title: Germ-line mutation of NKX3.1 cosegregates with hereditary prostate cancer and alters the homeodomain structure and function.
abstract: NKX3.1, a gene mapped to 8p21, is a member of the NK class of homeodomain proteins and is expressed primarily in the prostate. NKX3.1 exerts a growth-suppressive and differentiating effect on prostate epithelial cells. Because of its known functions and its location within a chromosomal region where evidence for prostate cancer linkage and somatic loss of heterozygosity is found, we hypothesize that sequence variants in the NKX3.1 gene increase prostate cancer risk. To address this, we first resequenced the NKX3.1 gene in 159 probands of hereditary prostate cancer families recruited at Johns Hopkins Hospital; each family has at least three first-degree relatives affected with prostate cancer. Twenty-one germ-line variants were identified in this analysis, including one previously described common nonsynonymous change (R52C), two novel rare nonsynonymous changes (A17T and T164A), and a novel common 18-bp deletion in the promoter. Overall, the germ-line variants were significantly linked to prostate cancer, with a peak heterogeneity logarithm of odds of 2.04 (P = 0.002) at the NKX3.1 gene. The rare nonsynonymous change, T164A, located in the homeobox domain of the gene, segregated with prostate cancer in a family with three affected brothers and one unaffected brother. Importantly, nuclear magnetic resonance solution structure analysis and circular dichroism studies showed this specific mutation to affect the stability of the homeodomain of the NKX3.1 protein and decreased binding to its cognate DNA recognition sequence. These results suggest that germ-line sequence variants in NKX3.1 may play a role in susceptibility to hereditary prostate cancer and underscore a role for NKX3.1 as a prostate cancer gatekeeper.
authors.affiliation: Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: S Lilly
authors.initials: SL
authors.lastname: Zheng
authors.forename: Jeong-ho
authors.initials: JH
authors.lastname: Ju
authors.forename: Bao-li
authors.initials: BL
authors.lastname: Chang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ortner
authors.forename: Jielin
authors.initials: J
authors.lastname: Sun
authors.forename: Sarah D
authors.initials: SD
authors.lastname: Isaacs
authors.forename: Jishang
authors.initials: J
authors.lastname: Sun
authors.forename: Kathy E
authors.initials: KE
authors.lastname: Wiley
authors.forename: Wennuan
authors.initials: W
authors.lastname: Liu
authors.forename: Micheas
authors.initials: M
authors.lastname: Zemedkun
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Walsh
authors.forename: James
authors.initials: J
authors.lastname: Ferretti
authors.forename: James
authors.initials: J
authors.lastname: Gruschus
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
authors.forename: Edward P
authors.initials: EP
authors.lastname: Gelmann
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
mesh_terms: D000595:Amino Acid Sequence; D020090:Chromosome Segregation; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C491178:NKX3-1 protein, human; D012333:RNA, Messenger; D014157:Transcription Factors