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Introduction: Approximately 10% of breast cancer (BC) cases result from hereditary causes. Genetic testing has been widely implemented in BC care to determine hereditary cancer syndromes and personalized medicine. Thus, identification of individuals carrying germline pathogenic variants could be useful to provide appropriate prophylactic or screening measures for each BC subtype, however, there are few formal recommendations for genetic testing in this sense so far. In this study, we assessed rare germline variants in a specific group of genes in order to determine the association with human epidermal growth factor 2 enriched (HER2+) BC phenotype through a systematic review and meta-analysis comparing subtypes overexpressing HER2 with other clinically recognized subtypes of BC. This review was registered with PROSPERO (ID: CRD42023447571)., Methods: We conducted an online literature search in PubMed (MEDLINE), Scopus, and EMBASE databases. We included original studies that investigated germline variants in HER2+ BC patients and selected the studies that reported only rare and/or pathogenic germline variants. We assessed the risk of bias and quality of the studies using the Joanna Briggs Institute Critical Appraisal checklists and the Modified Newcastle-Ottawa Scale for Genetic Studies, respectively. Considering hormone receptor and HER2 expression status, we compared gene-based risks initially in HR-HER2-, HR+HER2-, HR+HER2+, and HR-HER2+ groups, conducting separate meta-analyses using the random effects model for each comparison, and within them for each gene., Results: Of the total 36 studies describing germline variants, 11 studies provided information on the prevalence of variants in the different clinically relevant BC subtypes and allowed comparisons. Germline variants within eight genes showed significant differences when meta-analyzed between the BC groups: BRCA1 , BRCA2 , TP53 , ATM , CHEK2 , PALB2 , RAD51C , and BARD1 . Notably, TP53 , ATM , and CHEK2 germline variants were identified as predisposing factors for HER2+ subtypes, whereas BRCA1 , BRCA2 , PALB2 , RAD51C , and BARD1 germline variants were associated with a predisposition to low HER2 expression. Main concerns about bias and quality assessment were the lack of confounding factors control; and comparability or outcome assessment, respectively., Discussion: Our findings underscore the connection between germline variants and differential expression of the HER2 protein and BC subtypes., Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023447571., Competing Interests: CB receives speaker honorarium from Novartis, Bayer and Astrazeneca and research honorarium from Novartis. GaD receives speaker honorarium from Merck, Pfizer, GSK, Roche, Novartis, Bayer and Astrazeneca. DD provided consultancy services to Roche, Novartis, AstraZeneca, Lilly, Libbs, Pfizer, Dr. Reddy’s, Teva, United Medical, Daiichi Sankyo, Gilead. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2024 de Baumont, Cadore, Pedrotti, Curzel, Schuch, Bessel, Bordignon, Rosa, Macedo and Rosa.)

Severe COVID-19 is a systemic disorder involving excessive inflammatory response, metabolic dysfunction, multi-organ damage, and several clinical features. Here, we performed a transcriptome meta-analysis investigating genes and molecular mechanisms related to COVID-19 severity and outcomes. First, transcriptomic data of cellular models of SARS-CoV-2 infection were compiled to understand the first response to the infection. Then, transcriptomic data from lung autopsies of patients deceased due to COVID-19 were compiled to analyze altered genes of damaged lung tissue. These analyses were followed by functional enrichment analyses and gene-phenotype association. A biological network was constructed using the disturbed genes in the lung autopsy meta-analysis. Central genes were defined considering closeness and betweenness centrality degrees. A sub-network phenotype-gene interaction analysis was performed. The meta-analysis of cellular models found genes mainly associated with cytokine signaling and other pathogen response pathways. The meta-analysis of lung autopsy tissue found genes associated with coagulopathy, lung fibrosis, multi-organ damage, and long COVID-19. Only genes DNAH9 and FAM216B were found perturbed in both meta-analyses. BLNK, FABP4, GRIA1, ATF3, TREM2, TPPP, TPPP3, FOS, ALB, JUNB, LMNA, ADRB2, PPARG, TNNC1, and EGR1 were identified as central elements among perturbed genes in lung autopsy and were found associated with several clinical features of severe COVID-19. Central elements were suggested as interesting targets to investigate the relation with features of COVID-19 severity, such as coagulopathy, lung fibrosis, and organ damage., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

COVID-19 pandemic represented a worldwide major challenge in different areas, and efforts undertaken by the scientific community led to the understanding of some of the genetic determinants that influence the different COVID-19 outcomes. In this paper, we review the studies about the role of human genetics in COVID-19 severity and how Brazilian studies also contributed to those findings. Rare variants in genes related to Inborn Errors of Immunity (IEI) in the type I interferons pathway, and its phenocopies, have been described as being causative of severe outcomes. IEI and its phenocopies are present in Brazil, not only in COVID-19 patients, but also in autoimmune conditions and severe reactions to yellow fever vaccine. In addition, studies focusing on common variants and GWAS studies encompassing worldwide patients have found several loci associated with COVID-19 severity. A GWAS study including only Brazilian COVID-19 patients identified a new locus 1q32.1 associated with COVID-19 severity. Thus, more comprehensive studies considering the Brazilian genomic diversity should be performed, since they can help to reveal not only what are the genetic determinants that contribute to the different outcomes for COVID-19 in the Brazilian population, but in the understanding of human genetics in different health conditions.

Li-Fraumeni and Li-Fraumeni-like syndromes (LFS/LFL) are hereditary cancer predisposition disorders associated with germline mutations in the TP53 tumor suppressor gene. Here, we stably expressed LFS/LFL-associated p53 mutants R337H and G245S in p53-null H1299 cells to study their cellular and molecular effects. Mutant proteins showed distinct oligomerization states and opposing effects on cell proliferation and viability. Stable expression of p53 G245S enhanced cell proliferation and spheroid formation, while cells stably expressing p53 R337H showed reduced proliferation and clonogenicity, along with increased cell death. Mass spectrometry analysis revealed that proteins whose expression was induced by p53 R337H or p53 G245S expression were related to distinct metabolic profiles. Proteins upregulated by p53 G245S expression were associated with a Warburg phenotype, while proteins upregulated by p53 R337H expression were related to oxidative phosphorylation and fatty acid oxidation. Differences in mitochondrial mass and activity between cells stably expressing p53 R337H or p53 G245S were further corroborated by High Resolution Respirometry, flow cytometry and qPCR assays. The implications of the different oncogenic properties of p53 R337H and p53 G245S on the clinical manifestation and treatment of LFS/LFL patients carrying these mutations are discussed., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Background: Drug resistance is the main cause of therapy failure in advanced lung cancer. Although non-genetic mechanisms play important roles in tumor chemoresistance, drug-induced epigenetic reprogramming is still poorly understood., Materials and Methods: The A549 cell line was used to generate cells with non-genetic resistance to cisplatin (CDDP), namely A549/CDDP cells. Bioorthogonal non-canonical amino acid tagging (BONCAT) and mass spectrometry were used to identify proteins modulated by CDDP in A549 and A549/CDDP cells., Results: Proteins related to proteostasis, telomere maintenance, cell adhesion, cytoskeletal remodeling, and cell redox homeostasis were found enriched in both cell lines upon CDDP exposure. On the other hand, proteins involved in drug response, metabolic pathways and mRNA processing and splicing were up-regulated by CDDP only in A549/CDDP cells., Conclusion: Our study revealed proteome dynamics involved in the non-genetic response to CDDP, pointing out potential targets to monitor and overcome epigenetic resistance in lung cancer., Competing Interests: The Authors declare that no conflicts of interest exist with regard to the present study., (Copyright 2021, International Institute of Anticancer Research.)