Variation in NF- B Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer

Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that impact prognosis are not known. The nuclear factor-kappa B (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance—p < 2.5×10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with CARD11 (caspase recruitment domain family, member 11) rs41324349 in patients with mucinous EOC (HR 1.82, 95% CI 1.41–2.35, p=4.13×10−6) and TNFRSF13B (tumor necrosis factor receptor superfamily, member 13B) rs7501462 in patients with endometrioid EOC (HR 0.68, 95% CI 0.56–0.82, p=2.33×10−5). Other associations of note included TRAF2 (TNF receptor-associated factor 2) rs17250239 in patients with high-grade serous EOC (HR 0.84, 95% CI 0.77–0.92, p=6.49×10−5) and PLCG1 (phospholipase C, gamma 1) rs11696662 in patients with clear cell EOC (HR 0.43, 95% CI 0.26–0.73, p=4.56×10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies

Genome-wide association study of prostate cancer-specific survival

Free to read\ud \ud BACKGROUND: \ud \ud Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical.\ud \ud METHODS: \ud \ud We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR).\ud \ud RESULTS: \ud \ud We observed no significant association between genetic variants and prostate cancer survival.\ud \ud CONCLUSIONS: \ud \ud Common genetic variants with large impact on prostate cancer survival were not observed in this study.\ud \ud IMPACT: \ud \ud Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes

Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome

The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 × 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 × 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19-1.64; P = 5.6 × 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 × 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 × 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cance

Cohort profile: the ESC EURObservational Research Programme Non-ST-segment elevation myocardial infraction (NSTEMI) Registry

Aims The European Society of Cardiology (ESC) EURObservational Research Programme (EORP) Non-ST-segment elevation myocardial infarction (NSTEMI) Registry aims to identify international patterns in NSTEMI management in clinical practice and outcomes against the 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without ST-segment-elevation. Methods and results Consecutively hospitalised adult NSTEMI patients (n = 3620) were enrolled between 11 March 2019 and 6 March 2021, and individual patient data prospectively collected at 287 centres in 59 participating countries during a two-week enrolment period per centre. The registry collected data relating to baseline characteristics, major outcomes (inhospital death, acute heart failure, cardiogenic shock, bleeding, stroke/transient ischaemic attack, and 30-day mortality) and guideline-recommended NSTEMI care interventions: electrocardiogram pre- or in-hospital, prehospitalization receipt of aspirin, echocardiography, coronary angiography, referral to cardiac rehabilitation, smoking cessation advice, dietary advice, and prescription on discharge of aspirin, P2Y12 inhibition, angiotensin converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB), beta-blocker, and statin. Conclusion The EORP NSTEMI Registry is an international, prospective registry of care and outcomes of patients treated for NSTEMI, which will provide unique insights into the contemporary management of hospitalised NSTEMI patients, compliance with ESC 2015 NSTEMI Guidelines, and identify potential barriers to optimal management of this common clinical presentation associated with significant morbidity and mortality