Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status

Manuel Luedeke; Antje E. Rinckleb; Liesel M. Fitzgerald; Milan S. Geybels; Johanna Schleutker; Rosalind A. Eeles; Manuel R. Teixeira; Lisa Cannon-Albright; Elaine A. Ostrander; Steffen Weikert; Kathleen Herkommer; Tiina Wahlfors; Tapio Visakorpi; Katri A. Leinonen; Teuvo L. J. Tammela; Colin S. Cooper; Zsofia Kote-Jarai; Sandra Edwards; Chee L. Goh; Frank McCarthy; Chris Parker; Penny Flohr; Paula Paulo; Carmen Jerónimo; Rui Henrique; Hans Krause; Sven Wach; Verena Lieb; Tilman T. Rau; Walther Vogel; Rainer Kuefer; Matthias D. Hofer; Sven Perner; Mark A. Rubin; Archana M. Agarwal; Doug F. Easton; Ali Amin Al Olama; Sara Benlloch; The PRACTICAL consortium; Josef Hoegel; Janet L Stanford; Christiane Maier

doi:10.1093/hmg/ddw349

Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status

Manuel Luedeke, Antje E. Rinckleb, Liesel M. Fitzgerald, Milan S. Geybels, Johanna Schleutker, Rosalind A. Eeles, Manuel R. Teixeira, Lisa Cannon-Albright, Elaine A. Ostrander, Steffen Weikert, Kathleen Herkommer, Tiina Wahlfors, Tapio Visakorpi, Katri A. Leinonen, Teuvo L. J. Tammela, Colin S. Cooper, Zsofia Kote-Jarai, Sandra Edwards, Chee L. Goh, Frank McCarthyChris Parker, Penny Flohr, Paula Paulo, Carmen Jerónimo, Rui Henrique, Hans Krause, Sven Wach, Verena Lieb, Tilman T. Rau, Walther Vogel, Rainer Kuefer, Matthias D. Hofer, Sven Perner, Mark A. Rubin, Archana M. Agarwal, Doug F. Easton, Ali Amin Al Olama, Sara Benlloch, The PRACTICAL consortium, Josef Hoegel, Janet L Stanford, Christiane Maier

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Abstract

Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer (PrCa). Assuming two molecularly distinct subtypes, we have examined 27 common PrCa risk variants, previously identified in genome-wide association studies, for subtype specific associations in a total of 1,221 TMPRSS2:ERG phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with TMPRSS2:ERG data and 7,650 unaffected men from five centers we have found support for the hypothesis that several common risk variants are associated with one particular subtype rather than with PrCa in general. Risk variants were analyzed in case-case comparisons (296 TMPRSS2:ERG fusion-positive versus 256 fusion-negative cases) and an independent set of 669 cases with TMPRSS2:ERG data was established to replicate the top five candidates. Significant differences (p < 0.00185) between the two subtypes were observed for rs16901979 (8q24) and rs1859962 (17q24), which were enriched in TMPRSS2:ERG fusion-negative (OR = 0.53, p = 0.0007) and TMPRSS2:ERG fusion-positive PrCa (OR = 1.30, p = 0.0016), respectively. Expression quantitative trait locus analysis was performed to investigate mechanistic links between risk variants, fusion status and target gene mRNA levels. For rs1859962 at 17q24, genotype dependent expression was observed for the candidate target gene SOX9 in TMPRSS2:ERG fusion-positive PrCa, which was not evident in TMPRSS2:ERG negative tumors. The present study established evidence for the first two common PrCa risk variants differentially associated with TMPRSS2:ERG fusion status. TMPRSS2:ERG phenotyping of larger studies is required to determine comprehensive sets of variants with subtype-specific roles in PrCa.

