Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma.
Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma.
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DOI：
10.1056/nejmoa1505917
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发表时间：
2016-01-14
期刊：
影响因子：
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通讯作者：
Zuna R
中科院分区：
文献类型：
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作者：
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
乳头状肾细胞癌占肾细胞癌的15%，是一种异质性疾病，由不同类型的肾癌组成，包括惰性、多灶性表现的肿瘤和具有侵袭性、高致死性表型的孤立性肿瘤。关于散发性乳头状肾细胞癌的遗传基础知之甚少，对于晚期疾病没有有效的治疗方法。我们利用全外显子组测序、拷贝数、mRNA、microRNA、甲基化和蛋白质组学分析对161例原发性乳头状肾细胞癌进行了全面的分子表征。发现1型和2型乳头状肾细胞癌是以特定遗传改变为特征的不同类型的肾癌，2型根据影响患者生存的分子差异进一步分为三个单独的亚组。MET改变与1型肿瘤相关，而2型肿瘤的特征在于CDKN 2A沉默、SETD 2突变、TFE 3融合和NRF 2-ARE途径表达增加。CpG岛甲基化表型（CIMP）在2型乳头状肾细胞癌的一个独特的子集中被发现，其特征是生存率低和富马酸水合酶（FH）基因突变。1型和2型乳头状肾细胞癌在临床和生物学上是不同的。MET通路的改变与1型相关，NRF 2-ARE通路的激活与2型相关; 2型中的CDKN 2A缺失和CIMP表达不良预后。此外，根据分子和表型特征，2型乳头状肾细胞癌由至少3种亚型组成。
Papillary renal cell carcinoma, accounting for 15% of renal cell carcinoma, is a heterogeneous disease consisting of different 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; no effective forms of therapy for advanced disease exist. We performed comprehensive molecular characterization utilizing whole-exome sequencing, copy number, mRNA, microRNA, methylation and proteomic analyses of 161 primary papillary renal cell carcinomas. Type 1 and Type 2 papillary renal cell carcinomas were found to be different types of renal cancer characterized by specific genetic alterations, with Type 2 further classified into three individual subgroups based on molecular differences that influenced patient survival. MET alterations were associated with Type 1 tumors, whereas Type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-ARE pathway. A CpG island methylator phenotype (CIMP) was found in a distinct subset of Type 2 papillary renal cell carcinoma characterized by poor survival and mutation of the fumarate hydratase (FH) gene. Type 1 and Type 2 papillary renal cell carcinomas are clinically and biologically distinct. Alterations in the MET pathway are associated with Type 1 and activation of the NRF2-ARE pathway with Type 2; CDKN2A loss and CIMP in Type 2 convey a poor prognosis. Furthermore, Type 2 papillary renal cell carcinoma consists of at least 3 subtypes based upon molecular and phenotypic features.