المؤلفون: Amato, Carol M., Hintzsche, Jennifer D., Wells, Keith, Applegate, Allison, Gorden, Nicholas T., Vorwald, Victoria M., Tobin, Richard P., Nassar, Kelsey, Shellman, Yiqun G., Kim, Jihye, Medina, Theresa M., Rioth, Matthew, Lewis, Karl D., McCarter, Martin D., Gonzalez, Rene, Tan, Aik-Choon, Robinson, William A.

المصدر: Cancers; Jul2020, Vol. 12 Issue 7, p1943, 1p

مصطلحات موضوعية: MELANOMA prognosis, ANTIGENS, ANTINEOPLASTIC agents, CANCER patients, CELL lines, CELLULAR signal transduction, FLOW cytometry, IMMUNOTHERAPY, MELANOMA, METASTASIS, GENETIC mutation, TUMOR markers, DNA-binding proteins, TREATMENT effectiveness, GENE expression profiling, SEQUENCE analysis, IN vitro studies, PROGRAMMED cell death 1 receptors, PHARMACODYNAMICS

مستخلص: Immunotherapy, such as anti-PD1, has improved the survival of patients with metastatic melanoma. However, predicting which patients will respond to immunotherapy remains a significant knowledge gap. In this study we analyzed pre-immunotherapy treated tumors from 52 patients with metastatic melanoma and monitored their response based on RECIST 1.1 criteria. The responders group contained 21 patients that had a complete or partial response, while the 31 non-responders had stable or progressive disease. Whole exome sequencing (WES) was used to identify biomarkers of anti-PD1 response from somatic mutations between the two groups. Variants in codons G34 and G41 in NFKBIE, a negative regulator of NFkB, were found exclusively in the responders. Mutations in NKBIE-related genes were also enriched in the responder group compared to the non-responders. Patients that harbored NFKBIE-related gene mutations also had a higher mutational burden, decreased tumor volume with treatment, and increased progression-free survival. RNA sequencing on a subset of tumor samples identified that CD83 was highly expressed in our responder group. Additionally, Gene Set Enrichment Analysis showed that the TNFalpha signaling via NFkB pathway was one of the top pathways with differential expression in responders vs. non-responders. In vitro NFkB activity assays indicated that the G34E variant caused loss-of-function of NFKBIE, and resulted in activation of NFkB signaling. Flow cytometry assays indicated that G34E variant was associated with upregulation of CD83 in human melanoma cell lines. These results suggest that NFkB activation and signaling in tumor cells contributes to a favorable anti-PD1 treatment response, and clinical screening to include aberrations in NFkB-related genes should be considered. [ABSTRACT FROM AUTHOR]

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المؤلفون: Dimitrova, Irina K.¹, Richer, Jennifer K.², Rudolph, Michael C.¹, Spoelstra, Nicole S.², Reno, Elaine M.¹, Medina, Theresa M.², Bradford, Andrew P.¹ Andy.Bradford@UCHSC.edu

المصدر: Fertility & Sterility. Jun2009, Vol. 91 Issue 6, p2650-2663. 14p.

مصطلحات موضوعية: *GENE expression, *SMOOTH muscle tumors, *UTERINE fibroids, *REVERSE transcriptase polymerase chain reaction, *MYOMETRIUM, *METALLOPROTEINASES, *GENETICS, *DNA, *DNA probes, *NUCLEOTIDES, *POLYMERASE chain reaction, *PROTEOLYTIC enzymes, *RESEARCH funding, *RNA, *TRANSFERASES, *UTERINE tumors, *GENE expression profiling

مصطلحات جغرافية: DENVER (Colo.), COLORADO

الشركة/الكيان: UNIVERSITY of Colorado Hospital

مستخلص: Objective: To identify differentially expressed genes between fibroid and adjacent normal myometrium in an identical hormonal and genetic background.Design: Array analysis of three leiomyomata and matched adjacent normal myometrium in a single patient.Setting: University of Colorado Hospital.Patient(s): A single female undergoing medically indicated hysterectomy for symptomatic fibroids.Interventions(s): mRNA isolation and microarray analysis, reverse-transcriptase polymerase chain reaction, Western blotting, and immunohistochemistry.Main Outcome Measure(s): Changes in mRNA and protein levels in leiomyomata and matched normal myometrium.Result(s): Expression of 197 genes was increased and 619 decreased significantly by at least twofold, in leiomyomata relative to normal myometrium. Expression profiles between tumors were similar and normal myometrial samples showed minimal variation. Changes in, and variation of, expression of selected genes were confirmed in additional normal and leiomyoma samples from multiple patients.Conclusion(s): Analysis of multiple tumors from a single patient confirmed changes in expression of genes described in previous, apparently disparate, studies, and identified novel targets. Gene expression profiles in leiomyomata are consistent with increased activation of mitogenic pathways and inhibition of apoptosis. Down-regulation of genes implicated in invasion and metastasis, of cancers, was observed in fibroids. This expression pattern may underlie the benign nature of uterine leiomyomata and may aid in the differential diagnosis of leiomyosarcoma. [ABSTRACT FROM AUTHOR]