Key Points
-
Urothelial carcinoma has a high degree of mutational heterogeneity and a high frequency of somatic mutations compared with other solid tumours
-
The APOBEC family of enzymes, including APOBEC3B, are a source of hypermutation in urothelial carcinoma, resulting in a high frequency of TpC>T or G mutations
-
Urothelial carcinoma also has a high number of epigenetic changes and a high frequency of mutations in chromatin remodelling genes
-
Mutations in FGFR3 and KDM6A are more common in non-muscle-invasive bladder cancer (NMIBC) than muscle-invasive bladder cancer (MIBC), whereas mutations in PT53 and MLL2 are more common in MIBC
-
Upper tract urothelial carcinoma tumours seem to be genetically similar to urothelial carcinoma of the bladder, but further study with more samples is needed
-
The molecular pathways discovered in multiple high-throughput analyses of urothelial carcinoma might be therapeutically targetable in future clinical studies
Abstract
Survival of patients with urothelial carcinoma (including bladder cancer and upper tract urothelial carcinoma) is limited by our current approaches to staging, surgery, and chemotherapy. Large-scale, next-generation sequencing collaborations, such as The Cancer Genome Atlas, have already identified drivers and vulnerabilities of urothelial carcinoma. This disease has a high degree of mutational heterogeneity and a high frequency of somatic mutations compared with other solid tumours, potentially resulting in an increased neoantigen burden. Mutational heterogeneity is mediated by multiple factors including the apolipoprotein B mRNA editing enzyme catalytic polypeptide family of enzymes, smoking exposure, viral integrations, and intragene and intergene fusion proteins. The mutational landscape of urothelial carcinoma, including specific mutations in pathways and driver genes, such as FGFR3, ERBB2, PIK3CA, TP53, and STAG2, affects tumour aggressiveness and response to therapy. The next generation of therapies for urothelial carcinoma will be based on patient-specific targetable mutations found in individual tumours. This personalized-medicine approach to urothelial carcinoma has already resulted in unique clinical trial design and has the potential to improve patient outcomes and survival.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
United States Cancer Statistics Working Group. United States Cancer Statistics: 1999–2013 Cancer Incidence and Mortality Data. CDC http://www.cdc.gov/uscs (2015).
Antoni, S. et al. Bladder cancer incidence and mortality: a global overview and recent trends. Eur. Urol. 71, 96–108 (2017).
Abdollah, F. et al. Incidence, survival and mortality rates of stage-specific bladder cancer in United States: a trend analysis. Cancer Epidemiol. 37, 219–225 (2013).
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507, 315–322 (2014).
Guo, G. et al. Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation. Nat. Genet. 45, 1459–1463 (2013).
Gui, Y. et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat. Genet. 43, 875–878 (2011).
von der Maase, H. et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J. Clin. Oncol. 18, 3068–3077 (2000).
Rose, T. L. & Milowsky, M. I. Improving systemic chemotherapy for bladder cancer. Curr. Oncol. Rep. 18, 27 (2016).
Brown, S. D. et al. Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res. 24, 743–750 (2014).
Lawrence, M. S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).
Broad Institute. Mutation Analysis (MutSig 2CV v3.1). Broadinstitute.org http://gdac.broadinstitute.org/runs/analyses__latest/reports/cancer/BLCA/MutSigNozzleReport2CV/nozzle.html (2016).
Blaveri, E. et al. Bladder cancer stage and outcome byarray-based comparative genomic hybridization. Clin. Cancer Res. 11, 7012–7022 (2005).
Roberts, S. A. & Gordenin, D. A. Hypermutation in human cancer genomes: footprints and mechanisms. Nat. Rev. Cancer 14, 786–800 (2014).
Kandoth, C. et al. Mutational landscape and significance across 12 major cancer types. Nature 502, 333–339 (2013).
Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562 (2014).
Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).
Kardos, J. et al. Claudin-low bladder tumors are immune infiltrated and actively immune suppressed. JCI Insight 1, e85902 (2016).
Rosenberg, J. E. et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387, 1909–1920 (2016).
Mullane, S. A. et al. Correlation of APOBEC mRNA expression with overall survival and PD-l1 expression in urothelial carcinoma. Sci. Rep. 6, 27702 (2016).
Cancer Genome Atlas Research Network et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat. Genet. 45, 1113–1120 (2013).
Hoadley, K. A. et al. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 158, 929–944 (2014).
