Germline mutations in HOXB13 and prostate-cancer risk

Charles M. Ewing, Anna M. Ray, Ethan M. Lange, Kimberly A. Zuhlke, Christiane M. Robbins, Waibhav D. Tembe, Kathleen E. Wiley, Sarah D. Isaacs, Dorhyun Johng, Yunfei Wang, Chris Bizon, Guifang Yan, Marta Gielzak, Alan Wayne Partin, Vijayalakshmi Shanmugam, Tyler Izatt, Shripad Sinari, David W. Craig, S. Lilly Zheng, Patrick Walsh & 5 others James E. Montie, Jianfeng Xu, John D. Carpten, William B Isaacs, Kathleen A. Cooney

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Family history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage studies have implicated chromosome 17q21-22 as a possible location of a prostate-cancer susceptibility gene. METHODS:We screened more than 200 genes in the 17q21-22 region by sequencing germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. We tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations. RESULTS:Probands from four families were discovered to have a rare but recurrent mutation (G84E) in HOXB13 (rs138213197), a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these four families carried the mutation. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1401 control subjects (0.1%) (P = 8.5×10 -7). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P = 2.0×10 -6). CONCLUSIONS: The novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer. (Funded by the National Institutes of Health and others.)

Original languageEnglish (US)
Pages (from-to)141-149
Number of pages9
JournalNew England Journal of Medicine
Volume366
Issue number2
DOIs
StatePublished - Jan 12 2012

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Germ-Line Mutation
Prostatic Neoplasms
Mutation
Mutation Rate
Chromosomes, Human, Pair 22
Homeobox Genes
Neoplasm Genes
National Institutes of Health (U.S.)
DNA Sequence Analysis
Genes
Prostate
Transcription Factors
DNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ewing, C. M., Ray, A. M., Lange, E. M., Zuhlke, K. A., Robbins, C. M., Tembe, W. D., ... Cooney, K. A. (2012). Germline mutations in HOXB13 and prostate-cancer risk. New England Journal of Medicine, 366(2), 141-149. https://doi.org/10.1056/NEJMoa1110000

Germline mutations in HOXB13 and prostate-cancer risk. / Ewing, Charles M.; Ray, Anna M.; Lange, Ethan M.; Zuhlke, Kimberly A.; Robbins, Christiane M.; Tembe, Waibhav D.; Wiley, Kathleen E.; Isaacs, Sarah D.; Johng, Dorhyun; Wang, Yunfei; Bizon, Chris; Yan, Guifang; Gielzak, Marta; Partin, Alan Wayne; Shanmugam, Vijayalakshmi; Izatt, Tyler; Sinari, Shripad; Craig, David W.; Zheng, S. Lilly; Walsh, Patrick; Montie, James E.; Xu, Jianfeng; Carpten, John D.; Isaacs, William B; Cooney, Kathleen A.

In: New England Journal of Medicine, Vol. 366, No. 2, 12.01.2012, p. 141-149.

