βIII-tubulin overexpression is linked to agressive tumor features and genetic instability in urinary bladder cancer

Development of genetic instability is a hallmark of tumor progression. Type III ß-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 with >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 to 28% of genetically stable cancers, and in 50% of p53-positive cancers as compared to 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, non-invasive 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 non-invasive bladder cancers may be clinically useful to identify patients requiring particular close monitoring.