Novel prostate cancer susceptibility gene SP6 predisposes patients to aggressive disease

Csilla Sipeky; Teuvo L.J. Tammela; Anssi Auvinen; Johanna Schleutker

doi:10.1038/s41391-021-00378-5

Novel prostate cancer susceptibility gene SP6 predisposes patients to aggressive disease

Csilla Sipeky, Teuvo L.J. Tammela, Anssi Auvinen, Johanna Schleutker

Health Sciences

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Abstract

Prostate cancer (PrCa) is one of the most common cancers in men, but little is known about factors affecting its clinical outcomes. Genome-wide association studies have identified more than 170 germline susceptibility loci, but most of them are not associated with aggressive disease. We performed a genome-wide analysis of 185,478 SNPs in Finnish samples (2738 cases, 2400 controls) from the international Collaborative Oncological Gene-Environment Study (iCOGS) to find underlying PrCa risk variants. We identified a total of 21 common, low-penetrance susceptibility loci, including 10 novel variants independently associated with PrCa risk. Novel risk loci were located in the 8q24 (CASC8 rs16902147, OR 1.86, p_adj = 3.53 × 10⁻⁸ and rs58809953, OR 1.71, p_adj = 4.00 × 10⁻⁶; intergenic rs79012498, OR 1.81, p_adj = 4.26 × 10⁻⁸), 17q21 (SP6 rs2074187, OR 1.66, p_adj = 3.75 × 10⁻⁵), 11q13 (rs12795301, OR 1.42, p_adj = 2.89 × 10⁻⁵) and 8p21 (rs995432, OR 1.38, p_adj = 3.00 × 10⁻¹¹) regions. Here, we describe SP6, a transcription factor gene, as a new, potentially high-risk gene for PrCa. The intronic variant rs2074187 in SP6 was associated not only with overall susceptibility to PrCa (OR 1.66) but also with a higher odds ratio for aggressive PrCa (OR 1.89) and lower odds for non-aggressive PrCa (OR 1.43). Furthermore, the new intergenic variant rs79012498 at 8q24 conferred risk for aggressive PrCa. Our findings highlighted the power of a population-stratified approach to identify novel, clinically actionable germline PrCa risk loci and strongly suggested SP6 as a new PrCa candidate gene that may be involved in the pathogenesis of PrCa.

Original language	English
Journal	Prostate Cancer and Prostatic Diseases
Volume	24
Issue number	4
DOIs	https://doi.org/10.1038/s41391-021-00378-5
Publication status	Published - 2021
Publication type	A1 Journal article-refereed

Funding

Acknowledgements The authors particularly thank the patients, who participated in this study. FinRSPC Study Group members are acknowledged for the FinRSPC cohort: Ulf-Håkan Stenman, Faculty of Medicine, University of Helsinki, Finland and Department of Clinical Chemistry, Helsinki University Hospital, Helsinki, Finland; Paula Kujala, Department of Pathology, Fimlab Laboratories, Tampere, Finland; Kirsi Talala Finnish Cancer Registry, Mass Screening Registry, Helsinki, Finland; Kimmo Taari Department of Urology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. We thank Dr Samuel Heron for language check. This work was financially supported by the Academy of Finland (#310105 to JS, #123054 and #260931 to AA), the Sigrid Juselius Foundation (to JS), Cancer Foundation Finland sr (to JS), Cancer Foundation Finland sr (Movember grant for prostate cancer research to AA) and State Research Funding (VTR) Turku University Hospital (#M3002 to JS) and Tampere University Hospital (grants # 9E089, 9F100, 9G096, 9H099, 9L085, 9N064 and 9R002 to TLJT). We thank the members from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium who are provided in the Supplement/footnotes. Information of the consortium can be found at http://practical.icr.ac.uk/. This study would not have been possible without the contributions of the following: Per Hall (COGS); Douglas F. Easton, Paul Pharoah, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang (BCAC), Andrew Berchuck (OCAC), Rosalind A. Eeles, Douglas F. Easton, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Georgia Chenevix-Trench, Antonis Antoniou, Lesley McGuffog, Fergus Couch and Ken Offit (CIMBA), Joe Dennis, Alison M. Dunning, Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Javier Benitez, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit, Jacques Simard and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissière and Frederic Robidoux and the staff of the McGill University and Génome Québec Innovation Centre, Stig E. Bojesen, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/ A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/ A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112—the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. Authors declare no conflicts of interest, including relevant financial interests, activities, relationships, and affiliations.