Zack, T. I. et al. Pan-cancer patterns of somatic copy number alteration. Nat. Genet. 45, 1134–1140 (2013).
Petljak, M. & Alexandrov, L. B. Understanding mutagenesis through delineation of mutational signatures in human cancer. Carcinogenesis 37, 531–540 (2016).
Lawrence, M. S. et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505, 495–501 (2014).
Swanton, C., McGranahan, N., Starrett, G. J. & Harris, R. S. APOBEC enzymes: mutagenic fuel for cancer evolution and heterogeneity. Cancer Discov. 5, 704–712 (2015).
Harris, R. S., Petersen-Mahrt, S. K. & Neuberger, M. S. RNA editing enzyme APOBEC1 and some of its homologs can act as DNA mutators. Mol. Cell 10, 1247–1253 (2002).
Harris, R. S. & Liddament, M. T. Retroviral restriction by APOBEC proteins. Nat. Rev. Immunol. 4, 868–877 (2004).
Mangeat, B. et al. Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature 424, 99–103 (2003).
Roberts, S. A. et al. Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions. Mol. Cell 46, 424–435 (2012).
Burns, M. B. et al. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 494, 366–370 (2013).
Kim, J. et al. Invasive bladder cancer: genomic insights and therapeutic promise. Clin. Cancer Res. 21, 4514–4524 (2015).
Winnepenninckx, B. et al. CGG-repeat expansion in the DIP2B gene is associated with the fragile site FRA12A on chromosome 12q13.1. Am. J. Hum. Genet. 80, 221–231 (2007).
Bell, J. T. et al. DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. Genome Biol. 12, R10 (2011).
Williams, S. V., Hurst, C. D. & Knowles, M. A. Oncogenic FGFR3 gene fusions in bladder cancer. Hum. Mol. Genet. 22, 795–803 (2013).
di Martino, E., Tomlinson, D. C. & Knowles, M. A. A. Decade of FGF receptor research in bladder cancer: past, present, and future challenges. Adv. Urol. 2012, 429213 (2012).
Bakkar, A. A. et al. FGFR3 and TP53 gene mutations define two distinct pathways in urothelial cell carcinoma of the bladder. Cancer Res. 63, 8108–8112 (2003).
van Rhijn, B. W. G. et al. FGFR3 and P53 characterize alternative genetic pathways in the pathogenesis of urothelial cell carcinoma. Cancer Res. 64, 1911–1914 (2004).
Lamy, A. et al. Molecular profiling of bladder tumors based on the detection of FGFR3 and TP53 mutations. J. Urol. 176, 2686–2689 (2006).
Liu, X. et al. Clinical significance of fibroblast growth factor receptor-3 mutations in bladder cancer: a systematic review and meta-analysis. Genet. Mol. Res. 13, 1109–1120 (2014).
Pouessel, D. et al. Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti-FGFR3 treatment. Ann. Oncol. 27, 1311–1316 (2016).
Sethakorn, N. & O'Donnell, P. H. Spectrum of genomic alterations in FGFR3: current appraisal of the potential role of FGFR3 in advanced urothelial carcinoma. BJU Int. 118, 681–691 (2016).
Nelson, K. N. et al. Oncogenic gene fusion FGFR3-TACC3 is regulated by tyrosine phosphorylation. Mol. Cancer Res. http://dx.doi.org/10.1158/1541-7786.MCR-15-0497 (2016).
Singh, D. et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 337, 1231–1235 (2012).
Sfakianos, J. P. et al. Genomic characterization of upper tract urothelial carcinoma. Eur. Urol. 68, 970–977 (2015).
Wu, Y. M. et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 3, 636–647 (2013).
Katoh, M. & Nakagama, H. FGF receptors: cancer biology and therapeutics. Med. Res. Rev. 34, 280–300 (2014).
Acquaviva, J. et al. FGFR3 translocations in bladder cancer: differential sensitivity to HSP90 inhibition based on drug metabolism. Mol. Cancer Res. 12, 1042–1054 (2014).
Katoh, M. FGFR inhibitors: effects on cancer cells, tumor microenvironment and whole-body homeostasis (review). Int. J. Mol. Med. 38, 3–15 (2016).
Shigehara, K., Sasagawa, T. & Namiki, M. Human papillomavirus infection and pathogenesis in urothelial cells: a mini-review. J. Infect. Chemother. 20, 741–747 (2014).
Alexander, R. E. et al. Human papillomavirus (HPV)-induced neoplasia in the urinary bladder: a missing link? Histol. Histopathol. 31, 595–600 (2015).
