum dose rates of 50 MGy s−1. At all temperatures and dose rates, the integrated diffraction intensity for a fixed crystal orientation shows non-exponential decays with dose. Non-exponential decays are a consequence of non-uniform illumination and the resulting spatial evolution of diffracted intensity within the illuminated crystal volume. To quantify radiation-damage lifetimes and the damage state of diffracting crystal regions, a revised diffraction-weighted dose (DWD) is defined and it is shown that for Gaussian beams the DWD becomes nearly independent of actual dose at large doses. An apparent delayed onset of radiation damage seen in some intensity–dose curves is in fact a consequence of damage. Intensity fluctuations at high dose rates may arise from the impulsive release of gaseous damage products. Accounting for these effects, data collection at the highest dose rates increases crystal radiation lifetimes near 300 K (but not at 100 K) by a factor of ∼1.5–2 compared with those observed at conventional dose rates. Improved quantification and modeling of the complex spatio-temporal evolution of protein microcrystal diffraction in intense microbeams will enable more efficient data collection, and will be essential in improving the accuracy of structure factors and structural models

Data for "A microfabricated fixed path length silicon sample holder improves background subtraction for cryoSAXS"

The application of small-angle X-ray scattering (SAXS) for high-throughput characterization of biological macromolecules in solution is limited by radiation damage. By cryocooling samples, radiation damage and required sample volumes can be reduced by orders of magnitude. However, the challenges of reproducibly creating the identically sized vitrified samples necessary for conventional background subtraction limit the widespread adoption of this method. Fixed path length silicon sample holders for cryoSAXS have been micro fabricated to address these challenges. They have low background scattering and X-ray absorption, require only 640 nl of sample, and allow reproducible sample cooling. Data collected in the sample holders from a nominal illuminated sample volume of 2.5 nl are reproducible down to q ’ 0.02 Å-1, agree with previous cryoSAXS work and are of sufficient quality for reconstructions that match measured crystal structures. These sample holders thus allow faster, more routine cryoSAXS data collection. Additional development is required to reduce sample fracturing and improve data quality at low q

Circulating Proteome for Pulmonary Nodule Malignancy.

BackgroundWhile lung cancer screening with low-dose computed tomography (LDCT) is rolling out in many areas of the world, differentiating indeterminate pulmonary nodules remains a major challenge. We conducted one of the first systematic investigations of circulating protein markers to differentiate malignant versus benign screen-detected pulmonary nodules.MethodsBased on four international LDCT screening studies, we assayed 1078 protein markers using pre-diagnostic blood samples from 1253 participants based on a nested case-control design. Protein markers were measured using proximity extension assays and data were analyzed using multivariable logistic regression, random forest, and penalized regressions. Protein burden scores for overall nodule malignancy (PBS-overall) and imminent tumors (PBS-imminent) were estimated.ResultsWe identified 36 potentially informative circulating protein markers differentiating malignant from benign nodules, representing a tightly connected biological network. Ten markers were found to be particularly relevant for imminent lung cancer diagnoses within one year. Increases in PBS-overall and PBS-imminent by 1 standard deviation were associated with odds ratios of 2.29(95%CI = 1.95-2.72), and 2.81(95%CI = 2.27-3.54) for nodule malignancy overall, and within 1 year of diagnosis, respectively. Both PBS-overall and PBS-imminent were substantially higher for those with malignant nodules compared to those with benign nodules even when limited to LungRADS category 4 (p ConclusionsCirculating protein markers can help to differentiate malignant from benign pulmonary nodules. Validation with an independent CT-screening study will be required prior to clinical implementation

Mapping the conformational landscape of a dynamic enzyme by multitemperature and XFEL crystallography.

Determining the interconverting conformations of dynamic proteins in atomic detail is a major challenge for structural biology. Conformational heterogeneity in the active site of the dynamic enzyme cyclophilin A (CypA) has been previously linked to its catalytic function, but the extent to which the different conformations of these residues are correlated is unclear. We monitored the temperature dependences of these alternative conformations with eight synchrotron datasets spanning 100-310 K. Multiconformer models show that many alternative conformations in CypA are populated only at 240 K and above, yet others remain populated or become populated at 180 K and below. These results point to a complex evolution of conformational heterogeneity between 180-240 K that involves both thermal deactivation and solvent-driven arrest of protein motions in the crystal. Together, our multitemperature analyses and XFEL data motivate a new generation of temperature- and time-resolved experiments to structurally characterize the dynamic underpinnings of protein function