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Abstract A1-01: Translational genomics of urologic cancer genes

Michael L. Nickerson, Kate M. Im, Sevilay Turan, Guangwu Guo, Lee E. Moore, Dan Theodorescu,

Abstract: Next generation sequencing (NGS) of urologic tumor genomes has led to the detection of frequently altered cancer genes. We have characterized bladder (BCa), prostate (PCa), and kidney (RCC) tumor genomes using exome, whole genome, and transcriptome NGS; copy number and SNP arrays, and bisulfite sequencing for methylation to detect genomic alterations associated with disease. We recently examined BCa tumors from 54 U.S. patients and compared these to 99 Chinese patients to identify novel alterations of cancer genes encoding proteins associated with DNA and chromatin, including telomerase (TERT), stromal antigen 2 (STAG2), and BRCA1-associated protein-1 (BAP1). We are the first to show the TERT promoter is altered in BCa by both somatic and germline nucleotide changes in 37/54 (69%) and 30/54 (56%) tumors, respectively; and that TERT somatic alterations do not correlate with other cancer gene mutations examined by exome NGS. Most TERT germline variants were novel (19/20), and three variants were confirmed as both somatic and germline in distinct tumors, including the most frequent variant, c. – 245 T>C (rs2853669). We show somatic promoter alterations are associated with increased TERT expression but, paradoxically, with significantly shorter telomeres in tumors as compared to matched normal tissue. STAG2 was altered by somatic deleterious sequence changes, genomic deletions, and promoter CpG hypermethylation. Mutations are associated with reduced patient survival and tumor cell aneuploidy based on an increased number of chromosomal arm copy number changes. Somatic BAP1 mutations are primarily deleterious sequence changes that occurred preferentially in U.S. Caucasian as compared to Chinese BCa patients. BAP1 mutations are associated with papillary histologic features in a subset of tumors and with mutations in the histone lysine–specific demethylase 6A (KDM6A/UTX) gene. BAP1 mutations contribute to a significant number of tumors with somatic and rare germline variants in BRCA pathway genes, including BRCA1, BRCA2, PALB2, and ATM. We experimentally examined the function of KDM6A since it is the most frequently altered chromatin modifying gene in 24% of tumors. KDM6A loss in human BCa cells enhanced in vitro proliferation, in vivo tumor growth, and cell migration, confirming KDM6A loss drives the BCa phenotype. A comparison of BCa and other urologic tumor genomes allows us to identify several emergent common characteristics. Significant numbers of tumors are altered by rare, disease-associated germline cancer gene variants that likely have substantive effects on cancer risk and which likely influence the subsequent accrual of somatic alterations. These likely contribute to the missing heritability that is observed by cancer epidemiology studies. Many cancer genes are altered by characteristic frequencies of nonsynonymous sequence changes, promoter variants, copy number variation, and hypermethylation, that are routinely observed for a given gene-tissue-patient ethnicity combination. Approximately 4-5 tumor suppressors are altered for each oncogene, and interactions between altered cancer genes affect the resulting biological functions. In BCa, we show KDM6A loss increases cell proliferation which likely results in shorter telomeres even though TERT expression is increased. We identified altered cancer genes such as STAG2 that are associated with discrete clinical aspects of the disease phenotype, namely aneuploidy and reduced patient survival indicating a lethal subtype of disease. Cancer genes on the X chromosome such as STAG2 and KDM6A have a single copy in men and likely contribute to the gender bias observed in cancer. Finally, cancer gene alterations can identify patients likely to respond to a currently approved therapy. BAP1 and BRCA pathway alterations define BCa, PCa, and RCC tumors with a common DNA repair deficiency that might be exploited by targeted therapies such as poly (ADP ribose) polymerase inhibitors.
Keywords: next generation sequencing / methylation / copy number / DNA repair / targeted therapies / aneuploidy / chromatin / epidemiology / transcriptome / TERT

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