MYC activation cooperates with Vhl and Ink4a/Arf loss to induce clear cell renal cell carcinoma

Sean T. Bailey; Aleisha M. Smith; Jordan Kardos; Sara E. Wobker; Harper L. Wilson; Bhavani Krishnan; Ryoichi Saito; Hyo Jin Lee; Jing Zhang; Samuel C. Eaton; Lindsay A. Williams; Ujjawal Manocha; Dorien J. Peters; Xinchao Pan; Thomas J. Carroll; Dean W. Felsher; Vonn Walter; Qing Zhang; Joel S. Parker; Jen Jen Yeh; Richard A. Moffitt; Janet Y. Leung; William Y. Kim

doi:10.1038/ncomms15770

MYC activation cooperates with Vhl and Ink4a/Arf loss to induce clear cell renal cell carcinoma

Sean T. Bailey, Aleisha M. Smith, Jordan Kardos, Sara E. Wobker, Harper L. Wilson, Bhavani Krishnan, Ryoichi Saito, Hyo Jin Lee, Jing Zhang, Samuel C. Eaton, Lindsay A. Williams, Ujjawal Manocha, Dorien J. Peters, Xinchao Pan, Thomas J. Carroll, Dean W. Felsher, Vonn Walter, Qing Zhang, Joel S. Parker, Jen Jen YehRichard A. Moffitt, Janet Y. Leung, William Y. Kim

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Abstract

Renal carcinoma is a common and aggressive malignancy whose histopathogenesis is incompletely understood and that is largely resistant to cytotoxic chemotherapy. We present two mouse models of kidney cancer that recapitulate the genomic alterations found in human papillary (pRCC) and clear cell RCC (ccRCC), the most common RCC subtypes. MYC activation results in highly penetrant pRCC tumours (MYC), while MYC activation, when combined with Vhl and Cdkn2a (Ink4a/Arf) deletion (VIM), produce kidney tumours that approximate human ccRCC. RNAseq of the mouse tumours demonstrate that MYC tumours resemble Type 2 pRCC, which are known to harbour MYC activation. Furthermore, VIM tumours more closely simulate human ccRCC. Based on their high penetrance, short latency, and histologic fidelity, these models of papillary and clear cell RCC should be significant contributions to the field of kidney cancer research.

Original language	English (US)
Article number	15770
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15770
State	Published - Jun 8 2017
Externally published	Yes

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Publisher Copyright:
© The Author(s) 2017.

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Bailey, S. T., Smith, A. M., Kardos, J., Wobker, S. E., Wilson, H. L., Krishnan, B., Saito, R., Lee, H. J., Zhang, J., Eaton, S. C., Williams, L. A., Manocha, U., Peters, D. J., Pan, X., Carroll, T. J., Felsher, D. W., Walter, V., Zhang, Q., Parker, J. S., ... Kim, W. Y. (2017). MYC activation cooperates with Vhl and Ink4a/Arf loss to induce clear cell renal cell carcinoma. Nature communications, 8, Article 15770. https://doi.org/10.1038/ncomms15770

Bailey, ST, Smith, AM, Kardos, J, Wobker, SE, Wilson, HL, Krishnan, B, Saito, R, Lee, HJ, Zhang, J, Eaton, SC, Williams, LA, Manocha, U, Peters, DJ, Pan, X, Carroll, TJ, Felsher, DW, Walter, V, Zhang, Q, Parker, JS, Yeh, JJ, Moffitt, RA, Leung, JY & Kim, WY 2017, 'MYC activation cooperates with Vhl and Ink4a/Arf loss to induce clear cell renal cell carcinoma', Nature communications, vol. 8, 15770. https://doi.org/10.1038/ncomms15770

