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 J 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

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)5-14
Number of pages10
JournalHuman Genetics
Volume132
Issue number1
DOIs
StatePublished - Jan 2013

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Prostatic Neoplasms
Mutation
Genes
Founder Effect
Disease Susceptibility
Haplotypes
Single Nucleotide Polymorphism
Neoplasms
Parents
Alleles
Odds Ratio
Confidence Intervals

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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HOXB13 is a susceptibility gene for prostate cancer : Results from the International Consortium for Prostate Cancer Genetics (ICPCG). / Xu, Jianfeng; Lange, Ethan M.; Lu, Lingyi; Zheng, Siqun L.; Wang, Zhong; Thibodeau, Stephen N; Cannon-Albright, Lisa A.; Teerlink, Craig C.; Camp, Nicola J.; Johnson, Anna M.; Zuhlke, Kimberly A.; Stanford, Janet L.; Ostrander, Elaine A.; Wiley, Kathleen E.; Isaacs, Sarah D.; Walsh, Patrick C.; Maier, Christiane; Luedeke, Manuel; Vogel, Walther; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo; Schaid, Daniel J; McDonnell, Shannon K.; Derycke, Melissa S.; Cancel-Tassin, Geraldine; Cussenot, Olivier; Wiklund, Fredrik; Grönberg, Henrik; Eeles, Ros; Easton, Doug; Kote-Jarai, Zsofia; Whittemore, Alice S.; Hsieh, Chih Lin; Giles, Graham G.; Hopper, John L.; Severi, Gianluca; Catalona, William J.; Mandal, Diptasri; Ledet, Elisa; Foulkes, William D.; Hamel, Nancy; Mahle, Lovise; Moller, Pal; Powell, Isaac; Bailey-Wilson, Joan E.; Carpten, John D.; Seminara, Daniela; Cooney, Kathleen A.; Isaacs, William B.

In: Human Genetics, Vol. 132, No. 1, 01.2013, p. 5-14.

Research output: Contribution to journalArticle

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, DJ, 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
Xu, Jianfeng ; Lange, Ethan M. ; Lu, Lingyi ; Zheng, Siqun L. ; Wang, Zhong ; Thibodeau, Stephen N ; Cannon-Albright, Lisa A. ; Teerlink, Craig C. ; Camp, Nicola J. ; Johnson, Anna M. ; Zuhlke, Kimberly A. ; Stanford, Janet L. ; Ostrander, Elaine A. ; Wiley, Kathleen E. ; Isaacs, Sarah D. ; Walsh, Patrick C. ; Maier, Christiane ; Luedeke, Manuel ; Vogel, Walther ; Schleutker, Johanna ; Wahlfors, Tiina ; Tammela, Teuvo ; Schaid, Daniel J ; McDonnell, Shannon K. ; Derycke, Melissa S. ; Cancel-Tassin, Geraldine ; Cussenot, Olivier ; Wiklund, Fredrik ; Grönberg, Henrik ; Eeles, Ros ; Easton, Doug ; Kote-Jarai, Zsofia ; Whittemore, Alice S. ; Hsieh, Chih Lin ; Giles, Graham G. ; Hopper, John L. ; Severi, Gianluca ; Catalona, William J. ; Mandal, Diptasri ; Ledet, Elisa ; Foulkes, William D. ; Hamel, Nancy ; Mahle, Lovise ; Moller, Pal ; Powell, Isaac ; Bailey-Wilson, Joan E. ; Carpten, John D. ; Seminara, Daniela ; Cooney, Kathleen A. ; Isaacs, William B. / HOXB13 is a susceptibility gene for prostate cancer : Results from the International Consortium for Prostate Cancer Genetics (ICPCG). In: Human Genetics. 2013 ; Vol. 132, No. 1. pp. 5-14.
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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.",
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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 J

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.

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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