Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma

Jianing Xu; Ed Reznik; Ho Joon Lee; Gunes Gundem; Philip Jonsson; Judy Sarungbam; Anna Bialik; Francisco Sanchez-Vega; Chad J. Creighton; Jake Hoekstra; Li Zhang; Peter Sajjakulnukit; Daniel Kremer; Zachary Tolstyka; Jozefina Casuscelli; Steve Stirdivant; Jie Tang; Nikolaus Schultz; Paul Jeng; Yiyu Dong; Wenjing Su; Emily H. Cheng; Paul Russo; Jonathan A. Coleman; Elli Papaemmanui; Ying Bei Chen; Victor E. Reuter; Chris Sander; Scott R. Kennedy; James J. Hsieh; Costas A. Lyssiotis; Satish K. Tickoo; A. Ari Hakimi

doi:10.7554/eLife.38986

Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma

Jianing Xu, Ed Reznik, Ho Joon Lee, Gunes Gundem, Philip Jonsson, Judy Sarungbam, Anna Bialik, Francisco Sanchez-Vega, Chad J. Creighton, Jake Hoekstra, Li Zhang, Peter Sajjakulnukit, Daniel Kremer, Zachary Tolstyka, Jozefina Casuscelli, Steve Stirdivant, Jie Tang, Nikolaus Schultz, Paul Jeng, Yiyu DongWenjing Su, Emily H. Cheng, Paul Russo, Jonathan A. Coleman, Elli Papaemmanui, Ying Bei Chen, Victor E. Reuter, Chris Sander, Scott R. Kennedy, James J. Hsieh, Costas A. Lyssiotis, Satish K. Tickoo, A. Ari Hakimi

Pathology

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

While genomic sequencing routinely identifies oncogenic alterations for the majority of cancers, many tumors harbor no discernable driver lesion. Here, we describe the exceptional molecular phenotype of a genomically quiet kidney tumor, clear cell papillary renal cell carcinoma (CCPAP). In spite of a largely wild-type nuclear genome, CCPAP tumors exhibit severe depletion of mitochondrial DNA (mtDNA) and RNA and high levels of oxidative stress, reflecting a shift away from respiratory metabolism. Moreover, CCPAP tumors exhibit a distinct metabolic phenotype uniquely characterized by accumulation of the sugar alcohol sorbitol. Immunohistochemical staining of primary CCPAP tumor specimens recapitulates both the depletion of mtDNA-encoded proteins and a lipid-depleted metabolic phenotype, suggesting that the cytoplasmic clarity in CCPAP is primarily related to the presence of glycogen. These results argue for non-genetic profiling as a tool for the study of cancers of unknown driver.

Original language	English (US)
Article number	e38986
Journal	eLife
Volume	8
DOIs	https://doi.org/10.7554/eLife.38986
State	Published - Mar 2019

ASJC Scopus subject areas

Neuroscience(all)
Immunology and Microbiology(all)
Biochemistry, Genetics and Molecular Biology(all)

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Xu, J., Reznik, E., Lee, H. J., Gundem, G., Jonsson, P., Sarungbam, J., Bialik, A., Sanchez-Vega, F., Creighton, C. J., Hoekstra, J., Zhang, L., Sajjakulnukit, P., Kremer, D., Tolstyka, Z., Casuscelli, J., Stirdivant, S., Tang, J., Schultz, N., Jeng, P., ... Ari Hakimi, A. (2019). Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma. eLife, 8, [e38986]. https://doi.org/10.7554/eLife.38986

Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma. / Xu, Jianing; Reznik, Ed; Lee, Ho Joon; Gundem, Gunes; Jonsson, Philip; Sarungbam, Judy; Bialik, Anna; Sanchez-Vega, Francisco; Creighton, Chad J.; Hoekstra, Jake; Zhang, Li; Sajjakulnukit, Peter; Kremer, Daniel; Tolstyka, Zachary; Casuscelli, Jozefina; Stirdivant, Steve; Tang, Jie; Schultz, Nikolaus; Jeng, Paul; Dong, Yiyu; Su, Wenjing; Cheng, Emily H.; Russo, Paul; Coleman, Jonathan A.; Papaemmanui, Elli; Chen, Ying Bei; Reuter, Victor E.; Sander, Chris; Kennedy, Scott R.; Hsieh, James J.; Lyssiotis, Costas A.; Tickoo, Satish K.; Ari Hakimi, A.

In: eLife, Vol. 8, e38986, 03.2019.

