Somatic molecular subtyping of prostate tumors from HOXB13 G84E carriers

Tamara Lotan, Alba Torres, Miao Zhang, Jeffrey J. Tosoian, Liana B. Guedes, Helen Fedor, Jessica Hicks, Charles M. Ewing, Sarah D. Isaacs, Dorhyun Johng, Angelo Michael Demarzo, William B Isaacs

Research output: Contribution to journalArticle

Abstract

A recurrent germline mutation (G84E) in the HOXB13 gene is associated with early onset and family history-positive prostate cancer in patients of European descent, occurring in up to 5% of prostate cancer families. To date, the molecular features of prostate tumors occurring in HOXB13 G84E carriers have not been studied in a large cohort of patients. We identified 101 heterozygous carriers of G84E who underwent radical prostatectomy for prostate cancer between 1985 and 2011 and matched these men by race, age and tumor grade to 99 HOXB13 wild-type controls. Immunostaining for HOXB13, PTEN, ERG, p53 and SPINK1 as well as RNA in situ hybridization for ETV1/4/5 were performed using genetically validated assays. Tumors from G84E carriers generally expressed HOXB13 protein at a level comparable to benign and wild-type glands. ETS gene expression (either ERG or ETV1/4/5) was seen in 36% (36/101) of tumors from G84E carriers compared to 68% (65/96) of the controls (p < 0.0001). PTEN was lost in 11% (11/101) of G84E carriers compared to 25% (25/99) of the controls (p = 0.014). PTEN loss was enriched among ERG-positive compared to ERG-negative tumors in both groups of patients. Nuclear accumulation of the p53 protein, indicative of underlying TP53 missense mutations, was uncommon in both groups, occurring in 1% (1/101) of the G84E carriers versus 2% (2/92) of the controls (p = NS). Taken together, these data suggest that genes other than ERG and PTEN may drive carcinogenesis/progression in the majority of men with germline HOXB13 mutations.

Original languageEnglish (US)
Pages (from-to)22772-22782
Number of pages11
JournalOncotarget
Volume8
Issue number14
DOIs
StatePublished - 2017

Fingerprint

Prostate
Prostatic Neoplasms
Germ-Line Mutation
Neoplasms
Missense Mutation
Prostatectomy
Genes
In Situ Hybridization
Carcinogenesis
Proteins
RNA
Gene Expression

Keywords

  • ERG
  • Familial prostate cancer
  • HOXB13 G84E
  • Prostatic adenocarcinoma
  • PTEN

ASJC Scopus subject areas

  • Oncology

Cite this

Somatic molecular subtyping of prostate tumors from HOXB13 G84E carriers. / Lotan, Tamara; Torres, Alba; Zhang, Miao; Tosoian, Jeffrey J.; Guedes, Liana B.; Fedor, Helen; Hicks, Jessica; Ewing, Charles M.; Isaacs, Sarah D.; Johng, Dorhyun; Demarzo, Angelo Michael; Isaacs, William B.

In: Oncotarget, Vol. 8, No. 14, 2017, p. 22772-22782.

Research output: Contribution to journalArticle

Lotan, T, Torres, A, Zhang, M, Tosoian, JJ, Guedes, LB, Fedor, H, Hicks, J, Ewing, CM, Isaacs, SD, Johng, D, Demarzo, AM & Isaacs, WB 2017, 'Somatic molecular subtyping of prostate tumors from HOXB13 G84E carriers', Oncotarget, vol. 8, no. 14, pp. 22772-22782. https://doi.org/10.18632/oncotarget.15196
Lotan T, Torres A, Zhang M, Tosoian JJ, Guedes LB, Fedor H et al. Somatic molecular subtyping of prostate tumors from HOXB13 G84E carriers. Oncotarget. 2017;8(14):22772-22782. https://doi.org/10.18632/oncotarget.15196
Lotan, Tamara ; Torres, Alba ; Zhang, Miao ; Tosoian, Jeffrey J. ; Guedes, Liana B. ; Fedor, Helen ; Hicks, Jessica ; Ewing, Charles M. ; Isaacs, Sarah D. ; Johng, Dorhyun ; Demarzo, Angelo Michael ; Isaacs, William B. / Somatic molecular subtyping of prostate tumors from HOXB13 G84E carriers. In: Oncotarget. 2017 ; Vol. 8, No. 14. pp. 22772-22782.
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abstract = "A recurrent germline mutation (G84E) in the HOXB13 gene is associated with early onset and family history-positive prostate cancer in patients of European descent, occurring in up to 5{\%} of prostate cancer families. To date, the molecular features of prostate tumors occurring in HOXB13 G84E carriers have not been studied in a large cohort of patients. We identified 101 heterozygous carriers of G84E who underwent radical prostatectomy for prostate cancer between 1985 and 2011 and matched these men by race, age and tumor grade to 99 HOXB13 wild-type controls. Immunostaining for HOXB13, PTEN, ERG, p53 and SPINK1 as well as RNA in situ hybridization for ETV1/4/5 were performed using genetically validated assays. Tumors from G84E carriers generally expressed HOXB13 protein at a level comparable to benign and wild-type glands. ETS gene expression (either ERG or ETV1/4/5) was seen in 36{\%} (36/101) of tumors from G84E carriers compared to 68{\%} (65/96) of the controls (p < 0.0001). PTEN was lost in 11{\%} (11/101) of G84E carriers compared to 25{\%} (25/99) of the controls (p = 0.014). PTEN loss was enriched among ERG-positive compared to ERG-negative tumors in both groups of patients. Nuclear accumulation of the p53 protein, indicative of underlying TP53 missense mutations, was uncommon in both groups, occurring in 1{\%} (1/101) of the G84E carriers versus 2{\%} (2/92) of the controls (p = NS). Taken together, these data suggest that genes other than ERG and PTEN may drive carcinogenesis/progression in the majority of men with germline HOXB13 mutations.",
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