title: HOXB13 overexpression is an independent predictor of early PSA recurrence in prostate cancer treated by radical prostatectomy.
abstract: HOXB13 is a prostate cancer susceptibility gene which shows a cancer predisposing (G84E) mutation in 0.1-0.6% of males. We analyzed the prognostic impact of HOXB13 expression by immunohistochemistry on a tissue microarray containing more than 12,400 prostate cancers. Results were compared to tumor phenotype, biochemical recurrence, androgen receptor (AR) and prostate specific antigen (PSA) as well as molecular subtypes defined by ERG status and genomic deletions of 3p, 5q, 6q, and PTEN. HOXB13 immunostaining was detectable in 51.7% of 10,216 interpretable cancers and considered strong in 9.6%, moderate in 19.7% and weak in 22.3% of cases. HOXB13 expression was linked to advanced pT stage, high Gleason grade, positive lymph node status (p < 0.0001 each), high pre-operative PSA levels (p = 0.01), TMPRSS2:ERG fusion, PTEN deletions, AR expression, cell proliferation, reduced PSA expression and early PSA recurrence (p < 0.0001 each). The prognostic value of HOXB13 was independent from established parameters including Gleason, stage, nodal stage and PSA. Co-expression analysis identified a subset of tumors with high HOXB13 and AR but low PSA expression that had a particularly poor prognosis. HOXB13 appears to be a promising candidate for clinical routine tests either alone or in combination with other markers, including AR and PSA.
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Cristina Villares
authors.initials: CV
authors.lastname: Zabalza
authors.affiliation: Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Adam
authors.affiliation: General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Burdelski
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Wilczak
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Corina
authors.initials: C
authors.lastname: Wittmer
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kraft
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Krech
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Steurer
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Koop
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Hube-Magg
authors.affiliation: Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Graefen
authors.affiliation: Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Heinzer
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Minner
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.affiliation: Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Germany.|Department of Urology, Section for Translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schlomm
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Maria Christina
authors.initials: MC
authors.lastname: Tsourlakis
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D018398:Homeodomain Proteins / Q000032:analysis / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000473:pathology*; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000473:pathology*; D011944:Receptors, Androgen / Q000096:biosynthesis; D046888:Tissue Array Analysis; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C484414:HOXB13 protein, human; D018398:Homeodomain Proteins; D011944:Receptors, Androgen; D017430:Prostate-Specific Antigen
keywords: ERG; HOXB13; PTEN; TMA; prostate cancer
references.citation: Mod Pathol. 2013 May;26(5):733-42
references.pmid: 23196798
references.citation: Mol Med Rep. 2012 Apr;5(4):901-4
references.pmid: 22293681
references.citation: BMC Med Genomics. 2014;7:50
references.pmid: 25115192
references.citation: Nature. 2011 Feb 10;470(7333):214-20
references.pmid: 21307934
references.citation: World J Urol. 2007 Mar;25(1):19-30
references.pmid: 17334767
references.citation: Clin Cancer Res. 2010 Mar 1;16(5):1553-60
references.pmid: 20179235
references.citation: Am J Pathol. 2012 Aug;181(2):401-12
references.pmid: 22705054