Pichler, R. et al. Low prevalence of HPV detection and genotyping in non-muscle invasive bladder cancer using single-step PCR followed by reverse line blot. World J. Urol. 33, 2145–2151 (2015).
Crivelli, J. J. et al. Effect of smoking on outcomes of urothelial carcinoma: a systematic review of the literature. Eur. Urol. 65, 742–754 (2014).
Wang, L. C. et al. Combining smoking information and molecular markers improves prognostication in patients with urothelial carcinoma of the bladder. Urol. Oncol. 32, 433–440 (2014).
Pottner, S., Behm, C., Bolt, H. M. & Follmann, W. Effects of cigarette smoke condensate on primary urothelial cells in vitro. J. Toxicol. Environ. Health A 75, 1194–1205 (2012).
Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).
Samowitz, W. S. et al. Association of smoking, CpG island methylator phenotype, and V600E BRAF mutations in colon cancer. J. Natl Cancer Inst. 98, 1731–1738 (2006).
Hughes, L. A. et al. The CpG island methylator phenotype: what's in a name? Cancer Res. 73, 5858–5868 (2013).
Mitra, A. P. et al. Combination of molecular alterations and smoking intensity predicts bladder cancer outcome: a report from the Los Angeles Cancer Surveillance Program. Cancer 119, 756–765 (2013).
Sun, Y. V. et al. Epigenomic association analysis identified smoking-related DNA methylation sites in African Americans. Hum. Genet. 132, 1027–1037 (2013).
Dogan, M. et al. The effect of smoking on DNA methylation of peripheral blood mononuclear cells from African American women. BMC Genomics 15, 151 (2014).
Harlid, S., Xu, Z., Panduri, V., Sandler, D. P. & Taylor, J. A. CpG sites associated with cigarette smoking: analysis of epigenome-wide data from the Sister Study. Environ. Health Perspect. 122, 673–678 (2014).
Teschendorff, A. E., West, J. & Beck, S. Age-associated epigenetic drift: implications, and a case of epigenetic thrift? Hum. Mol. Genet. 22, R7–R15 (2013).
Guida, F. et al. Dynamics of smoking-induced genome-wide methylation changes with time since smoking cessation. Hum. Mol. Genet. 24, 2349–2359 (2015).
Besingi, W. & Johansson, A. Smoke-related DNA methylation changes in the etiology of human disease. Hum. Mol. Genet. 23, 2290–2297 (2014).
van Dongen, J. et al. Genetic and environmental influences interact with age and sex in shaping the human methylome. Nat. Commun. 7, 11115 (2016).
Bhattacharya, A. et al. The inverse relationship between bladder and liver in 4-aminobiphenyl-induced DNA damage. Oncotarget 6, 836–845 (2014).
Lee, H. W. et al. Acrolein- and 4-aminobiphenyl-DNA adducts in human bladder mucosa and tumor tissue and their mutagenicity in human urothelial cells. Oncotarget 5, 2526–2540 (2014).
Feng, Z., Hu, W., Rom, W. N., Beland, F. A. & Tang, M. S. 4-Aminobiphenyl is a major etiological agent of human bladder cancer: evidence from its DNA binding spectrum in human p53 gene. Carcinogenesis 23, 1721–1727 (2002).
Letasiova, S. et al. Bladder cancer, a review of the environmental risk factors. Environ. Health 11 (Suppl. 1), S11 (2012).
Zeegers, M. P., Kellen, E., Buntinx, F. & van den Brandt, P. A. The association between smoking, beverage consumption, diet and bladder cancer: a systematic literature review. World J. Urol. 21, 392–401 (2004).
Feng, Z., Hu, W., Hu, Y. & Tang, M. S. Acrolein is a major cigarette-related lung cancer agent: preferential binding at p53 mutational hotspots and inhibition of DNA repair. Proc. Natl Acad. Sci. USA 103, 15404–15409 (2006).
Wang, H. T., Chen, T. Y., Weng, C. W., Yang, C. H. & Tang, M. S. Acrolein preferentially damages nucleolus eliciting ribosomal stress and apoptosis in human cancer cells. Oncotarget 7, 80450–80464 (2016).
Deng, Q. F. et al. Cigarette smoke extract induces the proliferation of normal human urothelial cells through the NF-κB pathway. Oncol. Rep. 35, 2665–2672 (2016).
