The Role of SPINK1 in ETS Rearrangement-Negative Prostate Cancers

Scott A. Tomlins; Daniel R. Rhodes; Jianjun Yu; Sooryanarayana Varambally; Rohit Mehra; Sven Perner; Francesca Demichelis; Beth E. Helgeson; Bharathi Laxman; David S. Morris; Qi Cao; Xuhong Cao; Ove Andrén; Katja Fall; Laura Johnson; John T. Wei; Rajal B. Shah; Hikmat Al-Ahmadie; James A. Eastham; Scott E. Eggener; Samson W. Fine; Kristina Hotakainen; Ulf Håkan Stenman; Alex Tsodikov; William L. Gerald; Hans Lilja; Victor E. Reuter; Phillip W. Kantoff; Peter T. Scardino; Mark A. Rubin; Anders S. Bjartell; Arul M. Chinnaiyan

doi:10.1016/j.ccr.2008.04.016

The Role of SPINK1 in ETS Rearrangement-Negative Prostate Cancers

Scott A. Tomlins, Daniel R. Rhodes, Jianjun Yu, Sooryanarayana Varambally, Rohit Mehra, Sven Perner, Francesca Demichelis, Beth E. Helgeson, Bharathi Laxman, David S. Morris, Qi Cao, Xuhong Cao, Ove Andrén, Katja Fall, Laura Johnson, John T. Wei, Rajal B. Shah, Hikmat Al-Ahmadie, James A. Eastham, Scott E. EggenerSamson W. Fine, Kristina Hotakainen, Ulf Håkan Stenman, Alex Tsodikov, William L. Gerald, Hans Lilja, Victor E. Reuter, Phillip W. Kantoff, Peter T. Scardino, Mark A. Rubin, Anders S. Bjartell, Arul M. Chinnaiyan^*

^*Corresponding author for this work

Institute of Pathology

236 Citations (Scopus)

Abstract

ETS gene fusions have been characterized in a majority of prostate cancers; however, the key molecular alterations in ETS-negative cancers are unclear. Here we used an outlier meta-analysis (meta-COPA) to identify SPINK1 outlier expression exclusively in a subset of ETS rearrangement-negative cancers (∼10% of total cases). We validated the mutual exclusivity of SPINK1 expression and ETS fusion status, demonstrated that SPINK1 outlier expression can be detected noninvasively in urine, and observed that SPINK1 outlier expression is an independent predictor of biochemical recurrence after resection. We identified the aggressive 22RV1 cell line as a SPINK1 outlier expression model and demonstrate that SPINK1 knockdown in 22RV1 attenuates invasion, suggesting a functional role in ETS rearrangement-negative prostate cancers.

Original language	English
Journal	Cancer Cell
Volume	13
Issue number	6
Pages (from-to)	519-528
Number of pages	10
ISSN	1535-6108
DOIs	https://doi.org/10.1016/j.ccr.2008.04.016
Publication status	Published - 10.06.2008

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Tomlins, S. A., Rhodes, D. R., Yu, J., Varambally, S., Mehra, R., Perner, S., Demichelis, F., Helgeson, B. E., Laxman, B., Morris, D. S., Cao, Q., Cao, X., Andrén, O., Fall, K., Johnson, L., Wei, J. T., Shah, R. B., Al-Ahmadie, H., Eastham, J. A., ... Chinnaiyan, A. M. (2008). The Role of SPINK1 in ETS Rearrangement-Negative Prostate Cancers. Cancer Cell, 13(6), 519-528. https://doi.org/10.1016/j.ccr.2008.04.016

@article{8df3e3e79b8f49b99ebf7c20c3f3b5d6,

title = "The Role of SPINK1 in ETS Rearrangement-Negative Prostate Cancers",

abstract = "ETS gene fusions have been characterized in a majority of prostate cancers; however, the key molecular alterations in ETS-negative cancers are unclear. Here we used an outlier meta-analysis (meta-COPA) to identify SPINK1 outlier expression exclusively in a subset of ETS rearrangement-negative cancers (∼10% of total cases). We validated the mutual exclusivity of SPINK1 expression and ETS fusion status, demonstrated that SPINK1 outlier expression can be detected noninvasively in urine, and observed that SPINK1 outlier expression is an independent predictor of biochemical recurrence after resection. We identified the aggressive 22RV1 cell line as a SPINK1 outlier expression model and demonstrate that SPINK1 knockdown in 22RV1 attenuates invasion, suggesting a functional role in ETS rearrangement-negative prostate cancers.",