references.citation: Differentiation. 2003 Oct;71(8):461-76
references.pmid: 14641327
references.citation: Am J Surg Pathol. 2014 May;38(5):615-26
references.pmid: 24722062
references.citation: Mod Pathol. 2007 Apr;20(4):467-73
references.pmid: 17334351
references.citation: N Engl J Med. 2012 Mar 15;366(11):981-90
references.pmid: 22417251
references.citation: Prostate. 2013 May;73(6):634-41
references.pmid: 23129385
references.citation: PLoS One. 2012;7(9):e45178
references.pmid: 23028830
references.citation: Mol Cancer. 2010;9:124
references.pmid: 20504375
references.citation: Virchows Arch. 2013 Dec;463(6):803-9
references.pmid: 24146108
references.citation: J Clin Oncol. 2011 Nov 10;29(32):4273-8
references.pmid: 21990413
references.citation: Cancer Res. 2010 Sep 1;70(17):6735-45
references.pmid: 20713528
references.citation: Cancer Epidemiol. 2013 Aug;37(4):424-7
references.pmid: 23541221
references.citation: Am J Cancer Res. 2011;1(5):604-17
references.pmid: 21994901
references.citation: Mod Pathol. 2008 Nov;21(11):1371-8
references.pmid: 18552821
references.citation: Oncogene. 2003 Feb 6;22(5):781-96
references.pmid: 12569372
references.citation: Mod Pathol. 2014 Jan;27(1):96-106
references.pmid: 23887301
references.citation: Bioessays. 2008 Oct;30(10):965-79
references.pmid: 18798525
references.citation: Clin Cancer Res. 2011 Sep 15;17(18):5878-88
references.pmid: 21791629
references.citation: Hum Pathol. 2013 Sep;44(9):1789-96
references.pmid: 23642739
references.citation: Cancer Res. 2013 Sep 1;73(17):5449-58
references.pmid: 23832664
references.citation: Cancer Cell. 2013 Feb 11;23(2):159-70
references.pmid: 23410972
references.citation: Cancer Epidemiol Biomarkers Prev. 2013 Apr;22(4):675-80
references.pmid: 23396964
references.citation: Prostate Cancer Prostatic Dis. 2014 Mar;17(1):64-9
references.pmid: 24145624
references.citation: Cancer Res. 2006 Nov 1;66(21):10242-6
references.pmid: 17079440
references.citation: J Natl Cancer Inst. 2014 Mar;106(3):dju007
references.pmid: 24610909
references.citation: N Engl J Med. 2012 Jan 12;366(2):141-9
references.pmid: 22236224
references.citation: Science. 2009 Nov 27;326(5957):1230
references.pmid: 19933109
references.citation: Prostate. 2013 Nov;73(15):1690-8
references.pmid: 23843146
references.citation: BMC Genomics. 2013;14:690
references.pmid: 24103217
references.citation: Cancer Cell. 2010 Jul 13;18(1):11-22
references.pmid: 20579941
references.citation: CA Cancer J Clin. 2013 Jan;63(1):11-30
references.pmid: 23335087
references.citation: Mod Pathol. 2013 Jul;26(7):975-83
references.pmid: 23370768
references.citation: Mol Cell. 2009 Nov 13;36(3):405-16
references.pmid: 19917249
references.citation: Eur Urol. 2008 Apr;53(4):750-7
references.pmid: 17964070
references.citation: Nat Med. 1998 Jul;4(7):844-7
references.pmid: 9662379
references.citation: Eur Urol. 2012 May;61(5):1019-24
references.pmid: 22336380
references.citation: J Pathol. 2013 Sep;231(1):130-41
references.pmid: 23794398
references.citation: Mol Oncol. 2013 Dec;7(6):1001-11
references.pmid: 23941784
references.citation: Hum Genet. 2013 Jan;132(1):1-4
references.pmid: 23001594
references.citation: Anat Cell Biol. 2010 Dec;43(4):284-93
references.pmid: 21267402
references.citation: Mol Cell Endocrinol. 2014 Mar 5;383(1-2):38-47
references.pmid: 24325868
references.citation: Hum Genet. 2013 Jan;132(1):5-14
references.pmid: 23064873
references.citation: J Mol Diagn. 2008 Jan;10(1):50-7
references.pmid: 18165275
references.citation: Cancer Res. 2013 May 1;73(9):2795-805
references.pmid: 23492366
references.citation: J Urol. 2013 Mar;189(3):849-53
references.pmid: 23036981
references.citation: Cancer. 2013 Jun 15;119(12):2282-90
references.pmid: 23575751
references.citation: Science. 2005 Oct 28;310(5748):644-8
references.pmid: 16254181
references.citation: BMC Cancer. 2011;11:507
references.pmid: 22142399
references.citation: Cancer Res. 2004 Dec 15;64(24):9185-92
references.pmid: 15604291