Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families.
BACKGROUND
Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive.


METHODS
Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed.


RESULTS
Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded.


CONCLUSIONS
Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.
Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224, USA. jebw@mail.nih.gov
Joan E
JE
Bailey-Wilson
Erica J
EJ
Childs
Cheryl D
CD
Cropp
Daniel J
DJ
Schaid
Jianfeng
J
Xu
Nicola J
NJ
Camp
Lisa A
LA
Cannon-Albright
James M
JM
Farnham
Asha
A
George
Isaac
I
Powell
John D
JD
Carpten
Graham G
GG
Giles
John L
JL
Hopper
Gianluca
G
Severi
Dallas R
DR
English
William D
WD
Foulkes
Lovise
L
Mæhle
Pål
P
Møller
Rosalind
R
Eeles
Douglas
D
Easton
Michelle
M
Guy
Steve
S
Edwards
Michael D
MD
Badzioch
Alice S
AS
Whittemore
Ingrid
I
Oakley-Girvan
Chih-Lin
CL
Hsieh
Latchezar
L
Dimitrov
Janet L
JL
Stanford
Danielle M
DM
Karyadi
Kerry
K
Deutsch
Laura
L
McIntosh
Elaine A
EA
Ostrander
Kathleen E
KE
Wiley
Sarah D
SD
Isaacs
Patrick C
PC
Walsh
Stephen N
SN
Thibodeau
Shannon K
SK
McDonnell
Scott
S
Hebbring
Ethan M
EM
Lange
Kathleen A
KA
Cooney
Teuvo L J
TL
Tammela
Johanna
J
Schleutker
Christiane
C
Maier
Sylvia
S
Bochum
Josef
J
Hoegel
Henrik
H
Grönberg
Fredrik
F
Wiklund
Monica
M
Emanuelsson
Geraldine
G
Cancel-Tassin
Antoine
A
Valeri
Olivier
O
Cussenot
William B
WB
Isaacs
D000483:Alleles; D041321:Chromosomes, Human, X; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D011471:Prostatic Neoplasms / Q000235:genetics*