Comprehensive Molecular Characterization of Urothelial Bladder Carcinoma

Overview

Journal Nature

Specialty Science

Date 2014 Jan 31

PMID 24476821

Citations 1466

Affiliations

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Abstract

Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.

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References

Samowitz W, Albertsen H, Sweeney C, Herrick J, Caan B, Anderson K . Association of smoking, CpG island methylator phenotype, and V600E BRAF mutations in colon cancer. J Natl Cancer Inst. 2006; 98(23):1731-8. DOI: 10.1093/jnci/djj468. View

Cibulskis K, Lawrence M, Carter S, Sivachenko A, Jaffe D, Sougnez C . Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013; 31(3):213-9. PMC: 3833702. DOI: 10.1038/nbt.2514. View

Nik-Zainal S, Alexandrov L, Wedge D, Van Loo P, Greenman C, Raine K . Mutational processes molding the genomes of 21 breast cancers. Cell. 2012; 149(5):979-93. PMC: 3414841. DOI: 10.1016/j.cell.2012.04.024. View

Goebell P, Knowles M . Bladder cancer or bladder cancers? Genetically distinct malignant conditions of the urothelium. Urol Oncol. 2010; 28(4):409-28. DOI: 10.1016/j.urolonc.2010.04.003. View

Lindgren D, Sjodahl G, Lauss M, Staaf J, Chebil G, Lovgren K . Integrated genomic and gene expression profiling identifies two major genomic circuits in urothelial carcinoma. PLoS One. 2012; 7(6):e38863. PMC: 3369837. DOI: 10.1371/journal.pone.0038863. View

Iyer G, Hanrahan A, Milowsky M, Al-Ahmadie H, Scott S, Janakiraman M . Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012; 338(6104):221. PMC: 3633467. DOI: 10.1126/science.1226344. View

von der Maase H, Sengelov L, Roberts J, Ricci S, Dogliotti L, Oliver T . Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005; 23(21):4602-8. DOI: 10.1200/JCO.2005.07.757. View

Shibata T, Ohta T, Tong K, Kokubu A, Odogawa R, Tsuta K . Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci U S A. 2008; 105(36):13568-73. PMC: 2533230. DOI: 10.1073/pnas.0806268105. View

Tontonoz P, Graves R, Budavari A, Erdjument-Bromage H, Lui M, Hu E . Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPAR gamma and RXR alpha. Nucleic Acids Res. 1994; 22(25):5628-34. PMC: 310126. DOI: 10.1093/nar/22.25.5628. View

10.

Lehmann A . The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases. Genes Dev. 2001; 15(1):15-23. DOI: 10.1101/gad.859501. View

11.

Ho P, Kurtova A, Chan K . Normal and neoplastic urothelial stem cells: getting to the root of the problem. Nat Rev Urol. 2012; 9(10):583-94. PMC: 3468664. DOI: 10.1038/nrurol.2012.142. View

12.

Lawrence M, Stojanov P, Polak P, Kryukov G, Cibulskis K, Sivachenko A . Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013; 499(7457):214-218. PMC: 3919509. DOI: 10.1038/nature12213. View

13.

Solomon D, Kim T, Diaz-Martinez L, Fair J, Elkahloun A, Harris B . Mutational inactivation of STAG2 causes aneuploidy in human cancer. Science. 2011; 333(6045):1039-43. PMC: 3374335. DOI: 10.1126/science.1203619. View

14.

Singh D, Chan J, Zoppoli P, Niola F, Sullivan R, Castano A . Transforming fusions of FGFR and TACC genes in human glioblastoma. Science. 2012; 337(6099):1231-5. PMC: 3677224. DOI: 10.1126/science.1220834. View

15.

Christofk H, Vander Heiden M, Harris M, Ramanathan A, Gerszten R, Wei R . The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008; 452(7184):230-3. DOI: 10.1038/nature06734. View

16.

Vaske C, Benz S, Sanborn J, Earl D, Szeto C, Zhu J . Inference of patient-specific pathway activities from multi-dimensional cancer genomics data using PARADIGM. Bioinformatics. 2010; 26(12):i237-45. PMC: 2881367. DOI: 10.1093/bioinformatics/btq182. View

17.

Hurst C, Platt F, Taylor C, Knowles M . Novel tumor subgroups of urothelial carcinoma of the bladder defined by integrated genomic analysis. Clin Cancer Res. 2012; 18(21):5865-5877. PMC: 5081094. DOI: 10.1158/1078-0432.CCR-12-1807. View

18.

Bose R, Kavuri S, Searleman A, Shen W, Shen D, Koboldt D . Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 2012; 3(2):224-37. PMC: 3570596. DOI: 10.1158/2159-8290.CD-12-0349. View

19.

Roberts S, Sterling J, Thompson C, Harris S, Mav D, Shah R . Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions. Mol Cell. 2012; 46(4):424-35. PMC: 3361558. DOI: 10.1016/j.molcel.2012.03.030. View

20.

Greulich H, Kaplan B, Mertins P, Chen T, Tanaka K, Yun C . Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2. Proc Natl Acad Sci U S A. 2012; 109(36):14476-81. PMC: 3437859. DOI: 10.1073/pnas.1203201109. View