author = "Tomlins, {Scott A.} and Rhodes, {Daniel R.} and Jianjun Yu and Sooryanarayana Varambally and Rohit Mehra and Sven Perner and Francesca Demichelis and Helgeson, {Beth E.} and Bharathi Laxman and Morris, {David S.} and Qi Cao and Xuhong Cao and Ove Andr{\'e}n and Katja Fall and Laura Johnson and Wei, {John T.} and Shah, {Rajal B.} and Hikmat Al-Ahmadie and Eastham, {James A.} and Eggener, {Scott E.} and Fine, {Samson W.} and Kristina Hotakainen and Stenman, {Ulf H{\aa}kan} and Alex Tsodikov and Gerald, {William L.} and Hans Lilja and Reuter, {Victor E.} and Kantoff, {Phillip W.} and Scardino, {Peter T.} and Rubin, {Mark A.} and Bjartell, {Anders S.} and Chinnaiyan, {Arul M.}",

note = "Funding Information: The authors thank Lei Wang, Anjana Menon, Xiaojun Jing, and Elise Nilsson for excellent technical support and Jill Macoska for the 22RV1 cell line. This work was supported in part by the US Department of Defense (grant W81XWH-08-1-0031 to A.M.C.); the National Institutes of Health (grant U54 DA021519-01A1 to A.M.C. and Prostate SPORE grant P50CA69568 to A.M.C. and R.B.S.); the Early Detection Research Network (grant UO1 CA111275-01 and grant UO1 CA113913 to A.M.C. and J.T.W.); the Prostate Cancer Foundation (S.A.T.); P50-CA92629 SPORE grant from the National Cancer Institute (P.W.K. and M.A.R.); Translational Cancer Research Fellowship Award TCR/05/009/2005 from the International Union Against Cancer (UICC); European Union 6th Framework contract LSHC-CT-2004-503011 (P-Mark); the Swedish Cancer Society (Projects 4294 and 3555); the Research Fund and the Cancer Research Fund of Malm{\"o} University Hospital; the Faculty of Medicine, Lund University; the Maud and Birger Gustavsson Foundation; the Gunnar Nilsson Cancer Foundation; the Finnish Cancer Foundation; the Sigrid Juselius Foundation; the Finnish Academy of Sciences; Helsinki University Central Hospital; and the University of Helsinki. S.A.T. is supported by a GPC Biotech Young Investigator Award from the Prostate Cancer Foundation. A.M.C. is supported by a Clinical Translational Research Award from the Burroughs Wellcome Foundation. S.A.T. and D.R.R. are Fellows of the University of Michigan Medical Scientist Training Program. Copyright: Copyright 2008 Elsevier B.V., All rights reserved.",

year = "2008",

month = jun,

day = "10",

doi = "10.1016/j.ccr.2008.04.016",

language = "English",

volume = "13",

pages = "519--528",

journal = "Cancer Cell",

issn = "1535-6108",

number = "6",

}

Tomlins, SA, Rhodes, DR, Yu, J, Varambally, S, Mehra, R, Perner, S, Demichelis, F, Helgeson, BE, Laxman, B, Morris, DS, Cao, Q, Cao, X, Andrén, O, Fall, K, Johnson, L, Wei, JT, Shah, RB, Al-Ahmadie, H, Eastham, JA, Eggener, SE, Fine, SW, Hotakainen, K, Stenman, UH, Tsodikov, A, Gerald, WL, Lilja, H, Reuter, VE, Kantoff, PW, Scardino, PT, Rubin, MA, Bjartell, AS & Chinnaiyan, AM 2008, 'The Role of SPINK1 in ETS Rearrangement-Negative Prostate Cancers', Cancer Cell, vol. 13, no. 6, pp. 519-528. https://doi.org/10.1016/j.ccr.2008.04.016

TY - JOUR

T1 - The Role of SPINK1 in ETS Rearrangement-Negative Prostate Cancers

AU - Tomlins, Scott A.

AU - Rhodes, Daniel R.

AU - Yu, Jianjun

AU - Varambally, Sooryanarayana

AU - Mehra, Rohit

AU - Perner, Sven

AU - Demichelis, Francesca

AU - Helgeson, Beth E.

AU - Laxman, Bharathi

AU - Morris, David S.

