HOXB13 is a susceptibility gene for prostate cancer: Results from the International Consortium for Prostate Cancer Genetics (ICPCG)

Jianfeng Xu; Ethan M. Lange; Lingyi Lu; Siqun L. Zheng; Zhong Wang; Stephen N. Thibodeau; Lisa A. Cannon-Albright; Craig C. Teerlink; Nicola J. Camp; Anna M. Johnson; Kimberly A. Zuhlke; Janet L. Stanford; Elaine A. Ostrander; Kathleen E. Wiley; Sarah D. Isaacs; Patrick C. Walsh; Christiane Maier; Manuel Luedeke; Walther Vogel; Johanna Schleutker; Tiina Wahlfors; Teuvo Tammela; Daniel Schaid; Shannon K. McDonnell; Melissa S. Derycke; Geraldine Cancel-Tassin; Olivier Cussenot; Fredrik Wiklund; Henrik Grönberg; Ros Eeles; Doug Easton; Zsofia Kote-Jarai; Alice S. Whittemore; Chih Lin Hsieh; Graham G. Giles; John L. Hopper; Gianluca Severi; William J. Catalona; Diptasri Mandal; Elisa Ledet; William D. Foulkes; Nancy Hamel; Lovise Mahle; Pal Moller; Isaac Powell; Joan E. Bailey-Wilson; John D. Carpten; Daniela Seminara; Kathleen A. Cooney; William B. Isaacs

doi:10.1007/s00439-012-1229-4

HOXB13 is a susceptibility gene for prostate cancer: Results from the International Consortium for Prostate Cancer Genetics (ICPCG)

Jianfeng Xu, Ethan M. Lange, Lingyi Lu, Siqun L. Zheng, Zhong Wang, Stephen N. Thibodeau, Lisa A. Cannon-Albright, Craig C. Teerlink, Nicola J. Camp, Anna M. Johnson, Kimberly A. Zuhlke, Janet L. Stanford, Elaine A. Ostrander, Kathleen E. Wiley, Sarah D. Isaacs, Patrick C. Walsh, Christiane Maier, Manuel Luedeke, Walther Vogel, Johanna SchleutkerTiina Wahlfors, Teuvo Tammela, Daniel Schaid, Shannon K. McDonnell, Melissa S. Derycke, Geraldine Cancel-Tassin, Olivier Cussenot, Fredrik Wiklund, Henrik Grönberg, Ros Eeles, Doug Easton, Zsofia Kote-Jarai, Alice S. Whittemore, Chih Lin Hsieh, Graham G. Giles, John L. Hopper, Gianluca Severi, William J. Catalona, Diptasri Mandal, Elisa Ledet, William D. Foulkes, Nancy Hamel, Lovise Mahle, Pal Moller, Isaac Powell, Joan E. Bailey-Wilson, John D. Carpten, Daniela Seminara, Kathleen A. Cooney, William B. Isaacs^*

^*Corresponding author for this work

Urology

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

162 Scopus citations

Abstract

Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10^-8 [odds ratio 4.42 (95 % confidence interval 2.56-7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10^-6). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.

Original language	English (US)
Pages (from-to)	5-14
Number of pages	10
Journal	Human Genetics
Volume	132
Issue number	1
DOIs	https://doi.org/10.1007/s00439-012-1229-4
State	Published - Jan 2013

ASJC Scopus subject areas

Genetics(clinical)
Genetics

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s00439-012-1229-4

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Xu, J., Lange, E. M., Lu, L., Zheng, S. L., Wang, Z., Thibodeau, S. N., Cannon-Albright, L. A., Teerlink, C. C., Camp, N. J., Johnson, A. M., Zuhlke, K. A., Stanford, J. L., Ostrander, E. A., Wiley, K. E., Isaacs, S. D., Walsh, P. C., Maier, C., Luedeke, M., Vogel, W., ... Isaacs, W. B. (2013). HOXB13 is a susceptibility gene for prostate cancer: Results from the International Consortium for Prostate Cancer Genetics (ICPCG). Human Genetics, 132(1), 5-14. https://doi.org/10.1007/s00439-012-1229-4

