title: Integrative bioinformatics links HNF1B with clear cell carcinoma and tumor-associated thrombosis.
abstract: 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.
authors.affiliation: Department of Pathology, Stanford University, Stanford, California, United States of America.
authors.forename: Justin
authors.initials: J
authors.lastname: Cuff
authors.forename: Keyan
authors.initials: K
authors.lastname: Salari
authors.forename: Nicole
authors.initials: N
authors.lastname: Clarke
authors.forename: Ghada E
authors.initials: GE
authors.lastname: Esheba
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Forster
authors.forename: Stephanie
authors.initials: S
authors.lastname: Huang
authors.forename: Robert B
authors.initials: RB
authors.lastname: West
authors.forename: John P
authors.initials: JP
authors.lastname: Higgins
authors.forename: Teri A
authors.initials: TA
authors.lastname: Longacre
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Pollack
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001777:Blood Coagulation; D001779:Blood Coagulation Factors / Q000235:genetics / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019295:Computational Biology; D019175:DNA Methylation; D016889:Endometrial Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012306:Risk; D020246:Venous Thrombosis / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D001779:Blood Coagulation Factors; C496495:HNF1B protein, human; D051539:Hepatocyte Nuclear Factor 1-beta; D006003:Glycogen; D005952:Glucose-6-Phosphatase
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1490-5
references.pmid: 15668393
references.citation: Acta Haematol. 2001;106(1-2):25-32
references.pmid: 11549774
references.citation: Thromb Haemost. 1994 Jun;71(6):719-22
references.pmid: 7974338
references.citation: N Engl J Med. 2008 Mar 13;358(11):1148-59
references.pmid: 18337604
references.citation: Virchows Arch. 2008 Feb;452(2):175-80
references.pmid: 18066692
references.citation: Cancer. 2007 Nov 15;110(10):2339-46
references.pmid: 17918266
references.citation: Gynecol Oncol. 1989 Jan;32(1):65-71
references.pmid: 2642454
references.citation: Nucleic Acids Res. 2003 Jan 1;31(1):374-8
references.pmid: 12520026
references.citation: Hum Mol Genet. 2006 Aug 1;15(15):2363-75
references.pmid: 16801329
references.citation: Gynecol Oncol. 1998 Aug;70(2):255-8
references.pmid: 9740700
references.citation: Mech Dev. 1999 Dec;89(1-2):211-3
references.pmid: 10559500
references.citation: Hum Reprod Update. 2000 Sep-Oct;6(5):495-504
references.pmid: 11045880
references.citation: Oncologist. 2006 Nov-Dec;11(10):1089-94
references.pmid: 17110628
references.citation: Thromb Haemost. 1999 May;81(5):680-3
references.pmid: 10365736
references.citation: N Engl J Med. 2010 Oct 14;363(16):1532-43
references.pmid: 20942669
references.citation: Mod Pathol. 2006 Jan;19(1):83-9
references.pmid: 16258507
references.citation: Exp Cell Res. 1999 Apr 10;248(1):1-9
references.pmid: 10094807
references.citation: Hematology Am Soc Hematol Educ Program. 2010;2010:144-9
references.pmid: 21239784
references.citation: Thromb Haemost. 1995 Jul;74(1):278-81
references.pmid: 8578472
references.citation: Arterioscler Thromb Vasc Biol. 2012 Mar;32(3):563-8
references.pmid: 22345594
references.citation: Nat Genet. 2008 Oct;40(10):1153-5
references.pmid: 18758462
references.citation: Lancet Oncol. 2005 Jun;6(6):401-10
references.pmid: 15925818
references.citation: Bioessays. 1992 Sep;14(9):579-87
references.pmid: 1365913
references.citation: J Clin Endocrinol Metab. 1980 Oct;51(4):765-70
references.pmid: 6252225
references.citation: Placenta. 2004 Apr;25 Suppl A:S26-31
references.pmid: 15033303
references.citation: J Exp Clin Cancer Res. 2009 Mar 02;28:30
references.pmid: 19254383
references.citation: Blood. 2007 Sep 15;110(6):1723-9
references.pmid: 17496204
references.citation: Oncology. 2000 Jun;59(1):50-6
references.pmid: 10895067
references.citation: N Engl J Med. 1998 Apr 23;338(17):1169-73
references.pmid: 9554856
references.citation: Medicine (Baltimore). 1999 Sep;78(5):285-91
references.pmid: 10499070
references.citation: Nat Genet. 2007 Aug;39(8):977-83
references.pmid: 17603485
references.citation: Hum Mutat. 2008 Jul;29(7):921-30
references.pmid: 18449899
references.citation: Oncogene. 2008 Jun 5;27(25):3635-40
references.pmid: 18212743
references.citation: Arch Intern Med. 2006 Feb 27;166(4):458-64
references.pmid: 16505267
references.citation: Am J Surg Pathol. 2009 Jan;33(1):14-21
references.pmid: 18830127
references.citation: Cancer. 1996 Nov 15;78(10):2157-63
references.pmid: 8918409
references.citation: Development. 1992 Nov;116(3):783-97
references.pmid: 1363228
references.citation: Am J Pathol. 2003 Dec;163(6):2503-12
references.pmid: 14633622
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references.pmid: 16199517
references.citation: Clin Obstet Gynecol. 2006 Dec;49(4):836-43
references.pmid: 17082678
references.citation: Circulation. 2003 Jun 17;107(23 Suppl 1):I9-16
references.pmid: 12814980
references.citation: AMIA Annu Symp Proc. 2009 Nov 14;2009:391-5
references.pmid: 20351886
references.citation: Nat Genet. 1997 Dec;17(4):384-5
references.pmid: 9398836
references.citation: J Med Genet. 2006 Jan;43(1):84-90
references.pmid: 15930087
references.citation: Nat Rev Cancer. 2006 Aug;6(8):593-602
references.pmid: 16862190
references.citation: Hum Pathol. 2007 Jul;38(7):1074-1080
references.pmid: 17442376
references.citation: Ann Intern Med. 2004 Apr 6;140(7):510-7
references.pmid: 15068978
references.citation: Cancer. 1971 Oct;28(4):1074-81
references.pmid: 5111739
references.citation: Biochim Biophys Acta. 2005 Dec 20;1731(3):179-90
references.pmid: 16297991
references.citation: PLoS One. 2011;6(7):e21121
references.pmid: 21754983
references.citation: Nature. 2005 Jul 7;436(7047):117-22
references.pmid: 16001072
references.citation: Cancer Res. 2002 Aug 15;62(16):4722-9
references.pmid: 12183431
references.citation: Cancer Res. 1998 Apr 15;58(8):1707-12
references.pmid: 9563487
references.citation: Lancet. 2000 May 6;355(9215):1627-32
references.pmid: 10821379
references.citation: Br J Cancer. 2006 Mar 27;94(6):914-21
references.pmid: 16479257
references.citation: Biochem Biophys Res Commun. 2001 Feb 2;280(4):1036-41
references.pmid: 11162631
references.citation: Gynecol Oncol. 1996 Mar;60(3):412-7
references.pmid: 8774649
references.citation: Haemostasis. 1997;27 Suppl 1:38-43
references.pmid: 9439757
references.citation: Hum Mol Genet. 2005 Mar 1;14(5):603-14
references.pmid: 15649945
references.citation: Blood. 1996 Nov 15;88(10):3698-703
references.pmid: 8916933
references.citation: Cancer Res. 2006 Feb 1;66(3):1354-62
references.pmid: 16452189