title: βIII-tubulin overexpression is linked to aggressive tumor features and genetic instability in urinary bladder cancer.
abstract: Development of genetic instability is a hallmark of tumor progression. Type III β-tubulin (TUBB3) is a component of microtubules involved in chromosome segregation. Its overexpression has been linked to adverse features of urinary bladder cancer. To investigate the role of TUBB3 for development of genetic instability, we compared TUBB3 expression with histopathological features and surrogate markers of genetic instability and tumor aggressiveness; copy number changes of HER2, TOP2A, CCND1, RAF1, and FGFR1; nuclear accumulation of p53, and cell proliferation in a tissue microarray (TMA) with more than 700 bladder cancers. TUBB3 expression was linked to high-grade and advanced-stage cancers (P<.0001), rapid cell proliferation (P<.0001), presence of multiple gene copy number alterations (P=.0008), and nuclear accumulation of p53 (P=.0008). Strong TUBB3 staining was found in 43% of urothelial cancers harboring copy number alterations as compared with 28% of genetically stable cancers, and in 50% of p53-positive cancers as compared with 30% of p53-negative tumors. The fraction of tumors with concomitant TUBB3 and p53 positivity increased with tumor stage and grade: 2% in pTaG1-2, 11% in pTaG3, 17% in pT1G2, 23% in pT1G3, and 32% in pT2-4 cancers (P<.0001). Importantly, strong TUBB3 overexpression was detectable in about 20% of low-grade, noninvasive cancers. In summary, our study demonstrates that TUBB3 overexpression is linked to an aggressive subtype of urinary bladder cancers, which is characterized by increased genetic instability, p53 alterations, and rapid cell proliferation. Detection of TUBB3 overexpression in genetically stable, low-grade, and noninvasive bladder cancers may be clinically useful to identify patients requiring particular close monitoring.
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hinsch
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Aref
authors.initials: A
authors.lastname: Chaker
authors.affiliation: General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Burdelski
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Koop
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Maria Christina
authors.initials: MC
authors.lastname: Tsourlakis
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Steurer
authors.affiliation: Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Rink
authors.affiliation: Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Till Simon
authors.initials: TS
authors.lastname: Eichenauer
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Wilczak
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Wittmer
authors.affiliation: Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Margit
authors.initials: M
authors.lastname: Fisch
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany. Electronic address: r.simon@uke.de.
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Büschek
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Clauditz
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Minner
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Jacobsen
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D001706:Biopsy; D049109:Cell Proliferation; D056915:DNA Copy Number Variations; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006801:Humans; D007150:Immunohistochemistry; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010641:Phenotype; D046888:Tissue Array Analysis; D014404:Tubulin / Q000032:analysis*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C495901:TP53 protein, human; C498585:TUBB3 protein, human; D014404:Tubulin; D016159:Tumor Suppressor Protein p53
keywords: Bladder cancer; Immunochemistry; Prognosis; TUBB3; Tubulin