Inter and intratumour heterogeneity: A barrier to individualized medical therapy in renal cell carcinoma?

Frontiers in Oncology

Volumn 2 MAY, Issue , 2012, Pages

  Fisher, Rosalie ^a   Larkin, James ^a   Swanton, Charles ^b  

^a ROYAL MARSDEN HOSPITAL   (United Kingdom)

^b IMPERIAL CANCER RESEARCH FUND   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA INTERFERON; AXITINIB; BEVACIZUMAB; FUMARATE HYDRATASE; HYPOXIA INDUCIBLE FACTOR; INTERLEUKIN 2; PAZOPANIB; SORAFENIB; SUCCINATE DEHYDROGENASE; SUNITINIB; TEMSIROLIMUS;

ANEUPLOIDY; CANCER RESEARCH; GENE MUTATION; GENE OVEREXPRESSION; GENERAL PATHOLOGICAL PARAMETERS; GENETIC HETEROGENEITY; HUMAN; KIDNEY CARCINOMA; NOTE; PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); SOMATIC MUTATION; TUMOR GROWTH;

EID: 84878585100     PISSN: None     EISSN: 2234943X     Source Type: Journal    
DOI: 10.3389/fonc.2012.00049     Document Type: Note

References (70)

1. Birkbak, N. J., Eklund, A. C., Li, Q., McClelland, S. E., Endesfelder, D., Tan, P., Tan, I. B., Richardson, A. L., Szallasi, Z., and Swanton, C. (2011). Paradoxical relationship between chromosomal instability and survival outcome in cancer. Cancer Res. 71, 3447-3452.
2. Bissig, H., Richter, J., Desper, R., Meier, V., Schraml, P., Schaffer, A. A., Sauter, G., Mihatsch, M. J., and Moch, H. (1999). Evaluation of the clonal relationship between primary and metastatic renal cell carcinoma by comparative genomic hybridization. Am. J. Pathol. 155, 267-274.
3. Carter, S. L., Eklund, A. C., Kohane, I. S., Harris, L. N., and Szallasi, Z. (2006). A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat. Genet. 38, 1043-1048.
4. Chapman, P. B., Hauschild, A., Robert, C., Haanen, J. B., Ascierto, P., Larkin, J., Dummer, R., Garbe, C., Testori, A., Maio, M., Hogg, D., Lorigan, P., Lebbe, C., Jouary, T., Schadendorf, D., Ribas, A., O'Day, S. J., Sosman, J. A., Kirkwood, J. M., Eggermont, A. M., Dreno, B., Nolop, K., Li, J., Nelson, B., Hou, J., Lee, R. J., Flaherty, K. T., and McArthur, G. A. (2011). Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507-2516.
5. Choueiri, T. K., Plantade, A., Elson, P., Negrier, S., Ravaud, A., Oudard, S., Zhou, M., Rini, B. I., Bukowski, R. M., and Escudier, B. (2008). Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J. Clin. Oncol. 26, 127-131.
6. Coppin, C., Porzsolt, F., Awa, A., Kumpf, J., Coldman, A., and Wilt, T. (2005). Immunotherapy for advanced renal cell cancer. Cochrane Database Syst. Rev. 1, CD001425.
7. Dalgliesh, G. L., Furge, K., Greenman, C., Chen, L., Bignell, G., Butler, A., Davies, H., Edkins, S., Hardy, C., Latimer, C., Teague, J., Andrews, J., Barthorpe, S., Beare, D., Buck, G., Campbell, P. J., Forbes, S., Jia, M., Jones, D., Knott, H., Kok, C. Y., Lau, K. W., Leroy, C., Lin, M. L., McBride, D. J., Maddison, M., Maguire, S., McLay, K., Menzies, A., Mironenko, T., Mulderrig, L., Mudie, L., O'Meara, S., Pleasance, E., Rajasingham, A., Shepherd, R., Smith, R., Stebbings, L., Stephens, P., Tang, G., Tarpey, P. S., Turrell, K., Dykema, K. J., Khoo, S. K., Petillo, D., Wondergem, B., Anema, J., Kahnoski, R. J., Teh, B. T., Stratton, M. R., and Futreal, P. A. (2010). Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360-363.
8. Del Bufalo, D., Ciuffreda, L., Trisciuoglio, D., Desideri, M., Cognetti, F., Zupi, G., and Milella, M. (2006). Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus. Cancer Res. 66, 5549-5554.
