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N Engl J Med. 2016 Jan 14;374(2):135-45. doi: 10.1056/NEJMoa1505917. Epub 2015 Nov 4.

Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma.

Cancer Genome Atlas Research Network, Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, Davis C, Wheeler DA, Murray BA, Schmidt L, Vocke CD, Peto M, Al Mamun AA, Shinbrot E, Sethi A, Brooks S, Rathmell WK, Brooks AN, Hoadley KA, Robertson AG, Brooks D, Bowlby R, Sadeghi S, Shen H, Weisenberger DJ, Bootwalla M, Baylin SB, Laird PW, Cherniack AD, Saksena G, Haake S, Li J, Liang H, Lu Y, Mills GB, Akbani R, Leiserson MD, Raphael BJ, Anur P, Bottaro D, Albiges L, Barnabas N, Choueiri TK, Czerniak B, Godwin AK, Hakimi AA, Ho TH, Hsieh J, Ittmann M, Kim WY, Krishnan B, Merino MJ, Mills Shaw KR, Reuter VE, Reznik E, Shelley CS, 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 JD, Penny RJ, Shelton C, Shelton WT, Sherman M, Thompson E, Yena P, Avedon MT, Bowen J, Gastier-Foster JM, Gerken M, Leraas KM, Lichtenberg TM, Ramirez NC, Santos T, Wise L, Zmuda E, Demchok JA, Felau I, Hutter CM, Sheth M, Sofia HJ, Tarnuzzer R, Wang Z, Yang L, Zenklusen JC, 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 YS, Carlsen R, Carter SL, Chao H, Chuah E, Clarke A, Covington KR, Dahdouli M, Dewal N, Dhalla N, Doddapaneni HV, Drummond JA, Gabriel SB, Gibbs RA, Guin R, Hale W, Hawes A, Hayes DN, Holt RA, Hoyle AP, Jefferys SR, Jones SJ, Jones CD, Kalra D, Kovar C, Lewis L, Li J, Ma Y, Marra MA, Mayo M, Meng S, Meyerson M, Mieczkowski PA, Moore RA, Morton D, Mose LE, Mungall AJ, Muzny D, Parker JS, Perou CM, Roach J, Schein JE, Schumacher SE, Shi Y, Simons JV, Sipahimalani P, Skelly T, Soloway MG, Sougnez C, Tam A, Tan D, Thiessen N, Veluvolu U, Wang M, Wilkerson MD, 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 JN, Zhu J, Albert M, Alexopoulou I, Andersen JJ, Auman JT, Bartlett J, Bastacky S, Bergsten J, Blute ML, Boice L, Bollag RJ, Boyd J, Castle E, Chen YB, Cheville JC, 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 JK, McMeekin S, Myers J, Nelson J, Parfitt J, Parwani A, Petrelli N, Rabeno B, Roy S, Salner AL, Slaton J, Stanton M, Thompson RH, Thorne L, Tucker K, Weinberger PM, Winemiller C, Zach LA, Zuna R.

Collaborators (239)

Linehan W, Spellman PT, Creighton CJ, Ricketts CJ, Wheeler DA, Spellman PT, Murray BA, Fei SS, Davis C, Schmidt L, Vocke CD, Peto M, Al Mamun AA, Ricketts CJ, Shinbrot E, Sethi A, Wheeler DA, Brooks S, Rathmell W, Brooks AN, Hoadley KA, Creighton CJ, Robertson A, Brooks D, Bowlby R, Sadeghi S, Shen H, Weisenberger DJ, Bootwalla M, Baylin SB, Laird PW, Murray BA, Cherniack AD, Saksena G, Haake S, Li J, Liang H, Lu Y, Mills GB, Akbani R, Leiserson MD, Raphael BJ, Hoadley KA, Creighton CJ, Fei SS, Anur P, Bottaro D, Ricketts CJ, Albiges L, Barnabas N, Choueiri TK, Czerniak B, Godwin AK, Hakimi AA, Ho TH, Hsieh J, Ittmann M, Kim WY, Krishnan B, Linehan W, Merino MJ, Mills Shaw KR, Rathmell W, Reuter VE, Reznik E, Shelley CS, 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 JD, Penny RJ, Shelton C, Shelton W, Sherman M, Thompson E, Yena P, Avedon MT, Bowen J, Gastier-Foster JM, Gerken M, Leraas KM, Lichtenberg TM, Ramirez NC, Santos T, Wise L, Zmuda E, Demchok JA, Felau I, Hutter CM, Sheth M, Sofia HJ, Tarnuzzer R, Wang Z, Yang L, Zenklusen JC, Zhang JJ, 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 YS, Carlsen R, Carter SL, Chao H, Chuah E, Clarke A, Covington KR, Dahdouli M, Dewal N, Dhalla N, Doddapaneni H, Drummond JA, Gabriel SB, Gibbs RA, Guin R, Hale W, Hawes A, Hayes D, Holt RA, Hoyle AP, Jefferys SR, Jones SJ, Jones CD, Kalra D, Kovar C, Lewis L, Li J, Ma Y, Marra MA, Mayo M, Meng S, Meyerson M, Mieczkowski PA, Moore RA, Morton D, Mose LE, Mungall AJ, Muzny D, Parker JS, Perou CM, Roach J, Schein JE, Schumacher SE, Shi Y, Simons JV, Sipahimalani P, Skelly T, Soloway MG, Sougnez C, Tam A, Tan D, Thiessen N, Veluvolu U, Wang M, Wilkerson MD, 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 JN, Zhu J, Albert M, Alexopoulou I, Andersen JJ, Auman J, Bartlett J, Bastacky S, Bergsten J, Blute ML, Boice L, Bollag RJ, Boyd J, Castle E, Chen YB, Cheville JC, 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 JK, McMeekin S, Myers J, Nelson J, Parfitt J, Parwani A, Petrelli N, Rabeno B, Roy S, Salner AL, Slaton J, Stanton M, Thompson R, Thorne L, Tucker K, Weinberger PM, Winemiller C, Zach LA, Zuna R.

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 renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).

PMID:
26536169
PMCID:
PMC4775252
DOI:
10.1056/NEJMoa1505917
[Indexed for MEDLINE]
Free PMC Article

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