Research output: Contribution to journalArticle

Ewing, CM, Ray, AM, Lange, EM, Zuhlke, KA, Robbins, CM, Tembe, WD, Wiley, KE, Isaacs, SD, Johng, D, Wang, Y, Bizon, C, Yan, G, Gielzak, M, Partin, AW, Shanmugam, V, Izatt, T, Sinari, S, Craig, DW, Zheng, SL, Walsh, P, Montie, JE, Xu, J, Carpten, JD, Isaacs, WB & Cooney, KA 2012, 'Germline mutations in HOXB13 and prostate-cancer risk', New England Journal of Medicine, vol. 366, no. 2, pp. 141-149. https://doi.org/10.1056/NEJMoa1110000
Ewing CM, Ray AM, Lange EM, Zuhlke KA, Robbins CM, Tembe WD et al. Germline mutations in HOXB13 and prostate-cancer risk. New England Journal of Medicine. 2012 Jan 12;366(2):141-149. https://doi.org/10.1056/NEJMoa1110000
Ewing, Charles M. ; Ray, Anna M. ; Lange, Ethan M. ; Zuhlke, Kimberly A. ; Robbins, Christiane M. ; Tembe, Waibhav D. ; Wiley, Kathleen E. ; Isaacs, Sarah D. ; Johng, Dorhyun ; Wang, Yunfei ; Bizon, Chris ; Yan, Guifang ; Gielzak, Marta ; Partin, Alan Wayne ; Shanmugam, Vijayalakshmi ; Izatt, Tyler ; Sinari, Shripad ; Craig, David W. ; Zheng, S. Lilly ; Walsh, Patrick ; Montie, James E. ; Xu, Jianfeng ; Carpten, John D. ; Isaacs, William B ; Cooney, Kathleen A. / Germline mutations in HOXB13 and prostate-cancer risk. In: New England Journal of Medicine. 2012 ; Vol. 366, No. 2. pp. 141-149.
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abstract = "BACKGROUND: Family history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage studies have implicated chromosome 17q21-22 as a possible location of a prostate-cancer susceptibility gene. METHODS:We screened more than 200 genes in the 17q21-22 region by sequencing germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. We tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations. RESULTS:Probands from four families were discovered to have a rare but recurrent mutation (G84E) in HOXB13 (rs138213197), a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these four families carried the mutation. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4{\%}), as compared with 1 in 1401 control subjects (0.1{\%}) (P = 8.5×10 -7). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1{\%}) than in those with late-onset, nonfamilial prostate cancer (0.6{\%}) (P = 2.0×10 -6). CONCLUSIONS: The novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer. (Funded by the National Institutes of Health and others.)",
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T1 - Germline mutations in HOXB13 and prostate-cancer risk

AU - Ewing, Charles M.

AU - Ray, Anna M.

AU - Lange, Ethan M.

AU - Zuhlke, Kimberly A.

AU - Robbins, Christiane M.

AU - Tembe, Waibhav D.

AU - Wiley, Kathleen E.

AU - Isaacs, Sarah D.

AU - Johng, Dorhyun

AU - Wang, Yunfei

AU - Bizon, Chris

AU - Yan, Guifang

AU - Gielzak, Marta

AU - Partin, Alan Wayne

AU - Shanmugam, Vijayalakshmi

AU - Izatt, Tyler

AU - Sinari, Shripad

AU - Craig, David W.

AU - Zheng, S. Lilly

AU - Walsh, Patrick

AU - Montie, James E.

AU - Xu, Jianfeng

AU - Carpten, John D.

AU - Isaacs, William B

AU - Cooney, Kathleen A.

PY - 2012/1/12

Y1 - 2012/1/12

N2 - BACKGROUND: Family history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage studies have implicated chromosome 17q21-22 as a possible location of a prostate-cancer susceptibility gene. METHODS:We screened more than 200 genes in the 17q21-22 region by sequencing germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. We tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations. RESULTS:Probands from four families were discovered to have a rare but recurrent mutation (G84E) in HOXB13 (rs138213197), a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these four families carried the mutation. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1401 control subjects (0.1%) (P = 8.5×10 -7). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P = 2.0×10 -6). CONCLUSIONS: The novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer. (Funded by the National Institutes of Health and others.)

AB - BACKGROUND: Family history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage studies have implicated chromosome 17q21-22 as a possible location of a prostate-cancer susceptibility gene. METHODS:We screened more than 200 genes in the 17q21-22 region by sequencing germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. We tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations. RESULTS:Probands from four families were discovered to have a rare but recurrent mutation (G84E) in HOXB13 (rs138213197), a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these four families carried the mutation. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1401 control subjects (0.1%) (P = 8.5×10 -7). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P = 2.0×10 -6). CONCLUSIONS: The novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer. (Funded by the National Institutes of Health and others.)

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