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Invasive Bladder Cancer: Genomic Insights and Therapeutic Promise Jaegil Kim1, Rehan Akbani2, Chad J

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Invasive Bladder Cancer: Genomic Insights and Therapeutic Promise Jaegil Kim1, Rehan Akbani2, Chad J Review Clinical Cancer Research Invasive Bladder Cancer: Genomic Insights and Therapeutic Promise Jaegil Kim1, Rehan Akbani2, Chad J. Creighton3, Seth P. Lerner3, John N. Weinstein2, Gad Getz1,4, and David J. Kwiatkowski1,5 Abstract Invasive bladder cancer, for which there have been few thera- unusually frequent in comparison with other cancers, and muta- peutic advances in the past 20 years, is a significant medical tion or amplification of transcription factors is also common. problem associated with metastatic disease and frequent mortal- Expression clustering analyses organize bladder cancers into four ity. Although previous studies had identified many genetic altera- principal groups, which can be characterized as luminal, immune tions in invasive bladder cancer, recent genome-wide studies have undifferentiated, luminal immune, and basal. The four groups provided a more comprehensive view. Here, we review those show markedly different expression patterns for urothelial differ- recent findings and suggest therapeutic strategies. Bladder cancer entiation (keratins and uroplakins) and immunity genes (CD274 has a high mutation rate, exceeded only by lung cancer and and CTLA4), among others. These observations suggest numerous melanoma. About 65% of all mutations are due to APOBEC- therapeutic opportunities, including kinase inhibitors and anti- mediated mutagenesis. There is a high frequency of mutations body therapies for genes in the canonical signaling pathways, and/or genomic amplification or deletion events that affect many histone deacetylase inhibitors and novel molecules for chromatin of the canonical signaling pathways involved in cancer develop- gene mutations, and immune therapies, which should be targeted ment: cell cycle, receptor tyrosine kinase, RAS, and PI-3-kinase/ to specific patients based on genomic profiling of their cancers. mTOR. In addition, mutations in chromatin-modifying genes are Clin Cancer Res; 21(20); 4514–24. Ó2015 AACR. Disclosure of Potential Conflicts of Interest S.P. Lerner reports receiving commercial research grants from Endo Pharmaceuticals and FKD Therapies, and is a consultant/advisory board member for BioCancell, Dendreon (uncompensated), Genentech, and OncoGenex Pharmaceuticals. No potential conflicts of interest were disclosed by the other authors. Editor's Disclosures The following editor(s) reported relevant financial relationships: J.R. Grandis—None. CME Staff Planners' Disclosures The members of the planning committee have no real or apparent conflicts of interest to disclose. Learning Objectives Upon completion of this activity, the participant should have a better understanding of the following aspects of bladder cancer: the genes commonly mutated and/or amplified, the mechanisms of mutation in bladder cancer, the classification of different bladder cancer types based upon expression profiles, and the genes whose mutations have potential for targeted therapy. Acknowledgment of Financial or Other Support This activity does not receive commercial support. Introduction diagnosed. Non–muscle-invasive bladder cancer (NMIBC), in Bladder cancer is a major cause of morbidity and mortality which the smooth muscle layer surrounding the bladder is not worldwide, with about 380,000 new cases and 150,000 deaths per invaded by tumor, accounts for about 80% of all bladder cancer year (1). It is notable among the common cancers in that both diagnoses (1). NMIBCs (Ta and T1) include both low- and high- preinvasive and invasive forms of the disease are commonly grade papillary tumors, and carcinoma in situ,aflat high-grade 1The Eli and Edythe L. Broad Institute of Massachusetts Institute of E-mail: [email protected]; and Jaegil Kim, The Eli and Edythe L. Broad 2 Technology and Harvard University, Cambridge, Massachusetts. Uni- Institute of Massachusetts Institute of Technology and Harvard University, 75 3 versity of Texas MD Anderson Cancer Center, Houston, Texas. Baylor Ames Street, Cambridge, MA 02139. Phone: 617-714-8655; Fax: 617-800-1758; College of Medicine, Houston,Texas. 4Massachusetts General Hospital, E-mail: [email protected] Harvard Medical School, Boston, Massachusetts. 5Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. doi: 10.1158/1078-0432.CCR-14-1215 Corresponding Authors: David J. Kwiatkowski, Brigham and Women's Hospital, 1 Blackfan Circle, Boston, MA 02115. Phone: 617-355-9005; Fax: 617-355-9016; Ó2015 American Association for Cancer Research. 