@article{7bf0e596d62c44e9b53995861bde0ae4,

title = "HOXB13 is a susceptibility gene for prostate cancer: Results from the International Consortium for Prostate Cancer Genetics (ICPCG)",

abstract = "Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10-8 [odds ratio 4.42 (95 % confidence interval 2.56-7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10-6). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.",

author = "Jianfeng Xu and Lange, {Ethan M.} and Lingyi Lu and Zheng, {Siqun L.} and Zhong Wang and Thibodeau, {Stephen N.} and Cannon-Albright, {Lisa A.} and Teerlink, {Craig C.} and Camp, {Nicola J.} and Johnson, {Anna M.} and Zuhlke, {Kimberly A.} and Stanford, {Janet L.} and Ostrander, {Elaine A.} and Wiley, {Kathleen E.} and Isaacs, {Sarah D.} and Walsh, {Patrick C.} and Christiane Maier and Manuel Luedeke and Walther Vogel and Johanna Schleutker and Tiina Wahlfors and Teuvo Tammela and Daniel Schaid and McDonnell, {Shannon K.} and Derycke, {Melissa S.} and Geraldine Cancel-Tassin and Olivier Cussenot and Fredrik Wiklund and Henrik Gr{\"o}nberg and Ros Eeles and Doug Easton and Zsofia Kote-Jarai and Whittemore, {Alice S.} and Hsieh, {Chih Lin} and Giles, {Graham G.} and Hopper, {John L.} and Gianluca Severi and Catalona, {William J.} and Diptasri Mandal and Elisa Ledet and Foulkes, {William D.} and Nancy Hamel and Lovise Mahle and Pal Moller and Isaac Powell and Bailey-Wilson, {Joan E.} and Carpten, {John D.} and Daniela Seminara and Cooney, {Kathleen A.} and Isaacs, {William B.}",

note = "Funding Information: Acknowledgments We would like to express our gratitude to the many families who participated in the studies involved in the International Consortium for Prostate Cancer Genetics (ICPCG). The ICPCG is funded by a grant from the National Institutes of Health U01 CA89600 (to W.B.I.). Additional support to members within the ICPCG is as follows: University of Michigan Group acknowledges NIH grants R01 CA79596, R01 CA079596-10-S1 (ARRA), R01 CA136621, and P50 CA69568. University of Utah Group: The authors thank the support from the University of Utah Huntsman Cancer Institute (to Lisa A. Cannon-Albright). FHCRC/NHGRI Group: Partial support was provided by the Fred Hutchinson Cancer Research Center (to Janet L. Stanford) and National Human Genome Research Institute (to Elaine A. Ostrander). ACTANE Group: We acknowledge support from CR-UK grant C5047/A7357 and the NIHR to the Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden NHS Foundation Trust and Prostate Action (to Ros Eeles), and Cancer Research UK (to Doug Easton). This work was also supported by the European Commission{\textquoteright}s Seventh Framework Programme grant agreement n° 223175 (HEALTH-F2-2009-223175), University of Ume{\aa} Group: Partial support was provided by Swedish Cancer Society and a Spear grant from the Ume{\aa} University Hospital, Ume{\aa}, Sweden (to Henrik Gr{\"o}nberg). University of Tampere Group: Partial support was provided from The Competitive Research Funding of the Pirkanmaa Hospital District (9M094), Finnish Cancer Organisations, Sigrid Juselius Foundation and Academy of Finland (116437 and 251074) (to Johanna Schleut-ker). Australian Group: Recruitment was funded by Cancer Council Victoria, Tattersalls and The Whitten Foundation; JLH is an Australia Fellow of the National Health and Medical Research Council. Northwestern University Group: Partial support was provided from Robert H Lurie Comprehensive Cancer Center and the Urological Research Foundation (to William J. Catalona). LSUHSC-NO Group: Louisiana Board of Regents, Centers for Disease Control and Prevention. Data Coordinating Center: Partial support was provided by NCI CA119069 and CA129684 (to Jianfeng Xu). We also thank other investigators who contributed to this work: ACTANE Group: Daniel Leongamornlert, Ed Saunders, Malgorzata Tymrakiewicz, Lynne O{\textquoteright}Brien, Emma Sawyer, Rosemary Wilkinson, and Stephen Edwards from The Institute of Cancer Research, Sutton, Surrey; Jacques Simard, from the Human Molecular Endocrinology Research Center, CHUL Research Center, Laval University, Quebec City, Canada; Timothy Bishop from Cancer Research UK, Genetic Epidemiology Laboratory, St James{\textquoteright} University Hospital, Leeds, UK; Michael Badzioch; Tokhir Dadaev, Lesley McGuffog, Koveela Govindasami, and Michelle Guy from the UKGPCS Team. University of Ulm Group: Antje Rinckleb and Mark Schrader from Department of Urology, University of Ulm, Germany; Josef Hoegel and Christian Kubisch from Institute of Human Genetics, University of Ulm, Germany; and Kathleen Herkommer from Department of Urology, Technical University of Munich, Germany. Fred Hutchinson Cancer Research Center Group: Laura McIntosh. We thank Liesel FitzGerald for helpful comments and review. William Foulkes thanks Celia Greenwood for advice.",