Research output: Contribution to journal › Article › peer-review

Xu, J, Reznik, E, Lee, HJ, Gundem, G, Jonsson, P, Sarungbam, J, Bialik, A, Sanchez-Vega, F, Creighton, CJ, Hoekstra, J, Zhang, L, Sajjakulnukit, P, Kremer, D, Tolstyka, Z, Casuscelli, J, Stirdivant, S, Tang, J, Schultz, N, Jeng, P, Dong, Y, Su, W, Cheng, EH, Russo, P, Coleman, JA, Papaemmanui, E, Chen, YB, Reuter, VE, Sander, C, Kennedy, SR, Hsieh, JJ, Lyssiotis, CA, Tickoo, SK & Ari Hakimi, A 2019, 'Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma', eLife, vol. 8, e38986. https://doi.org/10.7554/eLife.38986

Xu, Jianing ; Reznik, Ed ; Lee, Ho Joon ; Gundem, Gunes ; Jonsson, Philip ; Sarungbam, Judy ; Bialik, Anna ; Sanchez-Vega, Francisco ; Creighton, Chad J. ; Hoekstra, Jake ; Zhang, Li ; Sajjakulnukit, Peter ; Kremer, Daniel ; Tolstyka, Zachary ; Casuscelli, Jozefina ; Stirdivant, Steve ; Tang, Jie ; Schultz, Nikolaus ; Jeng, Paul ; Dong, Yiyu ; Su, Wenjing ; Cheng, Emily H. ; Russo, Paul ; Coleman, Jonathan A. ; Papaemmanui, Elli ; Chen, Ying Bei ; Reuter, Victor E. ; Sander, Chris ; Kennedy, Scott R. ; Hsieh, James J. ; Lyssiotis, Costas A. ; Tickoo, Satish K. ; Ari Hakimi, A. / Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma. In: eLife. 2019 ; Vol. 8.

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title = "Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma",

abstract = "While genomic sequencing routinely identifies oncogenic alterations for the majority of cancers, many tumors harbor no discernable driver lesion. Here, we describe the exceptional molecular phenotype of a genomically quiet kidney tumor, clear cell papillary renal cell carcinoma (CCPAP). In spite of a largely wild-type nuclear genome, CCPAP tumors exhibit severe depletion of mitochondrial DNA (mtDNA) and RNA and high levels of oxidative stress, reflecting a shift away from respiratory metabolism. Moreover, CCPAP tumors exhibit a distinct metabolic phenotype uniquely characterized by accumulation of the sugar alcohol sorbitol. Immunohistochemical staining of primary CCPAP tumor specimens recapitulates both the depletion of mtDNA-encoded proteins and a lipid-depleted metabolic phenotype, suggesting that the cytoplasmic clarity in CCPAP is primarily related to the presence of glycogen. These results argue for non-genetic profiling as a tool for the study of cancers of unknown driver.",

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AU - Jonsson, Philip

AU - Sarungbam, Judy

AU - Bialik, Anna

AU - Sanchez-Vega, Francisco

AU - Creighton, Chad J.

AU - Hoekstra, Jake

AU - Zhang, Li

AU - Sajjakulnukit, Peter

AU - Kremer, Daniel

AU - Tolstyka, Zachary

AU - Casuscelli, Jozefina

AU - Stirdivant, Steve

AU - Tang, Jie

AU - Schultz, Nikolaus

AU - Jeng, Paul

AU - Dong, Yiyu

AU - Su, Wenjing

AU - Cheng, Emily H.

AU - Russo, Paul

AU - Coleman, Jonathan A.

AU - Papaemmanui, Elli

AU - Chen, Ying Bei

AU - Reuter, Victor E.

AU - Sander, Chris

AU - Kennedy, Scott R.

AU - Hsieh, James J.

AU - Lyssiotis, Costas A.

AU - Tickoo, Satish K.

AU - Ari Hakimi, A.

PY - 2019/3

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N2 - While genomic sequencing routinely identifies oncogenic alterations for the majority of cancers, many tumors harbor no discernable driver lesion. Here, we describe the exceptional molecular phenotype of a genomically quiet kidney tumor, clear cell papillary renal cell carcinoma (CCPAP). In spite of a largely wild-type nuclear genome, CCPAP tumors exhibit severe depletion of mitochondrial DNA (mtDNA) and RNA and high levels of oxidative stress, reflecting a shift away from respiratory metabolism. Moreover, CCPAP tumors exhibit a distinct metabolic phenotype uniquely characterized by accumulation of the sugar alcohol sorbitol. Immunohistochemical staining of primary CCPAP tumor specimens recapitulates both the depletion of mtDNA-encoded proteins and a lipid-depleted metabolic phenotype, suggesting that the cytoplasmic clarity in CCPAP is primarily related to the presence of glycogen. These results argue for non-genetic profiling as a tool for the study of cancers of unknown driver.

AB - While genomic sequencing routinely identifies oncogenic alterations for the majority of cancers, many tumors harbor no discernable driver lesion. Here, we describe the exceptional molecular phenotype of a genomically quiet kidney tumor, clear cell papillary renal cell carcinoma (CCPAP). In spite of a largely wild-type nuclear genome, CCPAP tumors exhibit severe depletion of mitochondrial DNA (mtDNA) and RNA and high levels of oxidative stress, reflecting a shift away from respiratory metabolism. Moreover, CCPAP tumors exhibit a distinct metabolic phenotype uniquely characterized by accumulation of the sugar alcohol sorbitol. Immunohistochemical staining of primary CCPAP tumor specimens recapitulates both the depletion of mtDNA-encoded proteins and a lipid-depleted metabolic phenotype, suggesting that the cytoplasmic clarity in CCPAP is primarily related to the presence of glycogen. These results argue for non-genetic profiling as a tool for the study of cancers of unknown driver.

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Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma

Abstract

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