A powerful way to discover key genes playing causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here, we report high-resolution analyses of somatic copy-number alterations (SCNAs) from 3131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across multiple cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-κB pathway. We show that cancer cells harboring amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend upon expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in multiple cancer types.

The newly emerging coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China, but has rapidly spread all over the world. Some COVID-19 patients encounter a severe symptom of acute respiratory distress syndrome (ARDS) with high mortality. This high severity is dependent on a cytokine storm, most likely induced by the interleukin-6 (IL-6) amplifier, which is hyper-activation machinery that regulates the nuclear factor kappa B (NF-κB) pathway and stimulated by the simultaneous activation of IL-6-signal transducer and activator of transcription 3 (STAT3) and NF-κB signaling in non-immune cells including alveolar epithelial cells and endothelial cells. We hypothesize that IL-6-STAT3 signaling is a promising therapeutic target for the cytokine storm in COVID-19, because IL-6 is a major STAT3 stimulator, particularly during inflammation. We herein review the pathogenic mechanism and potential therapeutic targets of ARDS in COVID-19 patients.

BackgroundSquamous cell lung carcinomas account for approximately 25% of new lung carcinoma cases and 40,000 deaths per year in the United States. Although there are multiple genomically targeted therapies for lung adenocarcinoma, none has yet been reported in squamous cell lung carcinoma.Methodology/Principal FindingsUsing SNP array analysis, we found that a region of chromosome segment 8p11-12 containing three genes–WHSC1L1, LETM2, and FGFR1–is amplified in 3% of lung adenocarcinomas and 21% of squamous cell lung carcinomas. Furthermore, we demonstrated that a non-small cell lung carcinoma cell line harboring focal amplification of FGFR1 is dependent on FGFR1 activity for cell growth, as treatment of this cell line either with FGFR1-specific shRNAs or with FGFR small molecule enzymatic inhibitors leads to cell growth inhibition.Conclusions/SignificanceThese studies show that FGFR1 amplification is common in squamous cell lung cancer, and that FGFR1 may represent a promising therapeutic target in non-small cell lung cancer.

We assessed somatic alleles of six receptor tyrosine kinase genes mutated in lung adenocarcinoma for oncogenic activity. Five of these genes failed to score in transformation assays; however, novel recurring extracellular domain mutations of the receptor tyrosine kinase gene ERBB2 were potently oncogenic. These ERBB2 extracellular domain mutants were activated by two distinct mechanisms, characterized by elevated C-terminal tail phosphorylation or by covalent dimerization mediated by intermolecular disulfide bond formation. These distinct mechanisms of receptor activation converged upon tyrosine phosphorylation of cellular proteins, impacting cell motility. Survival of Ba/F3 cells transformed to IL-3 independence by the ERBB2 extracellular domain mutants was abrogated by treatment with small-molecule inhibitors of ERBB2, raising the possibility that patients harboring such mutations could benefit from ERBB2-directed therapy.HER2 | breast cancer | bladder cancer L ung cancer is the leading cause of cancer death, accounting for over 150,000 deaths annually in the United States alone (1). Current treatment options are thus inadequate for the majority of patients and additional therapies are needed. Mutationally activated oncogenes that promote tumorigenesis represent potential drug targets due to frequent dependency of tumor cells on such oncogenes (2, 3), and somatically altered receptor tyrosine kinases in particular have been successfully exploited as therapeutic targets in several cancers.The prototypical therapy targeted to a somatically activated tyrosine kinase oncogene is imatinib mesylate, which targets the BCR-ABL fusion protein in chronic myelogenous leukemia (4). Targeted therapies developed for lung cancer include gefitinib and erlotinib, small-molecule inhibitors of mutationally activated EGFR in lung adenocarcinoma (5-8), and crizotinib, a smallmolecule inhibitor of the EML4-ALK translocation product in lung adenocarcinoma (9). Trastuzumab, a monoclonal antibody inhibitor targeting ERBB2, and the small-molecule EGFR/ ERBB2 inhibitor lapatinib are effective in ERBB2-amplified patients with breast cancer (10, 11).The advent of next-generation sequencing technologies has enabled compilation of large somatic mutation datasets from cancer sequencing studies. Statistical methods that examine differences in gene mutation frequency can reveal evidence of positive selection; however, demonstration of the contribution of a mutated gene to tumorigenesis additionally requires functional validation. To identify new lung cancer oncogenes, we systematically assessed somatic alleles of significantly mutated receptor tyrosine kinase genes reported in patients with lung adenocarcinoma (12) for activity in cellular transformation assays.Although most receptor tyrosine kinase mutations tested failed to score, novel extracellular domain mutations of ERBB2 were oncogenic. Our results indicate a unique therapeutic opportunity for patients with lung and breast cancer who harbor extracellular domain mutations of ERBB2. Resul...

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[(18)F]FMM PET imaging detects Aβ deposition in patients along the continuum from normal cognitive status to dementia of AD and discriminates AD patients from HC subjects, similar to [(11)C]PIB PET.

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