Nam S. Vo

For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases. Jayasinghe et al. identify nearly 2,000 splice-site-creating mutations (SCMs) from over 8,000 tumor samples across 33 cancer types. They provide a more accurate interpretation of previously mis-annotated mutations, highlighting the importance of integrating data types to understand the functional and the clinical implications of splicing mutations in human disease.

In patients with resistant or poorly controlled hypertension and advanced chronic kidney disease, mineralocorticoid receptor antagonists are recommended; however, hyperkalemia limits their use. BLOCK-CKD was a phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group study that evaluated the safety, efficacy, and pharmacokinetics of KBP-5074, a nonsteroidal mineralocorticoid receptor antagonist, for uncontrolled hypertension in patients with stage 3b/4 chronic kidney disease. The study tested the hypothesis that addition of KBP-5074 to standard treatment lowers blood pressure without increased risk of hyperkalemia. Patients (N=162) were randomly assigned 1:1:1 to once-daily oral treatment with placebo, KBP-5074 0.25 mg, or KBP-5074 0.5 mg. The primary end point was systolic blood pressure change from baseline at day 84. Baseline mean (SD) systolic blood pressure was 155.3 (13.55) mm Hg. After 84 days, the placebo-subtracted treatment mean difference (SE) was −7.0 (3.37) mm Hg with KBP-5074 0.25 mg ( P =0.0399) and −10.2 (3.32) mm Hg with KBP-5074 0.5 mg ( P =0.0026). Hyperkalemia incidence, ≥5.6 <6 mmol/L, were similar among groups 5 (8.8%) placebo, 6 (11.8%) 0.25 mg, and 9 (16.7%) 0.5 mg patients. No hyperkalemia ≥6.0 mmol/L was observed. We conclude that KBP-5074 effectively lowers blood pressure with some risk of hyperkalemia in individuals with advanced chronic kidney disease and uncontrolled blood pressure. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03574363.

BACKGROUND AND OBJECTIVES: The genetic cause of medullary cystic kidney disease type 1 was recently identified as a cytosine insertion in the variable number of tandem repeat region of MUC1 encoding mucoprotein-1 (MUC1), a protein that is present in skin, breast, and lung tissue, the gastrointestinal tract, and the distal tubules of the kidney. The purpose of this investigation was to analyze the clinical characteristics of families and individuals with this mutation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Families with autosomal dominant interstitial kidney disease were referred for genetic analysis over a 14-year period. Families without UMOD or REN mutations prospectively underwent genotyping for the presence of the MUC1 mutation. Clinical characteristics were retrospectively evaluated in individuals with the MUC1 mutation and historically affected individuals (persons who were both related to genetically affected individuals in such a way that ensured that they could be genetically affected and had a history of CKD stage IV or kidney failure resulting in death, dialysis, or transplantation). RESULTS: Twenty-four families were identified with the MUC1 mutation. Of 186 family members undergoing MUC1 mutational analysis, the mutation was identified in 95 individuals, 91 individuals did not have the mutation, and111 individuals were identified as historically affected. Individuals with the MUC1 mutation suffered from chronic kidney failure with a widely variable age of onset of end stage kidney disease ranging from 16 to >80 years. Urinalyses revealed minimal protein and no blood. Ultrasounds of 35 individuals showed no medullary cysts. There were no clinical manifestations of the MUC1 mutation detected in the breasts, skin, respiratory system, or gastrointestinal tract. CONCLUSION: MUC1 mutation results in progressive chronic kidney failure with a bland urinary sediment. The age of onset of end stage kidney disease is highly variable, suggesting that gene-gene or gene-environment interactions contribute to phenotypic variability.