9. Escudier, B., Eisen, T., Stadler, W. M., Szczylik, C., Oudard, S., Siebels, M., Negrier, S., Chevreau, C., Solska, E., Desai, A. A., Rolland, F., Demkow, T., Hutson, T. E., Gore, M., Freeman, S., Schwartz, B., Shan, M., Simantov, R., and Bukowski, R. M. (2007a). Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med. 356, 125-134.
10. Escudier, B., Pluzanska, A., Koralewski, P., Ravaud, A., Bracarda, S., Szczylik, C., Chevreau, C., Filipek, M., Melichar, B., Bajetta, E., Gorbunova, V., Bay, J. O., Bodrogi, I., Jagiello-Gruszfeld, A., and Moore, N. (2007b). Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370, 2103-2111.
11. Fingar, D. C., Richardson, C. J., Tee, A. R., Cheatham, L., Tsou, C., and Blenis, J. (2004). mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol. Cell. Biol. 24, 200-216.
12. Fisher, R. A., Pender, A., Thillai, K., Chowdhury, S., Pickering, L. M., St. Rose, S., Gore, M. E., and Larkin, J. M. G. (2011). Observation prior to systemic therapy in patients with metastatic renal cell carcinoma in the kinase inhibitor era. J. Clin. Oncol. 29, abstr. 4630.
13. Gerlinger, M., Rowan, A., Horswell, S., Larkin, J., Endesfelder, D., Gronroos, E. P. M., Matthews, N., Stewart, A., Mcdonald, N., Butler, A., Jones, D., Raine, K., Santos, C., Varela, I., Nohadani, M., Eklund, A., Spencer-Dene, B., Clark, G., Pickering, L., Stamp, G., Gore, M., Szallasi, Z., Downward, J., Futreal, P. A., and Swanton, C. (2012). Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883-893.
14. Gerlinger, M., and Swanton, C. (2010). How Darwinian models inform therapeutic failure initiated by clonal heterogeneity in cancer medicine. Br. J. Cancer 103, 1139-1143.
15. Guo, G., Gui, Y., Gao, S., Tang, A., Hu, X., Huang, Y., Jia, W., Li, Z., He, M., Sun, L., Song, P., Sun, X., Zhao, X., Yang, S., Liang, C., Wan, S., Zhou, F., Chen, C., Zhu, J., Li, X., Jian, M., Zhou, L., Ye, R., Huang, P., Chen, J., Jiang, T., Liu, X., Wang, Y., Zou, J., Jiang, Z., Wu, R., Wu, S., Fan, F., Zhang, Z., Liu, L., Yang, R., Liu, X., Wu, H., Yin, W., Zhao, X., Liu, Y., Peng, H., Jiang, B., Feng, Q., Li, C., XIe, J., Lu, J., Kristiansen, K., Li, Y., Zhang, X., Li, S., Wang, J., Yang, H., Cai, Z., and Wang, J. (2012). Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nat. Genet. 44, 17-19.
16. Harris, D. T. (1983). Hormonal therapy and chemotherapy of renal-cell carcinoma. Semin. Oncol. 10, 422-430.
17. Hudes, G., Carducci, M., Tomczak, P., Dutcher, J., Figlin, R., Kapoor, A., Staroslawska, E., Sosman, J., McDermott, D., Bodrogi, I., Kovacevic, Z., Lesovoy, V., Schmidt-Wolf, I. G., Barbarash, O., Gokmen, E., O'Toole, T., Lustgarten, S., Moore, L., and Motzer, R. J. (2007). Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356, 2271-2281.
18. Jemal, A., Siegel, R., Xu, J., and Ward, E. (2010). Cancer statistics, 2010. CA Cancer J. Clin. 60, 277-300.
19. Jonasch, E., McCutcheon, I. E., Waguespack, S. G., Wen, S., Davis, D. W., Smith, L. A., Tannir, N. M., Gombos, D. S., Fuller, G. N., and Matin, S. F. (2011). Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease. Ann. Oncol. 22, 2661-2666.
20. Kaelin, W. G. Jr. (2007). The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma. Clin. Cancer Res. 13, 680s-684s.