Original language	English
Pages (from-to)	5490-5499
Number of pages	10
Journal	Human Molecular Genetics
Volume	25
Issue number	24
Early online date	18 Oct 2016
DOIs	https://doi.org/10.1093/hmg/ddw349
Publication status	Published - 15 Dec 2016

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Luedeke, M., Rinckleb, A. E., Fitzgerald, L. M., Geybels, M. S., Schleutker, J., Eeles, R. A., Teixeira, M. R., Cannon-Albright, L., Ostrander, E. A., Weikert, S., Herkommer, K., Wahlfors, T., Visakorpi, T., Leinonen, K. A., Tammela, T. L. J., Cooper, C. S., Kote-Jarai, Z., Edwards, S., Goh, C. L., ... Maier, C. (2016). Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status. Human Molecular Genetics, 25(24), 5490-5499. https://doi.org/10.1093/hmg/ddw349

Luedeke, Manuel ; Rinckleb, Antje E. ; Fitzgerald, Liesel M. ; Geybels, Milan S. ; Schleutker, Johanna ; Eeles, Rosalind A. ; Teixeira, Manuel R. ; Cannon-Albright, Lisa ; Ostrander, Elaine A. ; Weikert, Steffen ; Herkommer, Kathleen ; Wahlfors, Tiina ; Visakorpi, Tapio ; Leinonen, Katri A. ; Tammela, Teuvo L. J. ; Cooper, Colin S. ; Kote-Jarai, Zsofia ; Edwards, Sandra ; Goh, Chee L. ; McCarthy, Frank ; Parker, Chris ; Flohr, Penny ; Paulo, Paula ; Jerónimo, Carmen ; Henrique, Rui ; Krause, Hans ; Wach, Sven ; Lieb, Verena ; Rau, Tilman T. ; Vogel, Walther ; Kuefer, Rainer ; Hofer, Matthias D. ; Perner, Sven ; Rubin, Mark A. ; Agarwal, Archana M. ; Easton, Doug F. ; Amin Al Olama, Ali ; Benlloch, Sara ; The PRACTICAL consortium ; Hoegel, Josef ; Stanford, Janet L ; Maier, Christiane. / Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 24. pp. 5490-5499.

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title = "Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status",

abstract = "Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer (PrCa). Assuming two molecularly distinct subtypes, we have examined 27 common PrCa risk variants, previously identified in genome-wide association studies, for subtype specific associations in a total of 1,221 TMPRSS2:ERG phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with TMPRSS2:ERG data and 7,650 unaffected men from five centers we have found support for the hypothesis that several common risk variants are associated with one particular subtype rather than with PrCa in general. Risk variants were analyzed in case-case comparisons (296 TMPRSS2:ERG fusion-positive versus 256 fusion-negative cases) and an independent set of 669 cases with TMPRSS2:ERG data was established to replicate the top five candidates. Significant differences (p < 0.00185) between the two subtypes were observed for rs16901979 (8q24) and rs1859962 (17q24), which were enriched in TMPRSS2:ERG fusion-negative (OR = 0.53, p = 0.0007) and TMPRSS2:ERG fusion-positive PrCa (OR = 1.30, p = 0.0016), respectively. Expression quantitative trait locus analysis was performed to investigate mechanistic links between risk variants, fusion status and target gene mRNA levels. For rs1859962 at 17q24, genotype dependent expression was observed for the candidate target gene SOX9 in TMPRSS2:ERG fusion-positive PrCa, which was not evident in TMPRSS2:ERG negative tumors. The present study established evidence for the first two common PrCa risk variants differentially associated with TMPRSS2:ERG fusion status. TMPRSS2:ERG phenotyping of larger studies is required to determine comprehensive sets of variants with subtype-specific roles in PrCa.",

