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Integrative Bioinformatics Links HNF1B with Clear Cell Carcinoma and Tumor-Associated Thrombosis
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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3767734/ https://www.ncbi.nlm.nih.gov/pubmed/24040285 http://dx.doi.org/10.1371/journal.pone.0074562 |
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author | Cuff, Justin Salari, Keyan Clarke, Nicole Esheba, Ghada E. Forster, Andrew D. Huang, Stephanie West, Robert B. Higgins, John P. Longacre, Teri A. Pollack, Jonathan R. |
author_facet | Cuff, Justin Salari, Keyan Clarke, Nicole Esheba, Ghada E. Forster, Andrew D. Huang, Stephanie West, Robert B. Higgins, John P. Longacre, Teri A. Pollack, Jonathan R. |
author_sort | Cuff, Justin |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-3767734 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-37677342013-09-13 Integrative Bioinformatics Links HNF1B with Clear Cell Carcinoma and Tumor-Associated Thrombosis Cuff, Justin Salari, Keyan Clarke, Nicole Esheba, Ghada E. Forster, Andrew D. Huang, Stephanie West, Robert B. Higgins, John P. Longacre, Teri A. Pollack, Jonathan R. PLoS One Research Article 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. Public Library of Science 2013-09-09 /pmc/articles/PMC3767734/ /pubmed/24040285 http://dx.doi.org/10.1371/journal.pone.0074562 Text en © 2013 Cuff et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Cuff, Justin Salari, Keyan Clarke, Nicole Esheba, Ghada E. Forster, Andrew D. Huang, Stephanie West, Robert B. Higgins, John P. Longacre, Teri A. Pollack, Jonathan R. Integrative Bioinformatics Links HNF1B with Clear Cell Carcinoma and Tumor-Associated Thrombosis |
title | Integrative Bioinformatics Links HNF1B with Clear Cell Carcinoma and Tumor-Associated Thrombosis |
title_full | Integrative Bioinformatics Links HNF1B with Clear Cell Carcinoma and Tumor-Associated Thrombosis |
title_fullStr | Integrative Bioinformatics Links HNF1B with Clear Cell Carcinoma and Tumor-Associated Thrombosis |
title_full_unstemmed | Integrative Bioinformatics Links HNF1B with Clear Cell Carcinoma and Tumor-Associated Thrombosis |
title_short | Integrative Bioinformatics Links HNF1B with Clear Cell Carcinoma and Tumor-Associated Thrombosis |
title_sort | integrative bioinformatics links hnf1b with clear cell carcinoma and tumor-associated thrombosis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3767734/ https://www.ncbi.nlm.nih.gov/pubmed/24040285 http://dx.doi.org/10.1371/journal.pone.0074562 |
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