21. Kim, W. Y., and Kaelin, W. G. (2004). Role of VHL gene mutation in human cancer. J. Clin. Oncol. 22, 4991-5004.
22. Krech, R. H., Baretton, G., Fonatsch, C., Diebold, J., Fruchtnicht, W., and Lohrs, U. (1990). Comparison of flow cytometric, static cytometry and tumor cytogenetic investigation results human renal cell carcinomas. Verh. Dtsch. Ges. Pathol. 74, 228-232.
23. Kwak, E. L., Bang, Y. J., Camidge, D. R., Shaw, A. T., Solomon, B., Maki, R. G., Ou, S. H., Dezube, B. J., Janne, P. A., Costa, D. B., Varella-Garcia, M., Kim, W. H., Lynch, T. J., Fidias, P., Stubbs, H., Engelman, J. A., Sequist, L. V., Tan, W., Gandhi, L., Mino-Kenudson, M., Wei, G. C., Shreeve, S. M., Ratain, M. J., Settleman, J., Christensen, J. G., Haber, D. A., Wilner, K., Salgia, R., Shapiro, G. I., Clark, J. W., and Iafrate, A. J. (2010). Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363, 1693-1703.
24. Larkin, J., Goh, X. Y., Vetter, M., Pickering, L., and Swanton, C. (2012). Epigenetic regulation in RCC: opportunities for therapeutic intervention? Nat. Rev. Urol. 9, 147-155.
25. Lee, A. J., Endesfelder, D., Rowan, A. J., Walther, A., Birkbak, N. J., Futreal, P. A., Downward, J., Szallasi, Z., Tomlinson, I. P., Howell, M., Kschischo, M., and Swanton, C. (2011). Chromosomal instability confers intrinsic multidrug resistance. Cancer Res. 71, 1858-1870.
26. Leibovich, B. C., Blute, M. L., Cheville, J. C., Lohse, C. M., Frank, I., Kwon, E. D., Weaver, A. L., Parker, A. S., and Zincke, H. (2003). Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer 97, 1663-1671.
27. Leibovich, B. C., Lohse, C. M., Crispen, P. L., Boorjian, S. A., Thompson, R. H., Blute, M. L., and Cheville, J. C. (2010). Histological subtype is an independent predictor of outcome for patients with renal cell carcinoma. J. Urol. 183, 1309-1315.
28. Ljungberg, B., Mehle, C., Stenling, R., and Roos, G. (1996). Heterogeneity in renal cell carcinoma and its impact no prognosis-a flow cytometric study. Br. J. Cancer 74, 123-127.
29. Ljungberg, B., Stenling, R., and Roos, G. (1985). DNA content in renal cell carcinoma with reference to tumor heterogeneity. Cancer 56, 503-508.
30. Lubensky, I. A., Schmidt, L., Zhuang, Z., Weirich, G., Pack, S., Zambrano, N., Walther, M. M., Choyke, P., Linehan, W. M., and Zbar, B. (1999). Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. Am. J. Pathol. 155, 517-526.
31. Maemondo, M., Inoue, A., Kobayashi, K., Sugawara, S., Oizumi, S., Isobe, H., Gemma, A., Harada, M., Yoshizawa, H., Kinoshita, I., Fujita, Y., Okinaga, S., Hirano, H., Yoshimori, K., Harada, T., Ogura, T., Ando, M., Miyazawa, H., Tanaka, T., Saijo, Y., Hagiwara, K., Morita, S., and Nukiwa, T. (2010). Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 362, 2380-2388.
32. Martignoni, G., Pea, M., Gobbo, S., Brunelli, M., Bonetti, F., Segala, D., Pan, C. C., Netto, G., Doglioni, C., Hes, O., Argani, P., and Chilosi, M. (2009). Cathepsin-K immunoreactivity distinguishes MiTF/TFE family renal translocation carcinomas from other renal carcinomas. Mod. Pathol. 22, 1016-1022.
33. Marusyk, A., and Polyak, K. (2010). Tumor heterogeneity: causes and consequences. Biochim. Biophys. Acta 1805, 105-117.
34. McClelland, S. E., Burrell, R. A., and Swanton, C. (2009). Chromosomal instability: a composite phenotype that influences sensitivity to chemotherapy. Cell Cycle 8, 3262-3266.
35. Moch, H., Presti, J. C. Jr., Sauter, G., Buchholz, N., Jordan, P., Mihatsch, M. J., and Waldman, F. M. (1996). Genetic aberrations detected by comparative genomic hybridization are associated with clinical outcome in renal cell carcinoma. Cancer Res. 56, 27-30.
