Malignant mesothelioma is an aggressive and lethal asbestos-related disease. Diagnosis of malignant mesothelioma is particularly challenging and is further complicated by the lack of disease subtype-specific markers. As a result, it is especially difficult to distinguish malignant mesothelioma from benign reactive mesothelial proliferations or reactive fibrosis. Additionally, mesothelioma diagnoses can be confounded by other anatomically related tumors that can invade the pleural or peritoneal cavities, collectively resulting in delayed diagnoses and greatly affecting patient management. High-throughput analyses have uncovered key genomic and epigenomic alterations driving malignant mesothelioma. These molecular features have the potential to better our understanding of malignant mesothelioma biology as well as to improve disease diagnosis and patient prognosis. Genomic approaches have been instrumental in identifying molecular events frequently occurring in mesothelioma. As such, we review the discoveries made using high-throughput technologies, including novel insights obtained from the analysis of the non-coding transcriptome, and the clinical potential of these genetic and epigenetic findings in mesothelioma. Furthermore, we aim to highlight the potential of these technologies in the future clinical applications of the novel molecular features in malignant mesothelioma.

Lung cancer is one of the most frequent tumors that metastasize to the brain. Brain metastasis (BM) is common in advanced cases, being the major cause of patient morbidity and mortality. BMs are thought to arise via the seeding of circulating tumor cells into the brain microvasculature. In brain tissue, the interaction with immune cells promotes a microenvironment favorable to the growth of cancer cells. Despite multimodal treatments and advances in systemic therapies, lung cancer patients still have poor prognoses. Therefore, there is an urgent need to identify the molecular drivers of BM and clinically applicable biomarkers in order to improve disease outcomes and patient survival. The goal of this review is to summarize the current state of knowledge on the mechanisms of the metastatic spread of lung cancer to the brain and how the metastatic spread is influenced by the brain microenvironment, and to elucidate the molecular determinants of brain metastasis regarding the role of genomic and transcriptomic changes, including coding and non-coding RNAs. We also present an overview of the current therapeutics and novel treatment strategies for patients diagnosed with BM from NSCLC.

Patients with ataxia-telangiectasia (A-T) lack a functional ATM kinase protein and exhibit defective repair of DNA double-stranded breaks and response to oxidative stress. We show that CRISPR/Cas9-assisted gene correction combined with piggyBac (PB) transposon-mediated excision of the selection cassette enables seamless restoration of functional ATM alleles in induced pluripotent stem cells from an A-T patient carrying compound heterozygous exonic missense/frameshift mutations, and from a patient with a homozygous splicing acceptor mutation of an internal coding exon. We show that the correction of one allele restores expression of ~ 50% of full-length ATM protein and ameliorates DNA damage-induced activation (auto-phosphorylation) of ATM and phosphorylation of its downstream targets, KAP-1 and H2AX. Restoration of ATM function also normalizes radiosensitivity, mitochondrial ROS production and oxidative-stress-induced apoptosis levels in A-T iPSC lines, demonstrating that restoration of a single ATM allele is sufficient to rescue key ATM functions. Our data further show that despite the absence of a functional ATM kinase, homology-directed repair and seamless correction of a pathogenic ATM mutation is possible. The isogenic pairs of A-T and gene-corrected iPSCs described here constitute valuable tools for elucidating the role of ATM in ageing and A-T pathogenesis.

Transcriptome sequencing has led to the widespread identification of long non-coding RNAs (lncRNAs). Subsequently, these genes have been shown to hold functional importance in human cellular biology, which can be exploited by tumors to drive the hallmarks of cancer. Due to the complex tertiary structure and unknown binding motifs of lncRNAs, there is a growing disparity between the number of lncRNAs identified and those that have been functionally characterized. As such, lncRNAs deregulated in cancer may represent critical components of cancer pathways that could serve as novel therapeutic intervention points. Pseudogenes are non-coding DNA sequences that are defunct relatives of their protein-coding parent genes but retain high sequence similarity. Interestingly, certain lncRNAs expressed from pseudogene loci have been shown to regulate the protein-coding parent genes of these pseudogenes in trans particularly because of this sequence complementarity. We hypothesize that this phenomenon occurs more broadly than previously realized, and that aberrant expression of lncRNAs overlapping pseudogene loci provides an alternative mechanism of cancer gene deregulation. Using RNA-sequencing data from two cohorts of lung adenocarcinoma, each paired with patient-matched non-malignant lung samples, we discovered 104 deregulated pseudogene-derived lncRNAs. Remarkably, many of these deregulated lncRNAs (i) were expressed from the loci of pseudogenes related to known cancer genes, (ii) had expression that significantly correlated with protein-coding parent gene expression, and (iii) had lncRNA protein-coding parent gene expression that was significantly associated with survival. Here, we uncover evidence to suggest the lncRNA-pseudogene-protein-coding gene axis as a prominent mechanism of cancer gene regulation in lung adenocarcinoma, and highlights the clinical utility of exploring the non-coding regions of the cancer transcriptome.

Recent studies have uncovered microRNAs (miRNAs) that have been overlooked in early genomic explorations, which show remarkable tissue- and context-specific expression. Here, we aim to identify and characterize previously unannotated miRNAs expressed in gastric adenocarcinoma (GA). Raw small RNA-sequencing data were analyzed using the miRMaster platform to predict and quantify previously unannotated miRNAs. A discovery cohort of 475 gastric samples (434 GA and 41 adjacent nonmalignant samples), collected by The Cancer Genome Atlas (TCGA), were evaluated. Candidate miRNAs were similarly assessed in an independent cohort of 25 gastric samples. We discovered 170 previously unannotated miRNA candidates expressed in gastric tissues. The expression of these novel miRNAs was highly specific to the gastric samples, 143 of which were significantly deregulated between tumor and nonmalignant contexts (p-adjusted < 0.05; fold change > 1.5). Multivariate survival analyses showed that the combined expression of one previously annotated miRNA and two novel miRNA candidates was significantly predictive of patient outcome. Further, the expression of these three miRNAs was able to stratify patients into three distinct prognostic groups (p = 0.00003). These novel miRNAs were also present in the independent cohort (43 sequences detected in both cohorts). Our findings uncover novel miRNA transcripts in gastric tissues that may have implications in the biology and management of gastric adenocarcinoma.