Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes

Previous studies have shown that the selective aldosterone blocker eplerenone, in doses of up to 200 mg/d, reduces albuminuria in patients with type 2 diabetes. This study was conducted to ascertain whether lower doses of eplerenone (50 or 100 mg/d) co-administered with the angiotensin-converting enzyme (ACE) inhibitor enalapril would produce a similar antialbuminuric effect while obviating the hyperkalemia observed previously. After open-label run-in with enalapril 20 mg/d, patients with diabetes and a urinary albumin:creatinine ratio (UACR) > or = 50 mg/g were randomly assigned to receive enalapril plus one of three double-blind daily treatments for 12 wk: placebo, eplerenone 50 mg (EPL50), or eplerenone 100 mg (EPL100). After week 4, amlodipine 2.5 to 10 mg/d was allowed for BP control (systolic/diastolic BP < or = 130/80 mmHg). The primary study end points were the percentage change from baseline at week 12 in UACR and the incidence of hyperkalemia. Secondary end points included percentage changes from baseline in UACR at weeks 4 and 8 and changes from baseline in systolic and diastolic BP. Treatment with EPL50 or EPL100 but not placebo significantly reduced albuminuria from baseline. By week 12, UACR was reduced by 7.4% in the placebo group, by 41.0% in the EPL50 group, and by 48.4% in the EPL100 group (both eplerenone groups, P < 0.001 versus placebo). The incidences of sustained and severe hyperkalemia were not significantly different in any of the three treatment arms and did not differ on the basis of quartile of estimated GFR (all NS). For the secondary end points, both eplerenone treatment groups significantly reduced albuminuria from baseline as early as week 4 (P < 0.001), whereas placebo treatment (including enalapril) did not result in any significant decreases in UACR. Systolic BP decreased significantly in all treatment groups at all time points, but, generally, all treatment groups experienced similar decreases in BP. Co-administration of EPL50 or EPL100 with an ACE inhibitor as compared with an ACE inhibitor alone significantly reduces albuminuria in patients with diabetes without producing significant increases in hyperkalemia

Comparative efficacy of aliskiren monotherapy and ramipril monotherapy in patients with stage 2 systolic hypertension: subgroup analysis of a double-blind, active comparator trial.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldAliskiren is the first direct renin inhibitor approved for the treatment of hypertension. Blood pressure (BP) control in stage 2 hypertension with aliskiren monotherapy has not been reported. This was a post hoc analysis of the subgroup of patients with stage 2 systolic hypertension (baseline mean sitting systolic BP [msSBP]≥160 mmHg) who completed the 12-week monotherapy phase of a 6-month, double-blind, randomized study. A total of 175 patients were randomized to aliskiren 150 mg (n = 88) or ramipril 5 mg (n = 87) with optional up-titration to aliskiren 300 mg or ramipril 10 mg, respectively, at weeks 6 and 12. In the subgroup of patients with stage 2 systolic hypertension, aliskiren lowered msSBP and mean sitting diastolic BP (msDBP) by 22.3/12.7 mmHg from baseline to week 12; compared with a reduction of 18.1/10.2 mmHg with ramipril. The maximum BP reductions achieved with aliskiren were 60.0/34.0 mmHg (from a baseline of 172.7/107.3 mmHg). Aliskiren was noninferior (P < 0.0001) to ramipril for SBP reduction with nonsignificant superiority (P = 0.052), and superior (P = 0.043) to ramipril for DBP reduction. The proportion of patients who achieved BP control (<140/90 mmHg) after 12 weeks of monotherapy was larger with aliskiren (34/88, 38.6%) than with ramipril (22/87, 25.3%; P = 0.038). In this post hoc analysis, 12 weeks of monotherapy with aliskiren 150-300 mg provided effective mean BP reductions (22/13 mmHg) and was superior to ramipril 5-10 mg in controlling BP in patients with stage 2 systolic hypertension

Comparative effects of aliskiren-based and ramipril-based therapy on the renin system during long-term (6 months) treatment and withdrawal in patients with hypertension

Introduction. This subgroup analysis assessed the effects of treatment based on the direct renin inhibitor, aliskiren, or the angiotensin-converting enzyme inhibitor, ramipril, on plasma renin activity (PRA), plasma renin concentration (PRC) and other biomarkers in a 26-week randomised, double-blind trial. Changes in PRA and PRC after stopping treatment were also assessed. Methods. After placebo run-in, 842 patients (mean sitting diastolic blood pressure (BP) 95-109 mmHg) were randomised to aliskiren 150 mg or ramipril 5 mg. Dose titration and hydrochlorothiazide addition were allowed after Week 6 and 12, respectively, for inadequate BP control. Patients completing active treatment were re-randomised to current regimen or placebo during a 4-week posttreatment phase. Results. BP reductions were independent of baseline PRA at Week 12, were greater with aliskiren - than ramipril-based therapy at Week 26 (17.9/ 13.3 vs. 15.2/12.0 mmHg, p \u3c 0.05) and persisted for longer after stopping aliskiren. Aliskiren-based therapy reduced geometric mean PRA (-63%, p \u3c 0.05; n = 103), while ramipril-based therapy increased PRA (+143%, p \u3c 0.05; n=100) at Week 26; PRC increased in both groups (aliskiren: +224% [n = 33], ramipril: +145% [n=39], both p \u3c 0.05). Four weeks after stopping aliskiren-based therapy, PRA remained 52% below pre-treatment baseline; PRA returned to baseline 2 weeks after stopping ramipril-based therapy. Conclusions. Aliskiren-based therapy produced sustained BP and PRA reductions over 26 weeks; ramipril-based therapy lowered BP and increased PRA. PRA reductions persisted 4 weeks after stopping aliskiren, suggesting an inhibitory effect beyond the elimination half-life of the drug