Geng, H. et al. Cigarette smoke extract-induced proliferation of normal human urothelial cells via the MAPK/AP-1 pathway. Oncol. Lett. 13, 469–475 (2017).
Brait, M. et al. Genome-wide methylation profiling and the PI3K-AKT pathway analysis associated with smoking in urothelial cell carcinoma. Cell Cycle 12, 1058–1070 (2013).
Ferris, J., Garcia, J., Berbel, O. & Ortega, J. A. Constitutional and occupational risk factors associated with bladder cancer. Actas Urol. Esp. 37, 513–522 (2013).
Kellen, E. et al. Does occupational exposure to PAHs, diesel and aromatic amines interact with smoking and metabolic genetic polymorphisms to increase the risk on bladder cancer?; the Belgian case control study on bladder cancer risk. Cancer Lett. 245, 51–60 (2007).
Freedman, N. D., Silverman, D. T., Hollenbeck, A. R., Schatzkin, A. & Abnet, C. C. Association between smoking and risk of bladder cancer among men and women. JAMA 306, 737–745 (2011).
Gao, X., Zhang, Y., Breitling, L. P. & Brenner, H. Relationship of tobacco smoking and smoking-related DNA methylation with epigenetic age acceleration. Oncotarget 7, 46878–46889 (2016).
Wang, M. et al. Cumulative effect of genome-wide association study-identified genetic variants for bladder cancer. Int. J. Cancer 135, 2653–2660 (2014).
Figueroa, J. D. et al. Genome-wide interaction study of smoking and bladder cancer risk. Carcinogenesis 35, 1737–1744 (2014).
Besaratinia, A., Cockburn, M. & Tommasi, S. Alterations of DNA methylome in human bladder cancer. Epigenetics 8, 1013–1022 (2013).
Esteller, M. Epigenetics in cancer. N. Engl. J. Med. 358, 1148–1159 (2008).
Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).
Maruyama, R. et al. Abberant promoter methylation profile of bladder cancer and its relationship to clinicopathologic features. Cancer Res. 61, 8659–8663 (2001).
Aine, M. et al. Integrative epigenomic analysis of differential DNA methylation in urothelial carcinoma. Genome Med. 7, 23 (2015).
Sjodahl, G. et al. A molecular taxonomy for urothelial carcinoma. Clin. Cancer Res. 18, 3377–3386 (2012).
Balbas-Martinez, C. et al. Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy. Nat. Genet. 45, 1464–1469 (2013).
Van Allen, E. M. et al. Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov. 4, 1140–1153 (2014).
Hernandez, S. et al. FGFR3 and Tp53 mutations in T1G3 transitional bladder carcinomas: independent distribution and lack of association with prognosis. Clin. Cancer Res. 11, 5444–5450 (2005).
Hernandez, S. et al. Prospective study of FGFR3 mutations as a prognostic factor in nonmuscle invasive urothelial bladder carcinomas. J. Clin. Oncol. 24, 3664–3671 (2006).
Lerner, S. P., Tangen, C. M., Sucharew, H., Wood, D. & Crawford, E. D. Patterns of recurrence and outcomes following induction bacillus Calmette-Guerin for high risk Ta, T1 bladder cancer. J. Urol. 177, 1727–1731 (2007).
Segal, R. et al. Prognostic factors and outcome in patients with T1 high-grade bladder cancer: can we identify patients for early cystectomy? BJU Int. 109, 1026–1030 (2012).
Gontero, P. et al. Prognostic factors and risk groups in T1G3 non-muscle-invasive bladder cancer patients initially treated with Bacillus Calmette-Guerin: results of a retrospective multicenter study of 2451 patients. Eur. Urol. 67, 74–82 (2015).
Lopez-Beltran, A. et al. Prognostic factors in stage T1 grade 3 bladder cancer survival: the role of G1-S modulators (p53, 21Waf1, 27kip1, Cyclin D1, and Cyclin D3) and proliferation index (ki67-MIB1). Eur. Urol. 45, 606–612 (2004).
Hedegaard, J. et al. Comprehensive transcriptional analysis of early-stage urothelial carcinoma. Cancer Cell 30, 27–42 (2016).
He, F., Melamed, J., Tang, M. S., Huang, C. & Wu, X. R. Oncogenic HRAS activates epithelial-to-mesenchymal transition and confers stemness to p53-deficient urothelial cells to drive muscle invasion of basal subtype carcinomas. Cancer Res. 75, 2017–2028 (2015).
Ross, J. S. et al. Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations. Cancer 122, 702–711 (2016).
