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About 4% to 7% of the non-small-cell lung cancer patients have anaplastic lymphoma kinase (ALK) rearrangements, and specific targeted therapies improve patients' outcomes significantly. ALK gene fusions are detected by immunohistochemistry or fluorescent in situ hybridization as gold standards in South America. Next-generation sequencing-based assays are a reliable alternative, able to perform simultaneous detection of multiple events from a single sample. We analyzed 4240 non-small-cell lung cancer samples collected in 37 hospitals from Chile, Brazil, and Peru, where ALK rearrangements were determined as part of their standard of care (SofC) using either immunohistochemistry or fluorescent in situ hybridization. A subset of 1450 samples was sequenced with the Oncomine Focus Assay (OFA), and the concordance with the SofC tests was measured. An orthogonal analysis was performed using a real-time quantitative PCR echinoderm microtubule-associated protein-like 4-ALK fusion detection kit. ALK fusion prevalence is similar for Chile (3.67%; N = 2142), Brazil (4.05%; N = 1013), and Peru (4.59%; N = 675). Although a comparison between OFA and SofC assays showed similar sensitivity, OFA had significantly higher specificity and higher positive predictive value, which opens new opportunities for a more specific determination of ALK gene rearrangements., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Aims: Breast cancer is one of the leading causes of woman deaths worldwide, being a major public health problem. It has been reported that the expression of the RNA-editing enzyme Adenosine Deaminase Acting on RNAs 1 (ADAR1) is upregulated in breast cancer, predicting poor prognosis in patients. A few reports in literature examine ADAR1 and long non-coding RNAs (lncRNAs) interplay in cancer and suggest key roles in cancer-related pathways. This study aimed to investigate whether ADAR1 could alter the expression levels of lncRNAs and explore how those changes are related to breast cancer biology., Main Methods: ADAR1 overexpression and knockdown studies were performed in breast cancer cell lines to analyze the effects over lncRNAs expression. Guilt-by-Association correlation analysis of the TCGA-BRCA cohort was performed to predict the function of the lncRNA LINC00944., Key Findings: Here, we show that LINC00944 is responsive to ADAR1 up- and downregulation in breast cancer cells. We found that LINC00944 expression has a strong relationship with immune signaling pathways. Further assessment of the TCGA-BRCA cohort showed that LINC00944 expression was positively correlated to tumor-infiltrating T lymphocytes and pro-apoptotic markers. Moreover, we found that LINC00944 expression was correlated to the age at diagnosis, tumor size, and estrogen and progesterone receptor expression. Finally, we show that low expression of LINC00944 is correlated to poor prognosis in breast cancer patients., Significance: Our study provides further evidence of the effect of ADAR1 over lncRNA expression levels, and on the participation of LINC00944 in breast cancer, suggesting to further investigate its potential role as prognostic biomarker., (Copyright © 2021 Elsevier Inc. All rights reserved.)

RNA editing has emerged as a novel mechanism in cancer progression. The double stranded RNA-specific adenosine deaminase (ADAR) modifies the expression of an important proportion of genes involved in cell cycle control, DNA damage response (DDR) and transcriptional processing, suggesting an important role of ADAR in transcriptome regulation. Despite the phenotypic implications of ADAR deregulation in several cancer models, the role of ADAR on DDR and proliferation in breast cancer has not been fully addressed. Here, we show that ADAR expression correlates significantly with clinical outcomes and DDR, cell cycle and proliferation mRNAs of previously reported edited transcripts in breast cancer patients. ADAR's knock-down in a breast cancer cell line produces stability changes of mRNAs involved in DDR and DNA replication. Breast cancer cells with reduced levels of ADAR show a decreased viability and an increase in apoptosis, displaying a significant decrease of their DDR activation, compared to control cells. These results suggest that ADAR plays an important role in breast cancer progression through the regulation of mRNA stability and expression of those genes involved in proliferation and DDR impacting the viability of breast cancer cells., Competing Interests: Declaration of competing interest RA, RAs, PP, EAS, AB, AIS and PR were Pfizer Chile employees., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Several mechanisms directing a rapid transcriptional reactivation of genes immediately after mitosis have been described. However, little is known about the maintenance of repressive signals during mitosis. In this work, we address the role of Ski in the repression of gene expression during M/G 1 transition in mouse embryonic fibroblasts (MEFs). We found that Ski localises as a distinct pair of dots at the pericentromeric region of mitotic chromosomes, and the absence of the protein is related to high acetylation and low tri-methylation of H3K9 in pericentromeric major satellite. Moreover, differential expression assays in early G 1 cells showed that the presence of Ski is significantly associated with repression of genes localised nearby to pericentromeric DNA. In mitotic cells, chromatin immunoprecipitation assays confirmed the association of Ski to major satellite and the promoters of the most repressed genes: Mmp3, Mmp10 and Mmp13. These genes are at pericentromeric region of chromosome 9. In these promoters, the presence of Ski resulted in increased H3K9 tri-methylation levels. This Ski-dependent regulation is also observed during interphase. Consequently, Mmp activity is augmented in Ski-/- MEFs. Altogether, these data indicate that association of Ski with the pericentromeric region of chromosomes during mitosis is required to maintain the silencing bookmarks of underlying chromatin., (Copyright © 2020 Elsevier Ltd. All rights reserved.)