Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets

Ying Bei Chen; Jianing Xu; Anders Jacobsen Skanderup; Yiyu Dong; A. Rose Brannon; Lu Wang; Helen H. Won; Patricia I. Wang; Gouri J. Nanjangud; Achim A. Jungbluth; Wei Li; Virginia Ojeda; A. Ari Hakimi; Martin H. Voss; Nikolaus Schultz; Robert J. Motzer; Paul Russo; Emily H. Cheng; Filippo G. Giancotti; William Lee; Michael F. Berger; Satish K. Tickoo; Victor E. Reuter; James J. Hsieh

doi:10.1038/ncomms13131

Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets

Ying Bei Chen, Jianing Xu, Anders Jacobsen Skanderup, Yiyu Dong, A. Rose Brannon, Lu Wang, Helen H. Won, Patricia I. Wang, Gouri J. Nanjangud, Achim A. Jungbluth, Wei Li, Virginia Ojeda, A. Ari Hakimi, Martin H. Voss, Nikolaus Schultz, Robert J. Motzer, Paul Russo, Emily H. Cheng, Filippo G. Giancotti, William LeeMichael F. Berger, Satish K. Tickoo, Victor E. Reuter, James J. Hsieh

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135 Scopus citations

Abstract

Renal cell carcinomas with unclassified histology (uRCC) constitute a significant portion of aggressive non-clear cell renal cell carcinomas that have no standard therapy. The oncogenic drivers in these tumours are unknown. Here we perform a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, single-nucleotide polymorphism array, fluorescence in situ hybridization, immunohistochemistry and cell-based assays. We identify recurrent somatic mutations in 29 genes, including NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%) and MTOR (8%). Integrated analysis reveals a subset of 26% uRCC characterized by NF2 loss, dysregulated Hippo-YAP pathway and worse survival, whereas 21% uRCC with mutations of MTOR, TSC1, TSC2 or PTEN and hyperactive mTORC1 signalling are associated with better clinical outcome. FH deficiency (6%), chromatin/DNA damage regulator mutations (21%) and ALK translocation (2%) distinguish additional cases. Altogether, this study reveals distinct molecular subsets for 76% of our uRCC cohort, which could have diagnostic and therapeutic implications.

Original language	English (US)
Article number	13131
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms13131
State	Published - Oct 7 2016

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Chen, Y. B., Xu, J., Skanderup, A. J., Dong, Y., Brannon, A. R., Wang, L., Won, H. H., Wang, P. I., Nanjangud, G. J., Jungbluth, A. A., Li, W., Ojeda, V., Hakimi, A. A., Voss, M. H., Schultz, N., Motzer, R. J., Russo, P., Cheng, E. H., Giancotti, F. G., ... Hsieh, J. J. (2016). Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets. Nature communications, 7, Article 13131. https://doi.org/10.1038/ncomms13131

Chen, YB, Xu, J, Skanderup, AJ, Dong, Y, Brannon, AR, Wang, L, Won, HH, Wang, PI, Nanjangud, GJ, Jungbluth, AA, Li, W, Ojeda, V, Hakimi, AA, Voss, MH, Schultz, N, Motzer, RJ, Russo, P, Cheng, EH, Giancotti, FG, Lee, W, Berger, MF, Tickoo, SK, Reuter, VE & Hsieh, JJ 2016, 'Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets', Nature communications, vol. 7, 13131. https://doi.org/10.1038/ncomms13131