Yan, M. et al. HER2 expression status in diverse cancers: review of results from 37,992 patients. Cancer Metastasis Rev. 34, 157–164 (2015).
Chen, P. C., Yu, H. J., Chang, Y. H. & Pan, C. C. Her2 amplification distinguishes a subset of non-muscle-invasive bladder cancers with a high risk of progression. J. Clin. Pathol. 66, 113–119 (2013).
Bellmunt, J. et al. HER2 as a target in invasive urothelial carcinoma. Cancer Med. 4, 844–852 (2015).
de Martino, M. et al. Impact of ERBB2 mutations on in vitro sensitivity of bladder cancer to lapatinib. Cancer Biol. Ther. 15, 1239–1247 (2014).
McHugh, L. A., Kriajevska, M., Mellon, J. K. & Griffiths, T. R. Combined treatment of bladder cancer cell lines with lapatinib and varying chemotherapy regimens — evidence of schedule-dependent synergy. Urology 69, 390–394 (2007).
Wulfing, C. et al. A single-arm, multicenter, open- label phase 2 study of lapatinib as the second-line treatment of patients with locally advanced or metastatic transitional cell carcinoma. Cancer 115, 2881–2890 (2009).
Galsky, M. D. et al. Target-specific, histology-independent, randomized discontinuation study of lapatinib in patients with HER2-amplified solid tumors. Invest. New Drugs 30, 695–701 (2012).
Hussain, M. H. et al. Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial. J. Clin. Oncol. 25, 2218–2224 (2007).
Narayan, V. et al. Cisplatin, gemcitabine, and lapatinib as neoadjuvant therapy for muscle-invasive bladder cancer. Cancer Res. Treat. 48, 1084–1091 (2016).
Siegel-Lakhai, W. S. et al. Phase I pharmacokinetic study of the safety and tolerability of lapatinib (GW572016) in combination with oxaliplatin/fluorouracil/leucovorin (FOLFOX4) in patients with solid tumors. Clin. Cancer Res. 13, 4495–4502 (2007).
LoRusso, P. M. et al. Phase I and pharmacokinetic study of lapatinib and docetaxel in patients with advanced cancer. J. Clin. Oncol. 26, 3051–3056 (2008).
Cerbone, L. et al. Results from a phase I study of lapatinib with gemcitabine and cisplatin in advanced or metastatic bladder cancer: EORTC Trial 30061. Oncology 90, 21–28 (2016).
Powels, T. et al. A phase II/III, double-blind, randomized trial comparing maintenance lapatinib versus placebo after first line chemotherapy in HER1/2 positive metastatic bladder cancer patients [abstract]. J. Clin. Oncol. 33 (Suppl.), 4505 (2015).
Lopez, J. S. & Banerji, U. Combine and conquer: challenges for targeted therapy combinations in early phase trials. Nat. Rev. Clin. Oncol. 14, 57–66 (2017).
Solomon, D. A. et al. Frequent truncating mutations of STAG2 in bladder cancer. Nat. Genet. 45, 1428–1430 (2013).
Li, X. et al. Loss of STAG2 causes aneuploidy in normal human bladder cells. Genet. Mol. Res. 14, 2638–2646 (2015).
Al-Ahmadie, H. A. et al. Frequent somatic CDH1 loss-of-function mutations in plasmacytoid variant bladder cancer. Nat. Genet. 48, 356–358 (2016).
Sylvester, R. J. et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur. Urol. 49, 466–467 (2006).
Kawanishi, H. et al. High throughput comparative genomic hybridization array analysis of multifocal urothelial cancers. Cancer Sci. 97, 746–752 (2006).
Kawanishi, H. et al. Genetic analysis of multifocal superficial urothelial cancers by array-based comparative genomic hybridisation. Br. J. Cancer 97, 260–266 (2007).
Letouze, E., Allory, Y., Bollet, M. A., Radvanyi, F. & Guyon, F. Analysis of the copy number profiles of several tumor samples from the same patient reveals the successive steps in tumorigenesis. Genome Biol. 11, R76 (2010).
van Tilborg, A. A. G. et al. Molecular evolution of multiple recurrent cancers of the bladder. Hum. Mol. Genet. 9, 2973–2980 (2000).
Bagrodia, A. et al. Genomic biomarkers for the prediction of stage and prognosis of upper tract urothelial carcinoma. J. Urol. 195, 1684–1689 (2016).
