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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Integrative Bioinformatics Links HNF1B with Clear Cell Carcinoma and Tumor-Associated Thrombosis
PLoS ONE, Volume 8, No. 9, Article e74562, Year 2013
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Description
Clear cell carcinoma (CCC) is a histologically distinct carcinoma subtype that arises in several organ systems and is marked by cytoplasmic clearing, attributed to abundant intracellular glycogen. Previously, transcription factor hepatocyte nuclear factor 1-beta (HNF1B) was identified as a biomarker of ovarian CCC. Here, we set out to explore more broadly the relation between HNF1B and carcinomas with clear cell histology. HNF1B expression, evaluated by immunohistochemistry, was significantly associated with clear cell histology across diverse gynecologic and renal carcinomas (P<0.001), as was hypomethylation of the HNF1B promoter (P<0.001). From microarray analysis, an empirically-derived HNF1B signature was significantly enriched for computationally-predicted targets (with HNF1 binding sites) (P<0.03), as well as genes associated with glycogen metabolism, including glucose-6-phophatase, and strikingly the blood clotting cascade, including fibrinogen, prothrombin and factor XIII. Enrichment of the clotting cascade was also evident in microarray data from ovarian CCC versus other histotypes (P<0.01), and HNF1B-associated prothrombin expression was verified by immunohistochemistry (P = 0.015). Finally, among gynecologic carcinomas with cytoplasmic clearing, HNF1B immunostaining was linked to a 3.0-fold increased risk of clinically-significant venous thrombosis (P = 0.043), and with a 2.3-fold increased risk (P = 0.011) in a combined gynecologic and renal carcinoma cohort. Our results define HNF1B as a broad marker of clear cell phenotype, and support a mechanistic link to glycogen accumulation and thrombosis, possibly reflecting (for gynecologic CCC) derivation from secretory endometrium. Our findings also implicate a novel mechanism of tumor-associated thrombosis (a major cause of cancer mortality), based on the direct production of clotting factors by cancer cells. © 2013 Cuff et al.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3767734/bin/pone.0074562.s001.doc
https://efashare.b-cdn.net/share/pmc/articles/PMC3767734/bin/pone.0074562.s002.doc
https://efashare.b-cdn.net/share/pmc/articles/PMC3767734/bin/pone.0074562.s003.doc
Authors & Co-Authors
Cuff, Justin
United States, Stanford
Stanford University School of Medicine
Salari, Keyan
United States, Stanford
Stanford University School of Medicine
United States, Palo Alto
Stanford University
Clarke, Nicole
United States, Stanford
Stanford University School of Medicine
Esheba, Ghada E.
United States, Stanford
Stanford University School of Medicine
Egypt, Tanta
Faculty of Medicine
Forster, Andrew D.
United States, Stanford
Stanford University School of Medicine
Huang, Stephanie
United States, Stanford
Stanford University School of Medicine
West, Robert B.
United States, Stanford
Stanford University School of Medicine
Higgins, John P.
United States, Stanford
Stanford University School of Medicine
Longacre, Teri A.
United States, Stanford
Stanford University School of Medicine
Pollack, Jonathan R.
United States, Stanford
Stanford University School of Medicine
Statistics
Citations: 10
Authors: 10
Affiliations: 3
Identifiers
Doi:
10.1371/journal.pone.0074562
e-ISSN:
19326203
Research Areas
Cancer
Study Design
Cohort Study