title: Germline mutations in HOXB13 and prostate-cancer risk.
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=8.5x10(-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=2.0x10(-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.).
authors.affiliation: Johns Hopkins University and the James Buchanan Brady Urological Institute, Baltimore, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Ewing
authors.forename: Anna M
authors.initials: AM
authors.lastname: Ray
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Lange
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Zuhlke
authors.forename: Christiane M
authors.initials: CM
authors.lastname: Robbins
authors.forename: Waibhav D
authors.initials: WD
authors.lastname: Tembe
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Wiley
authors.forename: Sarah D
authors.initials: SD
authors.lastname: Isaacs
authors.forename: Dorhyun
authors.initials: D
authors.lastname: Johng
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Wang
authors.forename: Chris
authors.initials: C
authors.lastname: Bizon
authors.forename: Guifang
authors.initials: G
authors.lastname: Yan
authors.forename: Marta
authors.initials: M
authors.lastname: Gielzak
authors.forename: Alan W
authors.initials: AW
authors.lastname: Partin
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Shanmugam
authors.forename: Tyler
authors.initials: T
authors.lastname: Izatt
authors.forename: Shripad
authors.initials: S
authors.lastname: Sinari
authors.forename: David W
authors.initials: DW
authors.lastname: Craig
authors.forename: S Lilly
authors.initials: SL
authors.lastname: Zheng
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Walsh
authors.forename: James E
authors.initials: JE
authors.lastname: Montie
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.forename: John D
authors.initials: JD
authors.lastname: Carpten
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Cooney
mesh_terms: D002886:Chromosomes, Human, Pair 17; D008040:Genetic Linkage; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA
chemical_list: C484414:HOXB13 protein, human; D018398:Homeodomain Proteins