Abstract 1105: Clinical associations between altered bladder cancer genes
Authors: Nickerson Michael L. , Im Kate M. , Turan Sevilay , Moore Lee E. , Dean Michael , Theodorescu Dan 
Published: August 2015

Abstract
Next generation sequencing (NGS) has identified frequently altered cancer genes in urologic cancers including bladder cancer (BCa). We examined BCa tumors from 54 U.S. patients using exome NGS and targeted sequencing, and compared these to 99 extensively characterized Chinese patient tumors (Guo et al., 2013). We are first to show that telomerase (TERT) is the gene most frequently altered by somatic sequence changes in 37/54 (69%) of tumors and that TERT is also altered by rare and common germline variants in 30/54 (56%) tumors. Most TERT germline variants were novel (19/20) and three variants were confirmed as both somatic and germline in distinct tumors, including c. - 245 T&gt;C (rs2853669), the most recurrent variant. A subset of variants created or altered transcription factor binding sites and promoter CpGs. Telomere length was significantly shorter in tumor versus adjacent normal tissue from the same patient (p = 0.004) indicating TERT minimally lengthens telomeres in rapidly proliferating BCa cells. Somatic TERT alterations were not associated with stage, grade, or alterations in other BCa genes identified by exome sequencing. STAG2 is altered by somatic mutations in 20/153 (13%) tumors and by X chromosome deletions and promoter hypermethylation. STAG2 mutant tumors had higher levels of aneuploidy (p = 0.01) and Kaplan-Meier analysis indicated a poor prognosis due to significantly shorter survival times (p &lt; 0.001). Somatic BAP1 alterations were associated with papillary histologic features in 15% of Caucasian patient tumors but were infrequently observed in Asian patients (p = 0.003), which remained marginally significant after accounting for differences in tumor grade and stage (p = 0.037). BAP1 mutations co-occurred with histone 3 lysine 27-specific demethylase (KDM6A) mutations (p = 0.017), indicating the cancer genes might provide complementary survival advantages to cancer cells. We find that cancer gene alterations are highly predictive of canonical features of the BCa phenotype and ∼4-5 tumor suppressors are altered for each oncogene. X chromosome cancer genes such as STAG2 and KDM6A have a single copy in men and their lethality (as shown for STAG2) likely contributes to the gender bias in cancer. We speculate that TERT alterations are early events in BCa and identification of somatic alterations in urine may provide a biomarker for early BCa diagnosis. BAP1 mutations contribute to frequent BRCA pathway alterations in BCa and indicate treatment with poly(ADP ribose) polymerase inhibitors would be effective.
Citation Format: Michael L. Nickerson, Kate M. Im, Sevilay Turan, Lee E. Moore, Michael Dean, Dan Theodorescu. Clinical associations between altered bladder cancer genes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1105. doi:10.1158/1538-7445.AM2015-1105