👤 Marja W Wessels

Malignant pleural mesothelioma (PM) is an aggressive cancer with limited treatment options. Although first-line nivolumab plus ipilimumab improves outcomes for some patients, a majority fail to respond. Mechanisms of immune resistance in PM remain poorly understood, underscoring the need for new clinically actionable drug targets to overcome immunotherapy resistance. We established an in silico pipeline to investigate the molecular basis of T-cell exclusion in bulk RNA-sequencing data from 448 patients across three immune checkpoint blockade (ICB)-naïve PM cohorts. We assessed genome-wide correlations between gene expression and a previously validated cytotoxic T-cell signature score. Candidate immune evasion genes were prioritized based on clinical relevance, drug availability, and experimental feasibility for follow-up translational research. The in silico pipeline produced a highly reproducible catalogue of genes whose expression inversely correlates with T-cell infiltration, including established immune evasion factors (e.g. SOX4, KDM5B, CMTM4) and five novel FDA-approved drug targets (SMO, GANAB, ERBB2, GABRA1, ODC1). Seven additional targets (ARNT, BMPR1B, GSK3B, ACVR1, BACE1, RPS6KB1, ULK1) with preclinical inhibitors were also identified. Notably, we identified a possible link between primary cilia, Hedgehog signaling and T-cell exclusion. We found that SMO expression correlated with poor clinical response to second-line nivolumab plus ipilimumab in PM, highlighting SMO as a promising therapeutic target and potential biomarker for treatment resistance. This comprehensive transcriptomic characterization of T-cell exclusion in PM reveals that targeting cilium-based Hedgehog signaling, in addition to multiple other actionable drug targets, could enhance the efficacy of ICB treatment in PM. Show less

There is overlap in genetic causes and cardiac features in noncompaction cardiomyopathy (NCCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM). The goal of this study was to predict phenotype and outcome in relatives according to the clinical features and genotype of NCCM index cases. Retrospective DNA and cardiac screening of relatives of 113 families from 143 index patients were used to classify NCCM cases according to the cardiac phenotype. These cases were classified as isolated NCCM, NCCM with left ventricular (LV) dilation (DCM), and NCCM with LV hypertrophy (HCM). In 58 (51%) families, screening identified 73 relatives with NCCM and 34 with DCM or HCM without NCCM. The yield of family screening was higher in families with a mutation (p < 0.001). Fifty-four families had a mutation. Nonpenetrance was observed in 37% of the relatives with a mutation. Index cases were more often symptomatic than affected relatives (p < 0.001). NCCM with DCM (53%) was associated with LV systolic dysfunction (p < 0.001), increased risk for major adverse cardiac events, mutations in the tail of MYH7 (p < 0.001), and DCM without NCCM in relatives (p < 0.001). Isolated NCCM (43%) was associated with a milder course, mutations in the head of MYH7, asymptomatic NCCM (42%) (p = 0.018), and isolated NCCM in relatives (p = 0.004). NCCM with HCM (4%) was associated with MYBPC3 and HCM without NCCM in relatives (p < 0.001). The phenotype of relatives may be predicted according to the NCCM phenotype and the mutation of index patients. NCCM phenotypes were related to outcome. In this way, clinical and genetic features of index patients may help prediction of outcome in relatives. Show less

Familial hypertrophic cardiomyopathy (HCM) is usually caused by autosomal dominant pathogenic mutations in genes encoding sarcomeric or sarcomere-associated cardiac muscle proteins. The disease mainly affects adults, although young children with severe HCM have also been reported. We describe four unrelated neonates with lethal cardiomyopathy, and performed molecular studies to identify the genetic defect. We also present a literature overview of reported patients with compound heterozygous or homozygous pathogenic MYBPC3 mutations and describe their clinical characteristics. All four children presented with feeding difficulties, failure to thrive, and dyspnea. They died from cardiac failure before age 13 weeks. Features of left ventricular noncompaction were diagnosed in three patients. In the fourth, hypertrabeculation was not a clear feature, but could not be excluded. All of them had septal defects. Two patients were compound heterozygotes for the pathogenic c.2373dup p.(Trp792fs) and c.2827C>T p.(Arg943*) mutations, and two were homozygous for the c.2373dup and c.2827C>T mutations. All patients with biallelic truncating pathogenic mutations in MYBPC3 reported so far (n=21) were diagnosed with severe cardiomyopathy and/or died within the first few months of life. In 62% (13/21), septal defects or a patent ductus arteriosus accompanied cardiomyopathy. In contrast to heterozygous pathogenic mutations, homozygous or compound heterozygous truncating pathogenic MYBPC3 mutations cause severe neonatal cardiomyopathy with features of left ventricular noncompaction and septal defects in approximately 60% of patients. Show less