4514 Clin Cancer Res; 21(20) October 15, 2015 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2015 American Association for Cancer Research. www.aacrjournals.org (bottom) seen in eachspeci TCGA bladder cancer sample. cancer genomes. Two ofMutation them signatures match in 238 the muscle-invasive APOBECFigure TCGA pattern, bladder 1. cancers. T A, Bayesian NMF (17) was used to identify signature, and the mutations, whereas the next, APOBEC2, consists of only C Downloaded from A B fi Normalized proportion c sequence. B, graph of the total number of mutations associated with Number of mutations Number of mutations 4,000 4,000 6,000 4,000 3,000 2,000 2,000 3,000 2,000 1,000 1,000 1,000 of signature 1,200 400 600 900 500 300 300 200 100 0.4 0.6 0.8 0.2 1.0 0 0 0 0 0 0 0 A—A A—C A—G fi A—T fth signature identi C—A C—C C–>A C—G C—T clincancerres.aacrjournals.org G—A G—C G—G G—T T—A T—C T—G T—T A—A Signature activity across 238 muscle-invasive TCGA bladdercancers TCGA 238muscle-invasive activityacross Signature A—C fi A—G bladdercancers TCGA in238muscle-invasive Mutation signatures ed by NMF analysis is of unknown origin. The A—T C—A C—C C–>G C—G C—T G—A G—C G—G G—T T—A T—C T—G T—T > A—A T mutations. The third mutation signature is that of CpG A—C CW - A—G A—T C—A on September 27, 2021. © 2015American Association for Cancer C—C C–>T > C—G T C—T Research. TW or T G—A G—C G—G G—T T—A T—C Motifs GW. The uppermost signature, APOBEC1, consists of both C fi T—G ve mutation signatures (top) and relative proportion of mutation types T—T A—A A—C A—G A—T C—A y C—C T–>A axis gives the number of mutations of each type at each C—G C—T G—A G—C G—G G—T T—A T—C T—G T—T A—A A—C A—G fi A—T ve patterns of mutation that occur in bladder © 2015 American Association for Cancer Research Cancer for © 2015AmericanAssociation Clin Cancer Res; 21(20) October 15, 2015 C—A C—C T–>C C—G C—T C>T _ CpG APOBEC2 APOBEC1 G—A Progress in Invasive Bladder Cancer G—C G—G > G—T TpG, the fourth is a POLE T—A T—C T—G T—T A—A A—C A—G A—T POLE Unknown C—A C—C T–>G C—G C—T G—A G—C > G—G TandC G—T T—A T—C T—G PBC >_p POLE C>T_CpG APOBEC2 APOBEC1 T—T Unknown > G 4515 Kim et al. 2000 1500 Nonsynonymous 1000 Synonymous 500 Mutations 0 1.0 C>T A>G 0.8 C>A A>C 0.6 C>G A>T 0.4 0.2 Spectrum 0.0 TCGA BGI NMI MI DFCI CNIO Cohorts TP53 (44%) HRAS (6%) ELF3 (10%) KDM6A (26%) ZFP36L1 (7%) CDKN1A (8%) RB1 (16%) PIK3CA (21%) ARID1A (23%) ERCC2 (10%) CDKN2A (5%) STAG2 (13%) FGFR3 (13%) EP300 (13%) RXRA (7%) RHOB (4%) RHOA (4%) TYRO3 (3%) MLL2 (17%) KRAS (3%) ERBB3 (11%) TGFBR1 (3%) ERBB2 (9%) KLF5 (5%) FAM47C (4%) BRWD1 (4%) ERBB4 (6%) IRS4 (2%) TXNIP (4%) TSC1 (6%) NFE2L2 (4%) CHIT1 (3%) C3orf70 (3%) MBD1 (3%) 200 100 0 In-frame indel Other nonsynonymous Missense Splice site Frame shift Nonsense No. of mutations © 2015 American Association for Cancer Research Figure 2. Significantly mutated genes (SMG) identified in 404 cases of bladder cancer. Mutation data used were from TCGA (238 invasive cases; ref. 10), the Beijing Genomics Institute (62 invasive cases and 37 NMIBC: 28 T1N0, 2 T1bN0, 1 T1Nx, 6 TaN0; ref. 11), the CNIO (Spanish National Cancer Research Centre; 2 invasive and 15 NMIBC: 3 TaG1, 2 TaG2, 1 TaG3, 3 T1G2, 6 T1G3; ref. 12), and the DFCI/Broad (50 invasive cases; ref. 13). Sequentially from top to bottom: mutation rate, mutation spectrum, non–muscle-invasive (NMI) versus muscle-invasive (MI), source of data, and genes with statistically significant levels of mutation (MutSig 2CV; ref. 19, FDR < 0.1) sorted by q value are shown. Colors indicate different mutation types, shown at bottom. The total number of mutations and the percent of samples with mutation in each gene are shown at left. The CNIO data were not included in MutSig analysis to identify SMGs. Mutations seen at allele fraction 5% were not included. Five genes (FAM82A2, STK39, ATP8P2, ZNF83,andGLT6D1) identified by Mutsig were also deleted due to suspicious mutation patterns. Note that bar plots at the top are truncated for a few cancers. tumor. NMIBC treatment consists of intravesical chemo- or immu- mean of 7.7, and median of 5.5 per Mb within coding regions, notherapy and requires regular cystoscopic monitoring for early amounting to 302 protein-coding mutations per cancer detection of recurrence and/or progression to invasive disease. (10). Lung adenocarcinoma, lung squamous cell carcinoma, Muscle-invasive bladder cancer, hereafter termed "invasive bladder and melanoma are the only major cancers studied by TCGA cancer," is characterized by a high risk of metastases to regional that have higher mutation rates. For those cancers, the causes pelvic lymph nodes and visceral sites, and is usually incurable are thought to be cigarette carcinogen mutagenesis (lung despite systemic chemotherapy.
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