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title = "Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets",

abstract = "Renal cell carcinomas with unclassified histology (uRCC) constitute a significant portion of aggressive non-clear cell renal cell carcinomas that have no standard therapy. The oncogenic drivers in these tumours are unknown. Here we perform a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, single-nucleotide polymorphism array, fluorescence in situ hybridization, immunohistochemistry and cell-based assays. We identify recurrent somatic mutations in 29 genes, including NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%) and MTOR (8%). Integrated analysis reveals a subset of 26% uRCC characterized by NF2 loss, dysregulated Hippo-YAP pathway and worse survival, whereas 21% uRCC with mutations of MTOR, TSC1, TSC2 or PTEN and hyperactive mTORC1 signalling are associated with better clinical outcome. FH deficiency (6%), chromatin/DNA damage regulator mutations (21%) and ALK translocation (2%) distinguish additional cases. Altogether, this study reveals distinct molecular subsets for 76% of our uRCC cohort, which could have diagnostic and therapeutic implications.",

author = "Chen, {Ying Bei} and Jianing Xu and Skanderup, {Anders Jacobsen} and Yiyu Dong and Brannon, {A. Rose} and Lu Wang and Won, {Helen H.} and Wang, {Patricia I.} and Nanjangud, {Gouri J.} and Jungbluth, {Achim A.} and Wei Li and Virginia Ojeda and Hakimi, {A. Ari} and Voss, {Martin H.} and Nikolaus Schultz and Motzer, {Robert J.} and Paul Russo and Cheng, {Emily H.} and Giancotti, {Filippo G.} and William Lee and Berger, {Michael F.} and Tickoo, {Satish K.} and Reuter, {Victor E.} and Hsieh, {James J.}",

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AU - Chen, Ying Bei

AU - Xu, Jianing

AU - Skanderup, Anders Jacobsen

AU - Dong, Yiyu

AU - Brannon, A. Rose

AU - Wang, Lu

AU - Won, Helen H.

AU - Wang, Patricia I.

AU - Nanjangud, Gouri J.

AU - Jungbluth, Achim A.

AU - Li, Wei

AU - Ojeda, Virginia

AU - Hakimi, A. Ari

AU - Voss, Martin H.

AU - Schultz, Nikolaus

AU - Motzer, Robert J.

AU - Russo, Paul

AU - Cheng, Emily H.

AU - Giancotti, Filippo G.

AU - Lee, William

AU - Berger, Michael F.

AU - Tickoo, Satish K.

AU - Reuter, Victor E.

AU - Hsieh, James J.

PY - 2016/10/7

Y1 - 2016/10/7

N2 - Renal cell carcinomas with unclassified histology (uRCC) constitute a significant portion of aggressive non-clear cell renal cell carcinomas that have no standard therapy. The oncogenic drivers in these tumours are unknown. Here we perform a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, single-nucleotide polymorphism array, fluorescence in situ hybridization, immunohistochemistry and cell-based assays. We identify recurrent somatic mutations in 29 genes, including NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%) and MTOR (8%). Integrated analysis reveals a subset of 26% uRCC characterized by NF2 loss, dysregulated Hippo-YAP pathway and worse survival, whereas 21% uRCC with mutations of MTOR, TSC1, TSC2 or PTEN and hyperactive mTORC1 signalling are associated with better clinical outcome. FH deficiency (6%), chromatin/DNA damage regulator mutations (21%) and ALK translocation (2%) distinguish additional cases. Altogether, this study reveals distinct molecular subsets for 76% of our uRCC cohort, which could have diagnostic and therapeutic implications.

AB - Renal cell carcinomas with unclassified histology (uRCC) constitute a significant portion of aggressive non-clear cell renal cell carcinomas that have no standard therapy. The oncogenic drivers in these tumours are unknown. Here we perform a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, single-nucleotide polymorphism array, fluorescence in situ hybridization, immunohistochemistry and cell-based assays. We identify recurrent somatic mutations in 29 genes, including NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%) and MTOR (8%). Integrated analysis reveals a subset of 26% uRCC characterized by NF2 loss, dysregulated Hippo-YAP pathway and worse survival, whereas 21% uRCC with mutations of MTOR, TSC1, TSC2 or PTEN and hyperactive mTORC1 signalling are associated with better clinical outcome. FH deficiency (6%), chromatin/DNA damage regulator mutations (21%) and ALK translocation (2%) distinguish additional cases. Altogether, this study reveals distinct molecular subsets for 76% of our uRCC cohort, which could have diagnostic and therapeutic implications.

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Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets

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