author = "Manuel Luedeke and Rinckleb, {Antje E.} and Fitzgerald, {Liesel M.} and Geybels, {Milan S.} and Johanna Schleutker and Eeles, {Rosalind A.} and Teixeira, {Manuel R.} and Lisa Cannon-Albright and Ostrander, {Elaine A.} and Steffen Weikert and Kathleen Herkommer and Tiina Wahlfors and Tapio Visakorpi and Leinonen, {Katri A.} and Tammela, {Teuvo L. J.} and Cooper, {Colin S.} and Zsofia Kote-Jarai and Sandra Edwards and Goh, {Chee L.} and Frank McCarthy and Chris Parker and Penny Flohr and Paula Paulo and Carmen Jer{\'o}nimo and Rui Henrique and Hans Krause and Sven Wach and Verena Lieb and Rau, {Tilman T.} and Walther Vogel and Rainer Kuefer and Hofer, {Matthias D.} and Sven Perner and Rubin, {Mark A.} and Agarwal, {Archana M.} and Easton, {Doug F.} and {Amin Al Olama}, Ali and Sara Benlloch and {The PRACTICAL consortium} and Josef Hoegel and Stanford, {Janet L} and Christiane Maier",

year = "2016",

month = dec,

day = "15",

doi = "10.1093/hmg/ddw349",

language = "English",

volume = "25",

pages = "5490--5499",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "24",

}

Luedeke, M, Rinckleb, AE, Fitzgerald, LM, Geybels, MS, Schleutker, J, Eeles, RA, Teixeira, MR, Cannon-Albright, L, Ostrander, EA, Weikert, S, Herkommer, K, Wahlfors, T, Visakorpi, T, Leinonen, KA, Tammela, TLJ, Cooper, CS, Kote-Jarai, Z, Edwards, S, Goh, CL, McCarthy, F, Parker, C, Flohr, P, Paulo, P, Jerónimo, C, Henrique, R, Krause, H, Wach, S, Lieb, V, Rau, TT, Vogel, W, Kuefer, R, Hofer, MD, Perner, S, Rubin, MA, Agarwal, AM, Easton, DF, Amin Al Olama, A, Benlloch, S, The PRACTICAL consortium, Hoegel, J, Stanford, JL & Maier, C 2016, 'Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status', Human Molecular Genetics, vol. 25, no. 24, pp. 5490-5499. https://doi.org/10.1093/hmg/ddw349

Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status. / Luedeke, Manuel; Rinckleb, Antje E.; Fitzgerald, Liesel M.; Geybels, Milan S.; Schleutker, Johanna; Eeles, Rosalind A.; Teixeira, Manuel R.; Cannon-Albright, Lisa; Ostrander, Elaine A.; Weikert, Steffen; Herkommer, Kathleen; Wahlfors, Tiina; Visakorpi, Tapio; Leinonen, Katri A.; Tammela, Teuvo L. J.; Cooper, Colin S.; Kote-Jarai, Zsofia; Edwards, Sandra; Goh, Chee L.; McCarthy, Frank; Parker, Chris; Flohr, Penny; Paulo, Paula; Jerónimo, Carmen; Henrique, Rui; Krause, Hans; Wach, Sven; Lieb, Verena; Rau, Tilman T.; Vogel, Walther; Kuefer, Rainer; Hofer, Matthias D.; Perner, Sven; Rubin, Mark A.; Agarwal, Archana M.; Easton, Doug F.; Amin Al Olama, Ali; Benlloch, Sara; The PRACTICAL consortium; Hoegel, Josef; Stanford, Janet L; Maier, Christiane.

In: Human Molecular Genetics, Vol. 25, No. 24, 15.12.2016, p. 5490-5499.

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

TY - JOUR

T1 - Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status

AU - Luedeke, Manuel

AU - Rinckleb, Antje E.

AU - Fitzgerald, Liesel M.

AU - Geybels, Milan S.

AU - Schleutker, Johanna

AU - Eeles, Rosalind A.

AU - Teixeira, Manuel R.

AU - Cannon-Albright, Lisa

AU - Ostrander, Elaine A.

AU - Weikert, Steffen

AU - Herkommer, Kathleen

AU - Wahlfors, Tiina

AU - Visakorpi, Tapio

AU - Leinonen, Katri A.

AU - Tammela, Teuvo L. J.

AU - Cooper, Colin S.

AU - Kote-Jarai, Zsofia

AU - Edwards, Sandra

AU - Goh, Chee L.

