Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma

Linehan, W. M., Spellman, P. T., Ricketts, C. J., Creighton, C. J., Fei, S. S., Davis, C., Wheeler, D. A., Murray, B. A., Schmidt, L., Vocke, C. D., Peto, M., Al Mamun, A. A. M., Shinbrot, E., Sethi, A., Brooks, S., Rathmell, W. K., Brooks, A. N., Hoadley, K. A., Robertson, A. G., Brooks, D., Bowlby, R., Sadeghi, S., Shen, H., Weisenberger, D. J., Bootwalla, M., Baylin, S. B., Laird, P. W., Cherniack, A. D., Saksena, G., Haake, S., Li, J., Liang, H., Lu, Y., Mills, G. B., Akbani, R., Leiserson, M. D. M., Raphael, B. J., Anur, P., Bottaro, D., Albiges, L., Barnabas, N., Choueiri, T. K., Czerniak, B., Godwin, A. K., Hakimi, A. A., Ho, T. H., Hsieh, J., Ittmann, M., Kim, W. Y., Krishnan, B., Merino, M. J., Shaw, K. R. M., Reuter, V. E., Reznik, E., Shelley, C. S., Shuch, B., Signoretti, S., Srinivasan, R., Tamboli, P., Thomas, G., Tickoo, S., Burnett, K., Crain, D., Gardner, J., Lau, K., Mallery, D., Morris, S., Paulauskis, J. D., Penny, R. J., Shelton, C., Shelton, W. T., Sherman, M., Thompson, E., Yena, P., Avedon, M. T., Bowen, J., Gastier-Foster, J. M., Gerken, M., Leraas, K. M., Lichtenberg, T. M., Ramirez, N. C., Santos, T., Wise, L., Zmuda, E., Demchok, J. A., Felau, I., Hutter, C. M., Sheth, M., Sofia, H. J., Tarnuzzer, R., Wang, Z., Yang, L., Zenklusen, J. C., Zhang, J., Ayala, B., Baboud, J., Chudamani, S., Liu, J., Lolla, L., Naresh, R., Pihl, T., Sun, Q., Wan, Y., Wu, Y., Ally, A., Balasundaram, M., Balu, S., Beroukhim, R., Bodenheimer, T., Buhay, C., Butterfield, Y. S. N., Carlsen, R., Carter, S. L., Chao, H., Chuah, E., Clarke, A., Covington, K. R., Dahdouli, M., Dewal, N., Dhalla, N., Doddapaneni, H. V., Drummond, J. A., Gabriel, S. B., Gibbs, R. A., Guin, R., Hale, W., Hawes, A., Hayes, D. N., Holt, R. A., Hoyle, A. P., Jefferys, S. R., Jones, S. J. M., Jones, C. D., Kalra, D., Kovar, C., Lewis, L., Li, J., Ma, Y., Marra, M. A., Mayo, M., Meng, S., Meyerson, M., Mieczkowski, P. A., Moore, R. A., Morton, D., Mose, L. E., Mungall, A. J., Muzny, D., Parker, J. S., Perou, C. M., Roach, J., Schein, J. E., Schumacher, S. E., Shi, Y., Simons, J. V., Sipahimalani, P., Skelly, T., Soloway, M. G., Sougnez, C., Tam, A., Tan, D., Thiessen, N., Veluvolu, U., Wang, M., Wilkerson, M. D., Wong, T., Wu, J., Xi, L., Zhou, J., Bedford, J., Chen, F., Fu, Y., Gerstein, M., Haussler, D., Kasaian, K., Lai, P., Ling, S., Radenbaugh, A., Van Den Berg, D., Weinstein, J. N., Zhu, J., Albert, M., Alexopoulou, I., Andersen, J. J., Auman, J. T., Bartlett, J., Bastacky, S., Bergsten, J., Blute, M. L., Boice, L., Bollag, R. J., Boyd, J., Castle, E., Chen, Y. B., Cheville, J. C., Curley, E., Davies, B., DeVolk, A., Dhir, R., Dike, L., Eckman, J., Engel, J., Harr, J., Hrebinko, R., Huang, M., Huelsenbeck-Dill, L., Iacocca, M., Jacobs, B., Lobis, M., Maranchie, J. K., McMeekin, S., Myers, J., Nelson, J., Parfitt, J., Parwani, A., Petrelli, N., Rabeno, B., Roy, S., Salner, A. L., Slaton, J., Stanton, M., Thompson, R. H., Thorne, L., Tucker, K., Weinberger, P. M., Winemiller, C., Zach, L. A., Zuna, R. (2016) Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. The New England Journal of Medicine, 374 (2). pp. 135-145. ISSN 1533-4406 (Electronic)

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Abstract

BACKGROUND Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist. METHODS We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis. RESULTS Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2'antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH). CONCLUSIONS Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renalcell carcinoma consisted of at least three subtypes based on molecular and phenotypic features.

Item Type:	Paper
Subjects:	diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA methylation bioinformatics > genomics and proteomics Investigative techniques and equipment > whole exome sequencing Investigative techniques and equipment > assays > whole exome sequencing
CSHL Authors:	Boyd, Jeff
Communities:	CSHL labs > Boyd lab
Depositing User:	Adrian Gomez
Date:	2016
Date Deposited:	13 Mar 2020 18:10
Last Modified:	13 Mar 2020 18:10
PMCID:	PMC4775252
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/39211

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