year = "2013",

month = jan,

doi = "10.1007/s00439-012-1229-4",

language = "English (US)",

volume = "132",

pages = "5--14",

journal = "Human Genetics",

issn = "0340-6717",

publisher = "Springer Verlag",

number = "1",

}

Xu, J, Lange, EM, Lu, L, Zheng, SL, Wang, Z, Thibodeau, SN, Cannon-Albright, LA, Teerlink, CC, Camp, NJ, Johnson, AM, Zuhlke, KA, Stanford, JL, Ostrander, EA, Wiley, KE, Isaacs, SD, Walsh, PC, Maier, C, Luedeke, M, Vogel, W, Schleutker, J, Wahlfors, T, Tammela, T, Schaid, D, McDonnell, SK, Derycke, MS, Cancel-Tassin, G, Cussenot, O, Wiklund, F, Grönberg, H, Eeles, R, Easton, D, Kote-Jarai, Z, Whittemore, AS, Hsieh, CL, Giles, GG, Hopper, JL, Severi, G, Catalona, WJ, Mandal, D, Ledet, E, Foulkes, WD, Hamel, N, Mahle, L, Moller, P, Powell, I, Bailey-Wilson, JE, Carpten, JD, Seminara, D, Cooney, KA & Isaacs, WB 2013, 'HOXB13 is a susceptibility gene for prostate cancer: Results from the International Consortium for Prostate Cancer Genetics (ICPCG)', Human Genetics, vol. 132, no. 1, pp. 5-14. https://doi.org/10.1007/s00439-012-1229-4

TY - JOUR

T1 - HOXB13 is a susceptibility gene for prostate cancer

T2 - Results from the International Consortium for Prostate Cancer Genetics (ICPCG)

AU - Xu, Jianfeng

AU - Lange, Ethan M.

AU - Lu, Lingyi

AU - Zheng, Siqun L.

AU - Wang, Zhong

AU - Thibodeau, Stephen N.

AU - Cannon-Albright, Lisa A.

AU - Teerlink, Craig C.

AU - Camp, Nicola J.

AU - Johnson, Anna M.

AU - Zuhlke, Kimberly A.

AU - Stanford, Janet L.

AU - Ostrander, Elaine A.

AU - Wiley, Kathleen E.

AU - Isaacs, Sarah D.

AU - Walsh, Patrick C.

AU - Maier, Christiane

AU - Luedeke, Manuel

AU - Vogel, Walther

AU - Schleutker, Johanna

AU - Wahlfors, Tiina

AU - Tammela, Teuvo

AU - Schaid, Daniel

AU - McDonnell, Shannon K.

AU - Derycke, Melissa S.

AU - Cancel-Tassin, Geraldine

AU - Cussenot, Olivier

AU - Wiklund, Fredrik

AU - Grönberg, Henrik

AU - Eeles, Ros

AU - Easton, Doug

AU - Kote-Jarai, Zsofia

AU - Whittemore, Alice S.

AU - Hsieh, Chih Lin

AU - Giles, Graham G.

AU - Hopper, John L.

AU - Severi, Gianluca

AU - Catalona, William J.

AU - Mandal, Diptasri

AU - Ledet, Elisa

AU - Foulkes, William D.

AU - Hamel, Nancy

AU - Mahle, Lovise

AU - Moller, Pal

AU - Powell, Isaac

AU - Bailey-Wilson, Joan E.

AU - Carpten, John D.

