Citations

Mutations in homologous recombination (HR) genes, including BRCA1 , BRCA2 , and the RAD51 paralog RAD51C , predispose to tumorigenesis and sensitize cancers to DNA-damaging agents and poly(ADP ribose) polymerase inhibitors. However, ∼800 missense variants of unknown significance have been identified for RAD51C alone, impairing cancer risk assessment and therapeutic strategies. Here, we interrogated >50 RAD51C missense variants, finding that mutations in residues conserved with RAD51 strongly predicted HR deficiency and disrupted interactions with other RAD51 paralogs. A cluster of mutations was identified in and around the Walker A box that led to impairments in HR, interactions with three other RAD51 paralogs, binding to single-stranded DNA, and ATP hydrolysis. We generated structural models of the two RAD51 paralog complexes containing RAD51C, RAD51B-RAD51C-RAD51D-XRCC2 and RAD51C-XRCC3. Together with our functional and biochemical analyses, the structural models predict ATP binding at the interface of RAD51C interactions with other RAD51 paralogs, similar to interactions between monomers in RAD51 filaments, and explain the failure of RAD51C variants in binding multiple paralogs. Ovarian cancer patients with variants in this cluster showed exceptionally long survival, which may be relevant to the reversion potential of the variants. This comprehensive analysis provides a framework for RAD51C variant classification. Importantly, it also provides insight into the functioning of the RAD51 paralog complexes.

AbstractBackgroundHis bundle pacing (HBP) is a physiological pacing strategy to preserve the electrical synchrony of ventricular conduction and left ventricular (LV) function. Left bundle branch pacing (LBBP) has emerged as an alternative physiological pacing technique.ObjectiveTo evaluate cardiac electrical and mechanical synchrony comparing LBBP and HBP in patients with permanent atrial fibrillation (AF).MethodsConsecutive patients with symptomatic bradycardia and AF were enrolled from January to June of 2019. The cardiac electrical and mechanical synchrony in different pacing mode were evaluated at baseline and after implantation.ResultsBoth HBP and LBBP were performed in 20 patients. LBBP significantly widened the QRS duration compared with the intrinsic conduction (113.2 ± 14.5 vs. 96.5 ± 16.2 ms; p = .01), while HBP did not (104.5 ± 22.3 vs. 96.5 ± 16.2 ms; p = .12). Both LBBP and HBP patients had similar LV myocardial strain measurements for the mechanical synchrony evaluation without significant change compared with baseline. There was no significant difference in right ventricular synchrony measurement between LBBP and HBP. Compared to HBP, LBBP had less interventricular synchrony (IMVD, 14.7 ± 9.2 vs. 3.1 ± 12.7 ms, p < .01; Ts‐LV‐RV, 37.9 ± 10.7 vs. 18.5 ± 10.8 ms, p < .001).ConclusionsAlthough LBBP's a physiological pacing mode can achieve a similar cardiac electrical and mechanical synchronization when compared to HBP, LBBP results in modest delay in RV activation, and the clinical implication remains to be studied.

Abstract The contribution of emphysema to lung cancer risk has been recognized, but the effect size needs to be further defined. In this study, 565 primary lung cancer cases were enrolled though a prospective lung cancer cohort at Mayo Clinic, and 450 controls were smokers participating in a lung cancer screening study in the same institution using spiral computed tomography (CT). Cases and controls were frequency matched on age, gender, race, smoking status, and residential region. CT imaging using standard protocol at the time of lung cancer diagnosis (case) or during the study (control) was assessed for emphysema by visual scoring CT analysis as a percentage of lung tissue destroyed. The clinical definition of emphysema was the diagnosis recorded in the medical documentation. Using multiple logistic regression models, emphysema (≥5% on CT) was found to be associated with a 3.8-fold increased lung cancer risk in Caucasians, with higher risk in subgroups of younger (&lt;65 years old, OR = 4.64), heavy smokers (≥40 pack-years, OR = 4.46), and small-cell lung cancer (OR = 5.62). When using &gt;0% or ≥10% emphysema on CT, lung cancer risk was 2.79-fold or 3.33-fold higher than controls. Compared with CT evaluation (using criterion ≥5%), the sensitivity, specificity, positive and negative predictive values, and the accuracy of the clinical diagnosis for emphysema in controls were 19%, 98%, 73%, 84%, and 83%, respectively. These results imply that an accurate evaluation of emphysema could help reliably identify individuals at greater risk of lung cancer among smokers. Cancer Prev Res; 4(1); 43–50. ©2010 AACR.

Abstract Background: Multiple recent genome-wide studies of single nucleotide polymorphisms (SNP) reported associations between candidate chromosome loci and lung cancer susceptibility. We evaluated five of the top candidate SNPs (rs402710, rs2736100, rs4324798, rs16969968, and rs8034191) for their effects on lung cancer risk and overall survival. Methods: Over 1,700 cases and 2,200 controls were included in this study. Seven independent, complementary case-control data sets were tested for risk assessment encompassing cigarette smokers and never smokers, using unrelated controls and unaffected full-sibling controls. Five patient groups were tested for survival prediction stratified by smoking status, histology subtype, and treatment. Results: After considering a history of chronic obstructive pulmonary disease as a risk factor altering lung cancer risk and comparing to sibling controls, none of the five SNPs remained significant. However, the variant rs4324798 was significant in predicting overall survival (hazard ratio, 0.46; 95% confidence interval, 0.30-0.73; P = 0.001) in small cell lung cancer. Conclusions: None of the five candidate SNPs in lung cancer risk can be confirmed in our study. The previously reported association could be explained by disparity in tobacco smoke exposure and chronic obstructive pulmonary disease history between cases and controls. Instead, we found rs4324798 to be an independent predictor in small cell lung cancer survival, warranting further elucidation of the underlying mechanisms.Cancer Epidemiol Biomarkers Prev; 19(1); 240–4