Spectrum of diverse genomic alterations define non-clear cell renal carcinoma

被引：302

作者：

Durinck, Steffen ^{[1
,2
]}

Stawiski, Eric W. ^{[1
,2
]}

Pavia-Jimenez, Andrea ^{[3
,4
,5
]}

Modrusan, Zora ^{[1
]}

Kapur, Payal ^{[3
,6
]}

Jaiswal, Bijay S. ^{[1
]}

Zhang, Na ^{[1
]}

Toffessi-Tcheuyap, Vanina ^{[3
,4
,5
]}

Nguyen, Thong T. ^{[1
]}

Pahuja, Kanika Bajaj ^{[1
]}

Chen, Ying-Jiun ^{[1
]}

Saleem, Sadia ^{[3
,4
]}

Chaudhuri, Subhra ^{[1
]}

Heldens, Sherry ^{[1
]}

Jackson, Marlena ^{[1
]}

Pena-Llopis, Samuel ^{[3
,4
,5
]}

Guillory, Joseph ^{[1
]}

Toy, Karen ^{[1
]}

Ha, Connie ^{[1
]}

Harris, Corissa J. ^{[1
]}

Holloman, Eboni ^{[3
,4
,5
]}

Hill, Haley M. ^{[3
,4
,5
]}

Stinson, Jeremy ^{[1
]}

Rivers, Celina Sanchez ^{[1
]}

Janakiraman, Vasantharajan ^{[1
]}

Wang, Weiru ^{[7
]}

Kinch, Lisa N. ^{[3
,8
,9
]}

Grishin, Nick V. ^{[3
,8
,9
]}

Haverty, Peter M. ^{[2
]}

Chow, Bernard ^{[1
]}

Gehring, Julian S. ^{[2
]}

Reeder, Jens ^{[2
]}

Pau, Gregoire ^{[2
]}

Wu, Thomas D. ^{[2
]}

Margulis, Vitaly ^{[3
,10
]}

Lotan, Yair ^{[3
,10
]}

Sagalowsky, Arthur ^{[3
,10
]}

Pedrosa, Ivan ^{[3
,11
,12
]}

de Sauvage, Frederic J. ^{[13
]}

Brugarolas, James ^{[3
,4
,5
]}

Seshagiri, Somasekar ^{[1
]}

机构：

[1] Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA

[2] Genentech Inc, Bioinformat & Computat Biol Dept, San Francisco, CA 94080 USA

[3] Univ Texas SW Med Ctr Dallas, Kidney Canc Program, Dallas, TX 75390 USA

[4] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA

[5] Univ Texas SW Med Ctr Dallas, Dept Dev Biol, Dallas, TX 75390 USA

[6] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA

[7] Genentech Inc, Dept Biol Struct, San Francisco, CA 94080 USA

[8] Genentech Inc, Dept Biochem, San Francisco, CA 94080 USA

[9] Howard Hughes Med Inst, Chevy Chase, MD USA

[10] Univ Texas SW Med Ctr Dallas, Dept Urol, Dallas, TX 75390 USA

[11] Univ Texas SW Med Ctr Dallas, Dept Radiol, Dallas, TX 75390 USA

[12] Univ Texas SW Med Ctr Dallas, Adv Imaging Res Ctr, Dallas, TX 75390 USA

[13] Genentech Inc, Dept Mol Oncol, San Francisco, CA 94080 USA

来源：

NATURE GENETICS | 2015年 / 47卷 / 01期

基金：

美国国家卫生研究院;

关键词：

ACTIVATED PROTEIN-KINASE; DIFFERENTIAL EXPRESSION ANALYSIS; MOLECULAR PATHOLOGY; TRANSCRIPTION FACTOR; SOMATIC MUTATIONS; MET PROTOONCOGENE; HEPATOCELLULAR-CARCINOMA; BIOCONDUCTOR PACKAGE; KIDNEY CANCER; GENE;

D O I：

10.1038/ng.3146

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

To further understand the molecular distinctions between kidney cancer subtypes, we analyzed exome, transcriptome and copy number alteration data from 167 primary human tumors that included renal oncocytomas and non-clear cell renal cell carcinomas (nccRCCs), consisting of papillary (pRCC), chromophobe (chRCC) and translocation (tRCC) subtypes. We identified ten significantly mutated genes in pRCC, including MET, NF2, SLC5A3, PNKD and CPQ. MET mutations occurred in 15% (10/65) of pRCC samples and included previously unreported recurrent activating mutations. In chRCC, we found TP53, PTEN, FAAH2, PDHB, PDXDC1 and ZNF765 to be significantly mutated. Gene expression analysis identified a five-gene set that enabled the molecular classification of chRCC, renal oncocytoma and pRCC. Using RNA sequencing, we identified previously unreported gene fusions, including ACTG1-MITF fusion. Ectopic expression of the ACTG1-MITF fusion led to cellular transformation and induced the expression of downstream target genes. Finally, we observed upregulation of the anti-apoptotic factor BIRC7 in MiTF-high RCC tumors, suggesting a potential therapeutic role for BIRC7 inhibitors.

引用

页码：13 / +

页数：12

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