Integrated Genomic Analysis of Sezary Syndrome
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ABSTRACT:
PROVIDER: PRJNA272829 | ENA |
REPOSITORIES: ENA
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Project description:Sezary syndrome is an aggressive cutaneous T cell lymphoma with pruritic skin inflammation and immune dysfunction, driven by neoplastic, clonal memory T cells in both peripheral blood and skin. To gain insight into how abnormal gene expression in Sezary syndrome promotes T cell dysfunction, lymphoproliferation and transformation, we first compared functional transcriptomic profiles of both resting and activated memory T cells from Sezary syndrome patients and normal donors. To differentiate gene expression associated with malignancy vs. benign inflammation and proliferation, we performed a within-platform meta-analysis of our data for Sezary syndrome and a GEO data set (GSE12079) for lymphocytic variant hypereosinophilic syndrome (L-HES). L-HES is a benign lymphoproliferation of clonal memory T cells that produces skin symptoms very similar to Sezary syndrome. This approach revealed gene expression changes unique to either Sezary syndrome or L-HES, and a subset of genes dysregulated in both SS and L-HES. L-HES patient 1 progressed to peripheral T cell lymphoma, and acquired Sezary-like gene expression during progression, suggesting that these genes contribute to neoplastic transformation.
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Project description:Comparative transcriptome profiles of patient-derived Sezary cells and cultured Sezary cell line (Hut78) mycosis fungoides cell line (Hut 102) and non-Sezary T cell leukemia cell line (Jurkat) relative to benign CD4+ T cells from individuals with no T cell malignancy. There are three goals. The first and primary goal is to establish a list of genes with differential expression between Sezary cells and the benign CD4+ T cell counter part from individuals without Sezary syndrome. A secondary goal is to examine if these differentially expresses genes in clinical samples of Sezary cells are preserved in Hut78 and Hut102 cells, which are the two most frequently used experimental cell models of Sezary cells in the research community. The third goal is to examine if these Sezary cell specific genes are also present in a non-Sezary T cell malignancy, such as Jurkat cells, which is derived from a non-Sezary cell T cell leukemia patient. Two color experiment, 6 biological replicates (6 unique patients) with Sezary syndrome, 1 Hut78 cell,1 Hut102 cell and 1 Jurkat cell lines as the experimental samples, each compared with a distinct individual with no T cell malignancy of the skin or the blood.
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Project description:Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation Although 75% of endometrial cancers are treated at an early stage, 15% to 20% of these recur. We performed an integrated analysis of genome-wide expression and copy-number data for primary endometrial carcinomas with extensive clinical and histopathological data to detect features predictive of recurrent disease. Unsupervised analysis of the expression data distinguished 2 major clusters with strikingly different phenotypes, including significant differences in disease-free survival. To identify possible mechanisms for these differences, we performed a global genomic survey of amplifications, deletions, and loss of heterozygosity, which identified 11 significantly amplified and 13 significantly deleted regions. Amplifications of 3q26.32 harboring the oncogene PIK3CA were associated with poor prognosis and segregated with the aggressive transcriptional cluster. Moreover, samples with PIK3CA amplification carried signatures associated with in vitro activation of PI3 kinase (PI3K), a signature that was shared by aggressive tumors without PIK3CA amplification. Tumors with loss of PTEN expression or PIK3CA overexpression that did not have PIK3CA amplification also shared the PI3K activation signature, high protein expression of the PI3K pathway member STMN1, and an aggressive phenotype in test and validation datasets. However, mutations of PTEN or PIK3CA were not associated with the same expression profile or aggressive phenotype. STMN1 expression had independent prognostic value. The results affirm the utility of systematic characterization of the cancer genome in clinically annotated specimens and suggest the particular importance of the PI3K pathway in patients who have aggressive endometrial cancer.
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