36. Moch, H., Schraml, P., Bubendorf, L., Richter, J., Gasser, T. C., Mihatsch, M. J., and Sauter, G. (1998). Intratumoral heterogeneity of von Hippel-Lindau gene deletions in renal cell carcinoma detected by fluorescence in situ hybridization. Cancer Res. 58, 2304-2309.
37. Motzer, R. J., Bacik, J., Mariani, T., Russo, P., Mazumdar, M., and Reuter, V. (2002a). Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear-cell histology. J. Clin. Oncol. 20, 2376-2381.
38. Motzer, R. J., Bacik, J., Murphy, B. A., Russo, P., and Mazumdar, M. (2002b). Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J. Clin. Oncol. 20, 289-296.
39. Motzer, R. J., Bander, N. H., and Nanus, D. M. (1996). Renal-cell carcinoma. N. Engl. J. Med. 335, 865-875.
40. Motzer, R. J., Escudier, B., Oudard, S., Hutson, T. E., Porta, C., Bracarda, S., Grunwald, V., Thompson, J. A., Figlin, R. A., Hollaender, N., Kay, A., and Ravaud, A. (2010). Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 116, 4256-4265.
41. Motzer, R. J., Hutson, T. E., Tomczak, P., Michaelson, M. D., Bukowski, R. M., Rixe, O., Oudard, S., Negrier, S., Szczylik, C., Kim, S. T., Chen, I., Bycott, P. W., Baum, C. M., and Figlin, R. A. (2007). Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N. Engl. J. Med. 356, 115-124.
42. Navin, N., Kendall, J., Troge, J., Andrews, P., Rodgers, L., McIndoo, J., Cook, K., Stepansky, A., Levy, D., Esposito, D., Muthuswamy, L., Krasnitz, A., McCombie, W. R., Hicks, J., and Wigler, M. (2011). Tumour evolution inferred by single-cell sequencing. Nature 472, 90-94.
43. Nickerson, M. L., Jaeger, E., Shi, Y., Durocher, J. A., Mahurkar, S., Zaridze, D., Matveev, V., Janout, V., Kollarova, H., Bencko, V., Navratilova, M., Szeszenia-Dabrowska, N., Mates, N., Mukeria, A., Holcatova, I., Schmidt, L. S., Toro, J. R., Karami, S., Hung, R., Gerard, G. F., Linehan, W. M., Merino, M., Zbar, B., Boffetta, P., Brennan, P., Rothman, N., Chow, W.-H., Waldman, F. M., and Moore, L. E. (2008). Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin. Cancer Res. 14, 4726-4734.
44. Nickerson, M. L., Warren, M. B., Toro, J. R., Matrosova, V., Glenn, G., Turner, M. L., Duray, P., Merino, M., Choyke, P., Pavlovich, C. P., Sharma, N., Walther, M., Munroe, D., Hill, R., Maher, E., Greenberg, C., Lerman, M. I., Linehan, W. M., Zbar, B., and Schmidt, L. S. (2002). Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumours of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell 2, 157-164.
45. Pan, C. C., Chen, P. C., and Chiang, H. (2004). Overexpression of KIT (CD117) in chromophobe renal cell carcinoma and renal oncocytoma. Am. J. Clin. Pathol. 121, 878-883.
46. Plimack, E. R., Jonasch, E., Bekele, B. N., Qiao, W., Tamboli, P., Ng, C. S., and Tannir, N. M. (2010). Sunitinib in papillary renal cell carcinoma: results from a single-arm phase II study. J. Clin. Oncol. 28, abstr. 4604.
47. Reuter, V. E. (2006). The pathology of renal epithelial neoplasms. Semin. Oncol. 33, 534-543.
48. Ricketts, C., Woodward, E. R., Killick, P., Morris, M. R., Astuti, D., Latif, F., and Maher, E. R. (2008). Germline SDHB mutations and familial renal cell carcinoma. J. Natl. Cancer Inst. 100, 1260-1262.
49. Rini, B. I., Escudier, B., Tomczak, P., Kaprin, A., Hutson, T. E., Szczylik, C., Tarazi, J. C., Rosbrook, B., Kim, S., and Motzer, R. J. (2011). Axitinib versus sorafenib as second-line therapy for metastatic renal cell carcinoma: results of phase III AXIS trial. J. Clin. Oncol. 29, abstr. 4503.