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title = "MYC activation cooperates with Vhl and Ink4a/Arf loss to induce clear cell renal cell carcinoma",

abstract = "Renal carcinoma is a common and aggressive malignancy whose histopathogenesis is incompletely understood and that is largely resistant to cytotoxic chemotherapy. We present two mouse models of kidney cancer that recapitulate the genomic alterations found in human papillary (pRCC) and clear cell RCC (ccRCC), the most common RCC subtypes. MYC activation results in highly penetrant pRCC tumours (MYC), while MYC activation, when combined with Vhl and Cdkn2a (Ink4a/Arf) deletion (VIM), produce kidney tumours that approximate human ccRCC. RNAseq of the mouse tumours demonstrate that MYC tumours resemble Type 2 pRCC, which are known to harbour MYC activation. Furthermore, VIM tumours more closely simulate human ccRCC. Based on their high penetrance, short latency, and histologic fidelity, these models of papillary and clear cell RCC should be significant contributions to the field of kidney cancer research.",

author = "Bailey, {Sean T.} and Smith, {Aleisha M.} and Jordan Kardos and Wobker, {Sara E.} and Wilson, {Harper L.} and Bhavani Krishnan and Ryoichi Saito and Lee, {Hyo Jin} and Jing Zhang and Eaton, {Samuel C.} and Williams, {Lindsay A.} and Ujjawal Manocha and Peters, {Dorien J.} and Xinchao Pan and Carroll, {Thomas J.} and Felsher, {Dean W.} and Vonn Walter and Qing Zhang and Parker, {Joel S.} and Yeh, {Jen Jen} and Moffitt, {Richard A.} and Leung, {Janet Y.} and Kim, {William Y.}",

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doi = "10.1038/ncomms15770",

language = "English (US)",

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AU - Bailey, Sean T.

AU - Smith, Aleisha M.

AU - Kardos, Jordan

AU - Wobker, Sara E.

AU - Wilson, Harper L.

AU - Krishnan, Bhavani

AU - Saito, Ryoichi

AU - Lee, Hyo Jin

AU - Zhang, Jing

AU - Eaton, Samuel C.

AU - Williams, Lindsay A.

AU - Manocha, Ujjawal

AU - Peters, Dorien J.

AU - Pan, Xinchao

AU - Carroll, Thomas J.

AU - Felsher, Dean W.

AU - Walter, Vonn

AU - Zhang, Qing

AU - Parker, Joel S.

AU - Yeh, Jen Jen

AU - Moffitt, Richard A.

AU - Leung, Janet Y.

AU - Kim, William Y.

PY - 2017/6/8

Y1 - 2017/6/8

N2 - Renal carcinoma is a common and aggressive malignancy whose histopathogenesis is incompletely understood and that is largely resistant to cytotoxic chemotherapy. We present two mouse models of kidney cancer that recapitulate the genomic alterations found in human papillary (pRCC) and clear cell RCC (ccRCC), the most common RCC subtypes. MYC activation results in highly penetrant pRCC tumours (MYC), while MYC activation, when combined with Vhl and Cdkn2a (Ink4a/Arf) deletion (VIM), produce kidney tumours that approximate human ccRCC. RNAseq of the mouse tumours demonstrate that MYC tumours resemble Type 2 pRCC, which are known to harbour MYC activation. Furthermore, VIM tumours more closely simulate human ccRCC. Based on their high penetrance, short latency, and histologic fidelity, these models of papillary and clear cell RCC should be significant contributions to the field of kidney cancer research.

AB - Renal carcinoma is a common and aggressive malignancy whose histopathogenesis is incompletely understood and that is largely resistant to cytotoxic chemotherapy. We present two mouse models of kidney cancer that recapitulate the genomic alterations found in human papillary (pRCC) and clear cell RCC (ccRCC), the most common RCC subtypes. MYC activation results in highly penetrant pRCC tumours (MYC), while MYC activation, when combined with Vhl and Cdkn2a (Ink4a/Arf) deletion (VIM), produce kidney tumours that approximate human ccRCC. RNAseq of the mouse tumours demonstrate that MYC tumours resemble Type 2 pRCC, which are known to harbour MYC activation. Furthermore, VIM tumours more closely simulate human ccRCC. Based on their high penetrance, short latency, and histologic fidelity, these models of papillary and clear cell RCC should be significant contributions to the field of kidney cancer research.

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MYC activation cooperates with Vhl and Ink4a/Arf loss to induce clear cell renal cell carcinoma

Abstract

Bibliographical note

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