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ASJC Scopus subject areas

Oncology
Urology
Cancer Research

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Cite this

@article{8618371e77cf4981813a4d518204337e,

title = "Novel prostate cancer susceptibility gene SP6 predisposes patients to aggressive disease",

abstract = "Prostate cancer (PrCa) is one of the most common cancers in men, but little is known about factors affecting its clinical outcomes. Genome-wide association studies have identified more than 170 germline susceptibility loci, but most of them are not associated with aggressive disease. We performed a genome-wide analysis of 185,478 SNPs in Finnish samples (2738 cases, 2400 controls) from the international Collaborative Oncological Gene-Environment Study (iCOGS) to find underlying PrCa risk variants. We identified a total of 21 common, low-penetrance susceptibility loci, including 10 novel variants independently associated with PrCa risk. Novel risk loci were located in the 8q24 (CASC8 rs16902147, OR 1.86, padj = 3.53 × 10−8 and rs58809953, OR 1.71, padj = 4.00 × 10−6; intergenic rs79012498, OR 1.81, padj = 4.26 × 10−8), 17q21 (SP6 rs2074187, OR 1.66, padj = 3.75 × 10−5), 11q13 (rs12795301, OR 1.42, padj = 2.89 × 10−5) and 8p21 (rs995432, OR 1.38, padj = 3.00 × 10−11) regions. Here, we describe SP6, a transcription factor gene, as a new, potentially high-risk gene for PrCa. The intronic variant rs2074187 in SP6 was associated not only with overall susceptibility to PrCa (OR 1.66) but also with a higher odds ratio for aggressive PrCa (OR 1.89) and lower odds for non-aggressive PrCa (OR 1.43). Furthermore, the new intergenic variant rs79012498 at 8q24 conferred risk for aggressive PrCa. Our findings highlighted the power of a population-stratified approach to identify novel, clinically actionable germline PrCa risk loci and strongly suggested SP6 as a new PrCa candidate gene that may be involved in the pathogenesis of PrCa.",

author = "Csilla Sipeky and Tammela, {Teuvo L.J.} and Anssi Auvinen and Johanna Schleutker",

note = "Funding Information: Acknowledgements The authors particularly thank the patients, who participated in this study. FinRSPC Study Group members are acknowledged for the FinRSPC cohort: Ulf-H{\aa}kan Stenman, Faculty of Medicine, University of Helsinki, Finland and Department of Clinical Chemistry, Helsinki University Hospital, Helsinki, Finland; Paula Kujala, Department of Pathology, Fimlab Laboratories, Tampere, Finland; Kirsi Talala Finnish Cancer Registry, Mass Screening Registry, Helsinki, Finland; Kimmo Taari Department of Urology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. We thank Dr Samuel Heron for language check. This work was financially supported by the Academy of Finland (#310105 to JS, #123054 and #260931 to AA), the Sigrid Juselius Foundation (to JS), Cancer Foundation Finland sr (to JS), Cancer Foundation Finland sr (Movember grant for prostate cancer research to AA) and State Research Funding (VTR) Turku University Hospital (#M3002 to JS) and Tampere University Hospital (grants # 9E089, 9F100, 9G096, 9H099, 9L085, 9N064 and 9R002 to TLJT). We thank the members from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium who are provided in the Supplement/footnotes. Information of the consortium can be found at http://practical.icr.ac.uk/. This study would not have been possible without the contributions of the following: Per Hall (COGS); Douglas F. Easton, Paul Pharoah, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang (BCAC), Andrew Berchuck (OCAC), Rosalind A. Eeles, Douglas F. Easton, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Georgia Chenevix-Trench, Antonis Antoniou, Lesley McGuffog, Fergus Couch and Ken Offit (CIMBA), Joe Dennis, Alison M. Dunning, Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Javier Benitez, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit, Jacques Simard and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissi{\`e}re and Frederic Robidoux and the staff of the McGill University and G{\'e}nome Qu{\'e}bec Innovation Centre, Stig E. Bojesen, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. Funding for the iCOGS infrastructure came from: the European Community{\textquoteright}s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/ A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/ A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112—the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. Authors declare no conflicts of interest, including relevant financial interests, activities, relationships, and affiliations. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

doi = "10.1038/s41391-021-00378-5",

language = "English",

volume = "24",

number = "4",

}

TY - JOUR

T1 - Novel prostate cancer susceptibility gene SP6 predisposes patients to aggressive disease

AU - Sipeky, Csilla

AU - Tammela, Teuvo L.J.