50. Rini, B. I., Halabi, S., Rosenberg, J. E., Stadler, W. M., Vaena, D. A., Ou, S. S., Archer, L., Atkins, J. N., Picus, J., Czaykowski, P., Dutcher, J., and Small, E. J. (2008). Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J. Clin. Oncol. 26, 5422-5428.
51. Roylance, R., Endesfelder, D., Gorman, P., Burrell, R. A., Sander, J., Tomlinson, I., Hanby, A. M., Speirs, V., Richardson, A. L., Birkbak, N. J., Eklund, A. C., Downward, J., Kschischo, M., Szallasi, Z., and Swanton, C. (2011). Relationship of extreme chromosomal instability with long-term survival in a retrospective analysis of primary breast cancer. Cancer Epidemiol. Biomarkers Prev. 20, 2183-2194.
52. Ruiz-Cerda, J. L., Hernandez, M., Sempere, A., O'Connor, J. E., Kimler, B. F., and Jimenez-Cruz, F. (1999). Intratumoral heterogeneity of DNA content in renal cell carcinoma and its prognostic significance. Cancer 86, 664-671.
53. Schmelzle, T., and Hall, M. N. (2000). TOR, a central controller of cell growth. Cell 103, 253-262.
54. Schmidt, L., Duh, F. M., Chen, F., Kishida, T., Glenn, G., Choyke, P., Scherer, S. W., Zhuang, Z., Lubensky, I., Dean, M., Allikmets, R., Chidambaram, A., Bergerheim, U. R., Feltis, J. T., Casadevall, C., Zamarron, A., Bernues, M., Richard, S., Lips, C. J., Walther, M. M., Tsui, L. C., Geil, L., Orcutt, M. L., Stackhouse, T., Lipan, J., Slife, L., Brauch, H., Decker, J., Niehans, G., Hughson, M. D., Moch, H., Storkel, S., Lerman, M. I., Linehan, W. M., and Zbar, B. (1997). Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat. Genet. 16, 68-73.
55. Slamon, D. J., Leyland-Jones, B., Shak, S., Fuchs, H., Paton, V., Bajamonde, A., Fleming, T., Eiermann, W., Wolter, J., Pegram, M., Baselga, J., and Norton, L. (2001). Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783-792.
56. Sternberg, C. N., Davis, I. D., Mardiak, J., Szczylik, C., Lee, E., Wagstaff, J., Barrios, C. H., Salman, P., Gladkov, O. A., Kavina, A., Zarba, J. J., Chen, M., McCann, L., Pandite, L., Roychowdhury, D. F., and Hawkins, R. E. (2010). Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J. Clin. Oncol. 28, 1061-1068.
57. Swanton, C., Larkin, J. M., Gerlinger, M., Eklund, A. C., Howell, M., Stamp, G., Downward, J., Gore, M., Futreal, P. A., Escudier, B., Andre, F., Albiges, L., Beuselinck, B., Oudard, S., Hoffmann, J., Gyorffy, B., Torrance, C. J., Boehme, K. A., Volkmer, H., Toschi, L., Nicke, B., Beck, M., and Szallasi, Z. (2010). Predictive biomarker discovery through the parallel integration of clinical trial and functional genomics datasets. Genome Med. 2, 53-63.
58. Swanton, C., Nicke, B., Schuett, M., Eklund, A. C., Ng, C., Li, Q., Hardcastle, T., Lee, A., Roy, R., East, P., Kschischo, M., Endesfelder, D., Wylie, P., Kim, S. N., Chen, J. G., Howell, M., Ried, T., Habermann, J. K., Auer, G., Brenton, J. D., Szallasi, Z., and Downward, J. (2009). Chromosomal instability determines taxane response. Proc. Natl. Acad. Sci. U.S.A. 106, 8671-8676.
59. Thomas, G. V., Tran, C., Mellinghoff, I. K., Welsbie, D. S., Chan, E., Fueger, B., Czernin, J., and Sawyers, C. L. (2006). Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat. Med. 12, 122-127.
