HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG).
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.
Data Coordinating Center for the ICPCG, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Jianfeng
J
Xu
Ethan M
EM
Lange
Lingyi
L
Lu
Siqun L
SL
Zheng
Zhong
Z
Wang
Stephen N
SN
Thibodeau
Lisa A
LA
Cannon-Albright
Craig C
CC
Teerlink
Nicola J
NJ
Camp
Anna M
AM
Johnson
Kimberly A
KA
Zuhlke
Janet L
JL
Stanford
Elaine A
EA
Ostrander
Kathleen E
KE
Wiley
Sarah D
SD
Isaacs
Patrick C
PC
Walsh
Christiane
C
Maier
Manuel
M
Luedeke
Walther
W
Vogel
Johanna
J
Schleutker
Tiina
T
Wahlfors
Teuvo
T
Tammela
Daniel
D
Schaid
Shannon K
SK
McDonnell
Melissa S
MS
DeRycke
Geraldine
G
Cancel-Tassin
Olivier
O
Cussenot
Fredrik
F
Wiklund
Henrik
H
Grönberg
Ros
R
Eeles
Doug
D
Easton
Zsofia
Z
Kote-Jarai
Alice S
AS
Whittemore
Chih-Lin
CL
Hsieh
Graham G
GG
Giles
John L
JL
Hopper
Gianluca
G
Severi
William J
WJ
Catalona
Diptasri
D
Mandal
Elisa
E
Ledet
William D
WD
Foulkes
Nancy
N
Hamel
Lovise
L
Mahle
Pal
P
Moller
Isaac
I
Powell
Joan E
JE
Bailey-Wilson
John D
JD
Carpten
Daniela
D
Seminara
Kathleen A
KA
Cooney
William B
WB
Isaacs
D019943:Amino Acid Substitution; D015331:Cohort Studies; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007390:International Agencies; D008297:Male; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics*; D044465:White People / Q000235:genetics
C484414:HOXB13 protein, human; D018398:Homeodomain Proteins