Truncating Mutations of STAG2 Define a Molecular Subgroup of Aneuploid Bladder Cancers with Poor Prognosis
David A Solomon, Jolanta Bondaruk, Shahrokh F Shariat, Zeng-Feng Wang, Abdel G Elkahloun, Shizhen Zhang, Neema Navai, Julia Gerard, Brian D Robinson, DaZhong Zhoung, Michael Rink, Bjorn Volkmer, Richard Hautmann, Rainer Kufer, Pancras CW Hogendoorn, George Netto, Dan Theodorescu, Jung-Sik Kim, Bogdan Czerniak, Markku Miettinen, Todd Waldman. Lombardi Cancer Center, Georgetown University, Washington, DC; University of California, San Francisco, CA; University of Texas MD Anderson Cancer Center, Houston, TX; Weill Cornell College of Medicine, New York, NY; National Cancer Institute, Bethesda, MD; National Human Genome Research Institute, Bethesda, MD; University Medical Center Hamburg, Hamburg, Germany; Hospital Kassel, Kassel, Germany; University Hospital Ulm, Ulm, Germany; Hospital Am Eichert, Goppingen, Germany; Leiden University Medical Center, Leiden, Netherlands; Johns Hopkins University School of Medicine, Baltimore, MD; University of Colorado Cancer Center, Aurora, CO
Background: Aneuploidy is among the most common hallmarks of cancer, yet the underlying genetic mechanisms are still poorly defined. We have recently identified STAG2 as a gene that is somatically mutated in human cancer and whose inactivation leads directly to chromosomal instability and aneuploidy (Solomon et al, Science 2011 Aug 19). However, the complete tumor spectrum harboring STAG2 mutations and the clinical significance of STAG2 inactivation in cancer remain undefined.
Design: We used IHC to screen a panel of 2,214 tumors from each of the major tumor types for somatic loss of STAG2 expression. Sanger sequencing of the STAG2 gene was performed on 109 urothelial carcinomas, and Affymetrix CytoscanHD Arrays were performed on STAG2 mutant tumors. Clinical data from 354 patients with bladder cancer treated with radical cystectomy was correlated with tumor STAG2 status.
Results: In addition to frequent loss in melanoma and Ewing's sarcoma as previously described, complete loss of STAG2 expression was discovered in 52/295 urothelial carcinomas (18%). STAG2 loss was only rarely present in all other tumor types examined. DNA sequencing revealed somatic mutations of STAG2 in 23/109 urothelial carcinomas (21%), the majority of which were nonsense or frameshift mutations. STAG2 mutation was found to be an early event in bladder tumorigenesis and correlated with the presence of numerous chromosomal copy number aberrations per tumor. Additionally, STAG2 loss in urothelial carcinoma patients was significantly associated with increased lymph node metastasis (p=0.02), earlier disease recurrence (p=0.03), and reduced cancer-specific survival (p=0.03).
Conclusions: These results identify STAG2 as the most commonly mutated gene in bladder cancer discovered to date, and demonstrate that STAG2 loss defines an aggressive subgroup of aneuploid bladder cancers with poor prognosis.
Category: Genitourinary (including renal tumors)
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 160, Monday Morning