Yap, K. L. et al. Whole-exome sequencing of muscle-invasive bladder cancer identifies recurrent mutations of UNC5C and prognostic importance of DNA repair gene mutations on survival. Clin. Cancer Res. 20, 6605–6617 (2014).
Plimack, E. R. et al. Defects in DNA repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer. Eur. Urol. 68, 959–967 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02177695 (2016).
Palma, N., Morris, J. C., Ali, S. M., Ross, J. S. & Pal, S. K. Exceptional response to pazopanib in a patient with urothelial carcinoma harboring FGFR3 activating mutation and amplification. Eur. Urol. 68, 168–170 (2015).
Ghosh, M., Brancato, S. J., Agarwal, P. K. & Apolo, A. B. Targeted therapies in urothelial carcinoma. Curr. Opin. Oncol. 26, 305–320 (2014).
Iyer, G. et al. Genome sequencing identifies a basis for everolimus sensitivity. Science 338, 221 (2012).
Wagle, N. et al. Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov. 4, 546–553 (2014).
Al-Ahmadie, H. et al. Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy. Cancer Discov. 4, 1014–1021 (2014).
Kurtoglu, M. et al. Elevating the horizon: emerging molecular and genomic targets in the treatment of advanced urothelial carcinoma. Clin. Genitourin. Cancer 13, 410–420 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02465060? (2016).
Cancer Research UK Clinical Trials Unit Glasgow. ATLANTIS: an adaptive multi-arm phase II trial of maintenance targeted therapy after chemotherapy in metastatic urothelial cancer. CRUKCTUGlasgow http://www.crukctuglasgow.org/eng.php?pid=atlantis (2016).
World Health Organization International Clinical Trials Registry Platform. An adaptive multi-arm phase II trial of maintenance targeted therapy after chemotherapy in metastatic urothelial cancer. WHO http://apps.who.int/trialsearch/Trial2.aspx?TrialID=ISRCTN25859465(2016).
ECOG-ACRIN Cancer Research Group. Executive summary: interim analysis of the NCI-MATCH trial. ECOG-ACRIN http://ecog-acrin.org/nci-match-eay131/interim-analysis (2016).
Acknowledgements
The results shown here are in part based upon data generated by the TCGA Research Network:https://cancergenome.nih.gov. J.J.M. is funded by a Veterans Health Administration Merit grant BX0033692-01
Author information
Authors and Affiliations
Contributions
A.P.G., D.F., E.M.S. and J.J.M. researched data for the article. A.P.G., D.F. and J.J.M. made substantial contributions to discussion of content and wrote the manuscript and all authors reviewed and edited the article before submisission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
FURTHER INFORMATION
Glossary
- Epigenetic
-
Any non-nucleotide alteration that effects gene expression by altering DNA. This can include methylation, histone modification, or chromatin condensation.
- Next-generation sequencing
-
(NGS). Refers to multiple high-throughput, scalable technologies used to sequence DNA and RNA.
- The Cancer Genome Atlas
-
(TCGA). A collaboration between the National Cancer Institute and National Human Genome Research Institute to evaluate the cancer mutations of 33 different tumours.
- Muscle-invasive bladder cancer
-
(MIBC). Cancers that invade the muscle (Stage ≥T2).
- Non-muscle-invasive bladder cancer
-
(NMIBC). Tumours that do not invade the muscle (Stage Tis, Ta, T1).
- Apolipoprotein B mRNA editing enzyme catalytic polypeptide
-
(APOBEC). An enzyme family that is involved in single-stranded DNA C>U deamination that cause a hypermutation phenotype.
Rights and permissions
About this article
Cite this article
Glaser, A., Fantini, D., Shilatifard, A. et al. The evolving genomic landscape of urothelial carcinoma. Nat Rev Urol 14, 215–229 (2017). https://doi.org/10.1038/nrurol.2017.11
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrurol.2017.11
This article is cited by
-
High expression of ABCF1 is an independent predictor of poor prognosis in bladder cancer
BMC Urology (2023)
-
Multi-omics analysis reveals critical metabolic regulators in bladder cancer
International Urology and Nephrology (2023)
-
Causal relationship between smoking status, smoking frequency and bladder cancer: a Mendelian randomization study
Genes & Genomics (2023)
-
Whole-exome sequencing identified mutational profiles of urothelial carcinoma post kidney transplantation
Journal of Translational Medicine (2022)
-
Diagnostische und prädiktive Marker in der Harntraktzytologie
Der Pathologe (2022)