AU - Auvinen, Anssi

AU - Schleutker, Johanna

N1 - Funding Information: Acknowledgements The authors particularly thank the patients, who participated in this study. FinRSPC Study Group members are acknowledged for the FinRSPC cohort: Ulf-Håkan Stenman, Faculty of Medicine, University of Helsinki, Finland and Department of Clinical Chemistry, Helsinki University Hospital, Helsinki, Finland; Paula Kujala, Department of Pathology, Fimlab Laboratories, Tampere, Finland; Kirsi Talala Finnish Cancer Registry, Mass Screening Registry, Helsinki, Finland; Kimmo Taari Department of Urology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. We thank Dr Samuel Heron for language check. This work was financially supported by the Academy of Finland (#310105 to JS, #123054 and #260931 to AA), the Sigrid Juselius Foundation (to JS), Cancer Foundation Finland sr (to JS), Cancer Foundation Finland sr (Movember grant for prostate cancer research to AA) and State Research Funding (VTR) Turku University Hospital (#M3002 to JS) and Tampere University Hospital (grants # 9E089, 9F100, 9G096, 9H099, 9L085, 9N064 and 9R002 to TLJT). We thank the members from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium who are provided in the Supplement/footnotes. Information of the consortium can be found at http://practical.icr.ac.uk/. This study would not have been possible without the contributions of the following: Per Hall (COGS); Douglas F. Easton, Paul Pharoah, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang (BCAC), Andrew Berchuck (OCAC), Rosalind A. Eeles, Douglas F. Easton, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Georgia Chenevix-Trench, Antonis Antoniou, Lesley McGuffog, Fergus Couch and Ken Offit (CIMBA), Joe Dennis, Alison M. Dunning, Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Javier Benitez, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit, Jacques Simard and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissière and Frederic Robidoux and the staff of the McGill University and Génome Québec Innovation Centre, Stig E. Bojesen, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/ A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/ A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112—the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. Authors declare no conflicts of interest, including relevant financial interests, activities, relationships, and affiliations. Publisher Copyright: © 2021, The Author(s).

PY - 2021

Y1 - 2021

N2 - Prostate cancer (PrCa) is one of the most common cancers in men, but little is known about factors affecting its clinical outcomes. Genome-wide association studies have identified more than 170 germline susceptibility loci, but most of them are not associated with aggressive disease. We performed a genome-wide analysis of 185,478 SNPs in Finnish samples (2738 cases, 2400 controls) from the international Collaborative Oncological Gene-Environment Study (iCOGS) to find underlying PrCa risk variants. We identified a total of 21 common, low-penetrance susceptibility loci, including 10 novel variants independently associated with PrCa risk. Novel risk loci were located in the 8q24 (CASC8 rs16902147, OR 1.86, padj = 3.53 × 10−8 and rs58809953, OR 1.71, padj = 4.00 × 10−6; intergenic rs79012498, OR 1.81, padj = 4.26 × 10−8), 17q21 (SP6 rs2074187, OR 1.66, padj = 3.75 × 10−5), 11q13 (rs12795301, OR 1.42, padj = 2.89 × 10−5) and 8p21 (rs995432, OR 1.38, padj = 3.00 × 10−11) regions. Here, we describe SP6, a transcription factor gene, as a new, potentially high-risk gene for PrCa. The intronic variant rs2074187 in SP6 was associated not only with overall susceptibility to PrCa (OR 1.66) but also with a higher odds ratio for aggressive PrCa (OR 1.89) and lower odds for non-aggressive PrCa (OR 1.43). Furthermore, the new intergenic variant rs79012498 at 8q24 conferred risk for aggressive PrCa. Our findings highlighted the power of a population-stratified approach to identify novel, clinically actionable germline PrCa risk loci and strongly suggested SP6 as a new PrCa candidate gene that may be involved in the pathogenesis of PrCa.

AB - Prostate cancer (PrCa) is one of the most common cancers in men, but little is known about factors affecting its clinical outcomes. Genome-wide association studies have identified more than 170 germline susceptibility loci, but most of them are not associated with aggressive disease. We performed a genome-wide analysis of 185,478 SNPs in Finnish samples (2738 cases, 2400 controls) from the international Collaborative Oncological Gene-Environment Study (iCOGS) to find underlying PrCa risk variants. We identified a total of 21 common, low-penetrance susceptibility loci, including 10 novel variants independently associated with PrCa risk. Novel risk loci were located in the 8q24 (CASC8 rs16902147, OR 1.86, padj = 3.53 × 10−8 and rs58809953, OR 1.71, padj = 4.00 × 10−6; intergenic rs79012498, OR 1.81, padj = 4.26 × 10−8), 17q21 (SP6 rs2074187, OR 1.66, padj = 3.75 × 10−5), 11q13 (rs12795301, OR 1.42, padj = 2.89 × 10−5) and 8p21 (rs995432, OR 1.38, padj = 3.00 × 10−11) regions. Here, we describe SP6, a transcription factor gene, as a new, potentially high-risk gene for PrCa. The intronic variant rs2074187 in SP6 was associated not only with overall susceptibility to PrCa (OR 1.66) but also with a higher odds ratio for aggressive PrCa (OR 1.89) and lower odds for non-aggressive PrCa (OR 1.43). Furthermore, the new intergenic variant rs79012498 at 8q24 conferred risk for aggressive PrCa. Our findings highlighted the power of a population-stratified approach to identify novel, clinically actionable germline PrCa risk loci and strongly suggested SP6 as a new PrCa candidate gene that may be involved in the pathogenesis of PrCa.

U2 - 10.1038/s41391-021-00378-5

DO - 10.1038/s41391-021-00378-5

M3 - Article

AN - SCOPUS:85106233964

SN - 1365-7852

VL - 24

JO - Prostate Cancer and Prostatic Diseases

JF - Prostate Cancer and Prostatic Diseases

IS - 4

ER -

Novel prostate cancer susceptibility gene SP6 predisposes patients to aggressive disease

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