60. Toro, J. R., Nickerson, M. L., Wei, M. H., Warren, M. B., Glenn, G. M., Turner, M. L., Stewart, L., Duray, P., Tourre, O., Sharma, N., Choyke, P., Stratton, P., Merino, M., Walther, M. M., Linehan, W. M., Schmidt, L. S., and Zbar, B. (2003). Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am. J. Hum. Genet. 73, 95-106.
61. UK, C. R. (2011). Cancer Statistics. Available at: http://info.cancerresearchuk.org/cancerstats/
62. van der Hout, A. H., van den Berg, E., van der Vlies, P., Dijkhuizen, T., Storkel, S., Oosterhuis, J. W., de Jong, B., and Buys, C. H. (1993). Loss of heterozygosity at the short arm of chromosome 3 in renal-cell cancer correlates with the cytological tumour type. Int. J. Cancer 53, 353-357.
63. van Haaften, G., Dalgliesh, G. L., Davies, H., Chen, L., Bignell, G., Greenman, C., Edkins, S., Hardy, C., O'Meara, S., Teague, J., Butler, A., Hinton, J., Latimer, C., Andrews, J., Barthorpe, S., Beare, D., Buck, G., Campbell, P. J., Cole, J., Forbes, S., Jia, M., Jones, D., Kok, C. Y., Leroy, C., Lin, M. L., McBride, D. J., Maddison, M., Maquire, S., McLay, K., Menzies, A., Mironenko, T., Mulderrig, L., Mudie, L., Pleasance, E., Shepherd, R., Smith, R., Stebbings, L., Stephens, P., Tang, G., Tarpey, P. S., Turner, R., Turrell, K., Varian, J., West, S., Widaa, S., Wray, P., Collins, V. P., Ichimura, K., Law, S., Wong, J., Yuen, S. T., Leung, S. Y., Tonon, G., DePinho, R. A., Tai, Y. T., Anderson, K. C., Kahnoski, R. J., Massie, A., Khoo, S. K., Teh, B. T., Stratton, M. R., and Futreal, P. A. (2009). Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat. Genet. 41, 521-523.
64. Varela, I., Tarpey, P., Raine, K., Huang, D., Ong, C. K., Stephens, P., Davies, H., Jones, D., Lin, M. L., Teague, J., Bignell, G., Butler, A., Cho, J., Dalgliesh, G. L., Galappaththige, D., Greenman, C., Hardy, C., Jia, M., Latimer, C., Lau, K. W., Marshall, J., McLaren, S., Menzies, A., Mudie, L., Stebbings, L., Largaespada, D. A., Wessels, L. F., Richard, S., Kahnoski, R. J., Anema, J., Tuveson, D. A., Perez-Mancera, P. A., Mustonen, V., Fischer, A., Adams, D. J., Rust, A., Chan-on, W., Subimerb, C., Dykema, K., Furge, K., Campbell, P. J., Teh, B. T., Stratton, M. R., and Futreal, P. A. (2011). Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539-542.
65. Vaziri, S. A., Tavares, E. J., Golshayan, A. R., Rini, B. I., Aydin, H., Zhou, M., Sercia, L., Wood, L., Ganapathi, M. K., Bukowski, R. M., and Ganapathi, R. (2012). Differing von Hippel Lindau genotype in paired primary and metastatic tumors in patients with clear cell renal cell carcinoma. Front. Oncol. 2:51. doi: 10.3389/fonc.2012.00051
66. Vickers, M. M., and Heng, D. Y. (2010). Prognostic and predictive biomarkers in renal cell carcinoma. Target Oncol. 5, 85-94.
67. Walther, A., Houlston, R., and Tomlinson, I. (2008). Association between chromosomal instability and prognosis in colorectal cancer: a meta-analysis. Gut 57, 941-950.
68. Yagoda, A., and Bander, N. H. (1989). Failure of cytotoxic chemotherapy, 1983-1988, and the emerging role of monoclonal antibodies for renal cancer. Urol. Int. 44, 338-345.
69. Yamazaki, K., Sakamoto, M., Ohta, T., Kanai, Y., Ohki, M., and Hirohashi, S. (2003). Overexpression of KIT in chromophobe renal cell carcinoma. Oncogene 22, 847-852.
70. Yusenko, M. V., Zubakov, D., and Kovacs, G. (2009). Gene expression profiling of chromophobe renal cell carcinomas and renal oncocytomas by Affymetrix GeneChip using pooled and individual tumours. Int. J. Biol. Sci. 5, 517-527.