AU - Seminara, Daniela

AU - Cooney, Kathleen A.

AU - Isaacs, William B.

N1 - Funding Information: Acknowledgments We would like to express our gratitude to the many families who participated in the studies involved in the International Consortium for Prostate Cancer Genetics (ICPCG). The ICPCG is funded by a grant from the National Institutes of Health U01 CA89600 (to W.B.I.). Additional support to members within the ICPCG is as follows: University of Michigan Group acknowledges NIH grants R01 CA79596, R01 CA079596-10-S1 (ARRA), R01 CA136621, and P50 CA69568. University of Utah Group: The authors thank the support from the University of Utah Huntsman Cancer Institute (to Lisa A. Cannon-Albright). FHCRC/NHGRI Group: Partial support was provided by the Fred Hutchinson Cancer Research Center (to Janet L. Stanford) and National Human Genome Research Institute (to Elaine A. Ostrander). ACTANE Group: We acknowledge support from CR-UK grant C5047/A7357 and the NIHR to the Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden NHS Foundation Trust and Prostate Action (to Ros Eeles), and Cancer Research UK (to Doug Easton). This work was also supported by the European Commission’s Seventh Framework Programme grant agreement n° 223175 (HEALTH-F2-2009-223175), University of Umeå Group: Partial support was provided by Swedish Cancer Society and a Spear grant from the Umeå University Hospital, Umeå, Sweden (to Henrik Grönberg). University of Tampere Group: Partial support was provided from The Competitive Research Funding of the Pirkanmaa Hospital District (9M094), Finnish Cancer Organisations, Sigrid Juselius Foundation and Academy of Finland (116437 and 251074) (to Johanna Schleut-ker). Australian Group: Recruitment was funded by Cancer Council Victoria, Tattersalls and The Whitten Foundation; JLH is an Australia Fellow of the National Health and Medical Research Council. Northwestern University Group: Partial support was provided from Robert H Lurie Comprehensive Cancer Center and the Urological Research Foundation (to William J. Catalona). LSUHSC-NO Group: Louisiana Board of Regents, Centers for Disease Control and Prevention. Data Coordinating Center: Partial support was provided by NCI CA119069 and CA129684 (to Jianfeng Xu). We also thank other investigators who contributed to this work: ACTANE Group: Daniel Leongamornlert, Ed Saunders, Malgorzata Tymrakiewicz, Lynne O’Brien, Emma Sawyer, Rosemary Wilkinson, and Stephen Edwards from The Institute of Cancer Research, Sutton, Surrey; Jacques Simard, from the Human Molecular Endocrinology Research Center, CHUL Research Center, Laval University, Quebec City, Canada; Timothy Bishop from Cancer Research UK, Genetic Epidemiology Laboratory, St James’ University Hospital, Leeds, UK; Michael Badzioch; Tokhir Dadaev, Lesley McGuffog, Koveela Govindasami, and Michelle Guy from the UKGPCS Team. University of Ulm Group: Antje Rinckleb and Mark Schrader from Department of Urology, University of Ulm, Germany; Josef Hoegel and Christian Kubisch from Institute of Human Genetics, University of Ulm, Germany; and Kathleen Herkommer from Department of Urology, Technical University of Munich, Germany. Fred Hutchinson Cancer Research Center Group: Laura McIntosh. We thank Liesel FitzGerald for helpful comments and review. William Foulkes thanks Celia Greenwood for advice.

PY - 2013/1

Y1 - 2013/1

N2 - Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10-8 [odds ratio 4.42 (95 % confidence interval 2.56-7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10-6). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.

AB - Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10-8 [odds ratio 4.42 (95 % confidence interval 2.56-7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10-6). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.

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UR - http://www.scopus.com/inward/citedby.url?scp=84872308743&partnerID=8YFLogxK

U2 - 10.1007/s00439-012-1229-4

DO - 10.1007/s00439-012-1229-4

M3 - Article

C2 - 23064873

AN - SCOPUS:84872308743

SN - 0340-6717

VL - 132

SP - 5

EP - 14

JO - Human Genetics

JF - Human Genetics

IS - 1

ER -

HOXB13 is a susceptibility gene for prostate cancer: Results from the International Consortium for Prostate Cancer Genetics (ICPCG)

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