AU - Cao, Qi

AU - Cao, Xuhong

AU - Andrén, Ove

AU - Fall, Katja

AU - Johnson, Laura

AU - Wei, John T.

AU - Shah, Rajal B.

AU - Al-Ahmadie, Hikmat

AU - Eastham, James A.

AU - Eggener, Scott E.

AU - Fine, Samson W.

AU - Hotakainen, Kristina

AU - Stenman, Ulf Håkan

AU - Tsodikov, Alex

AU - Gerald, William L.

AU - Lilja, Hans

AU - Reuter, Victor E.

AU - Kantoff, Phillip W.

AU - Scardino, Peter T.

AU - Rubin, Mark A.

AU - Bjartell, Anders S.

AU - Chinnaiyan, Arul M.

N1 - Funding Information: The authors thank Lei Wang, Anjana Menon, Xiaojun Jing, and Elise Nilsson for excellent technical support and Jill Macoska for the 22RV1 cell line. This work was supported in part by the US Department of Defense (grant W81XWH-08-1-0031 to A.M.C.); the National Institutes of Health (grant U54 DA021519-01A1 to A.M.C. and Prostate SPORE grant P50CA69568 to A.M.C. and R.B.S.); the Early Detection Research Network (grant UO1 CA111275-01 and grant UO1 CA113913 to A.M.C. and J.T.W.); the Prostate Cancer Foundation (S.A.T.); P50-CA92629 SPORE grant from the National Cancer Institute (P.W.K. and M.A.R.); Translational Cancer Research Fellowship Award TCR/05/009/2005 from the International Union Against Cancer (UICC); European Union 6th Framework contract LSHC-CT-2004-503011 (P-Mark); the Swedish Cancer Society (Projects 4294 and 3555); the Research Fund and the Cancer Research Fund of Malmö University Hospital; the Faculty of Medicine, Lund University; the Maud and Birger Gustavsson Foundation; the Gunnar Nilsson Cancer Foundation; the Finnish Cancer Foundation; the Sigrid Juselius Foundation; the Finnish Academy of Sciences; Helsinki University Central Hospital; and the University of Helsinki. S.A.T. is supported by a GPC Biotech Young Investigator Award from the Prostate Cancer Foundation. A.M.C. is supported by a Clinical Translational Research Award from the Burroughs Wellcome Foundation. S.A.T. and D.R.R. are Fellows of the University of Michigan Medical Scientist Training Program. Copyright: Copyright 2008 Elsevier B.V., All rights reserved.

PY - 2008/6/10

Y1 - 2008/6/10

N2 - ETS gene fusions have been characterized in a majority of prostate cancers; however, the key molecular alterations in ETS-negative cancers are unclear. Here we used an outlier meta-analysis (meta-COPA) to identify SPINK1 outlier expression exclusively in a subset of ETS rearrangement-negative cancers (∼10% of total cases). We validated the mutual exclusivity of SPINK1 expression and ETS fusion status, demonstrated that SPINK1 outlier expression can be detected noninvasively in urine, and observed that SPINK1 outlier expression is an independent predictor of biochemical recurrence after resection. We identified the aggressive 22RV1 cell line as a SPINK1 outlier expression model and demonstrate that SPINK1 knockdown in 22RV1 attenuates invasion, suggesting a functional role in ETS rearrangement-negative prostate cancers.

AB - ETS gene fusions have been characterized in a majority of prostate cancers; however, the key molecular alterations in ETS-negative cancers are unclear. Here we used an outlier meta-analysis (meta-COPA) to identify SPINK1 outlier expression exclusively in a subset of ETS rearrangement-negative cancers (∼10% of total cases). We validated the mutual exclusivity of SPINK1 expression and ETS fusion status, demonstrated that SPINK1 outlier expression can be detected noninvasively in urine, and observed that SPINK1 outlier expression is an independent predictor of biochemical recurrence after resection. We identified the aggressive 22RV1 cell line as a SPINK1 outlier expression model and demonstrate that SPINK1 knockdown in 22RV1 attenuates invasion, suggesting a functional role in ETS rearrangement-negative prostate cancers.

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U2 - 10.1016/j.ccr.2008.04.016

DO - 10.1016/j.ccr.2008.04.016

M3 - Journal articles

C2 - 18538735

AN - SCOPUS:44449139593

SN - 1535-6108

VL - 13

SP - 519

EP - 528

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

The Role of SPINK1 in ETS Rearrangement-Negative Prostate Cancers

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