AU - McCarthy, Frank

AU - Parker, Chris

AU - Flohr, Penny

AU - Paulo, Paula

AU - Jerónimo, Carmen

AU - Henrique, Rui

AU - Krause, Hans

AU - Wach, Sven

AU - Lieb, Verena

AU - Rau, Tilman T.

AU - Vogel, Walther

AU - Kuefer, Rainer

AU - Hofer, Matthias D.

AU - Perner, Sven

AU - Rubin, Mark A.

AU - Agarwal, Archana M.

AU - Easton, Doug F.

AU - Amin Al Olama, Ali

AU - Benlloch, Sara

AU - The PRACTICAL consortium

AU - Hoegel, Josef

AU - Stanford, Janet L

AU - Maier, Christiane

PY - 2016/12/15

Y1 - 2016/12/15

N2 - Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer (PrCa). Assuming two molecularly distinct subtypes, we have examined 27 common PrCa risk variants, previously identified in genome-wide association studies, for subtype specific associations in a total of 1,221 TMPRSS2:ERG phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with TMPRSS2:ERG data and 7,650 unaffected men from five centers we have found support for the hypothesis that several common risk variants are associated with one particular subtype rather than with PrCa in general. Risk variants were analyzed in case-case comparisons (296 TMPRSS2:ERG fusion-positive versus 256 fusion-negative cases) and an independent set of 669 cases with TMPRSS2:ERG data was established to replicate the top five candidates. Significant differences (p < 0.00185) between the two subtypes were observed for rs16901979 (8q24) and rs1859962 (17q24), which were enriched in TMPRSS2:ERG fusion-negative (OR = 0.53, p = 0.0007) and TMPRSS2:ERG fusion-positive PrCa (OR = 1.30, p = 0.0016), respectively. Expression quantitative trait locus analysis was performed to investigate mechanistic links between risk variants, fusion status and target gene mRNA levels. For rs1859962 at 17q24, genotype dependent expression was observed for the candidate target gene SOX9 in TMPRSS2:ERG fusion-positive PrCa, which was not evident in TMPRSS2:ERG negative tumors. The present study established evidence for the first two common PrCa risk variants differentially associated with TMPRSS2:ERG fusion status. TMPRSS2:ERG phenotyping of larger studies is required to determine comprehensive sets of variants with subtype-specific roles in PrCa.

AB - Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer (PrCa). Assuming two molecularly distinct subtypes, we have examined 27 common PrCa risk variants, previously identified in genome-wide association studies, for subtype specific associations in a total of 1,221 TMPRSS2:ERG phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with TMPRSS2:ERG data and 7,650 unaffected men from five centers we have found support for the hypothesis that several common risk variants are associated with one particular subtype rather than with PrCa in general. Risk variants were analyzed in case-case comparisons (296 TMPRSS2:ERG fusion-positive versus 256 fusion-negative cases) and an independent set of 669 cases with TMPRSS2:ERG data was established to replicate the top five candidates. Significant differences (p < 0.00185) between the two subtypes were observed for rs16901979 (8q24) and rs1859962 (17q24), which were enriched in TMPRSS2:ERG fusion-negative (OR = 0.53, p = 0.0007) and TMPRSS2:ERG fusion-positive PrCa (OR = 1.30, p = 0.0016), respectively. Expression quantitative trait locus analysis was performed to investigate mechanistic links between risk variants, fusion status and target gene mRNA levels. For rs1859962 at 17q24, genotype dependent expression was observed for the candidate target gene SOX9 in TMPRSS2:ERG fusion-positive PrCa, which was not evident in TMPRSS2:ERG negative tumors. The present study established evidence for the first two common PrCa risk variants differentially associated with TMPRSS2:ERG fusion status. TMPRSS2:ERG phenotyping of larger studies is required to determine comprehensive sets of variants with subtype-specific roles in PrCa.

U2 - 10.1093/hmg/ddw349

DO - 10.1093/hmg/ddw349

M3 - Article

VL - 25

SP - 5490

EP - 5499

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 24

ER -