Pooled genome linkage scan of aggressive prostate cancer: results from the International Consortium for Prostate Cancer Genetics.
While it is widely appreciated that prostate cancers vary substantially in their propensity to progress to a life-threatening stage, the molecular events responsible for this progression have not been identified. Understanding these molecular mechanisms could provide important prognostic information relevant to more effective clinical management of this heterogeneous cancer. Hence, through genetic linkage analyses, we examined the hypothesis that the tendency to develop aggressive prostate cancer may have an important genetic component. Starting with 1,233 familial prostate cancer families with genome scan data available from the International Consortium for Prostate Cancer Genetics, we selected those that had at least three members with the phenotype of clinically aggressive prostate cancer, as defined by either high tumor grade and/or stage, resulting in 166 pedigrees (13%). Genome-wide linkage data were then pooled to perform a combined linkage analysis for these families. Linkage signals reaching a suggestive level of significance were found on chromosomes 6p22.3 (LOD = 3.0), 11q14.1-14.3 (LOD = 2.4), and 20p11.21-q11.21 (LOD = 2.5). For chromosome 11, stronger evidence of linkage (LOD = 3.3) was observed among pedigrees with an average at diagnosis of 65 years or younger. Other chromosomes that showed evidence for heterogeneity in linkage across strata were chromosome 7, with the strongest linkage signal among pedigrees without male-to-male disease transmission (7q21.11, LOD = 4.1), and chromosome 21, with the strongest linkage signal among pedigrees that had African American ancestry (21q22.13-22.3; LOD = 3.2). Our findings suggest several regions that may contain genes which, when mutated, predispose men to develop a more aggressive prostate cancer phenotype. This provides a basis for attempts to identify these genes, with potential clinical utility for men with aggressive prostate cancer and their relatives.
Schaid
Daniel J
DJ
Harwick 7, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. schaid@mayo.edu
McDonnell
Shannon K
SK
Zarfas
Katherine E
KE
Cunningham
Julie M
JM
Hebbring
Scott
S
Thibodeau
Stephen N
SN
Eeles
Rosalind A
RA
Easton
Douglas F
DF
Foulkes
William D
WD
Simard
Jacques
J
Giles
Graham G
GG
Hopper
John L
JL
Mahle
Lovise
L
Moller
Pal
P
Badzioch
Michael
M
Bishop
D Timothy
DT
Evans
Chris
C
Edwards
Steve
S
Meitz
Julia
J
Bullock
Sarah
S
Hope
Questa
Q
Guy
Michelle
M
Hsieh
Chih-lin
CL
Halpern
Jerry
J
Balise
Raymond R
RR
Oakley-Girvan
Ingrid
I
Whittemore
Alice S
AS
Xu
Jianfeng
J
Dimitrov
Latchezar
L
Chang
Bao-Li
BL
Adams
Tamara S
TS
Turner
Aubrey R
AR
Meyers
Deborah A
DA
Friedrichsen
Danielle M
DM
Deutsch
Kerry
K
Kolb
Suzanne
S
Janer
Marta
M
Hood
Leroy
L
Ostrander
Elaine A
EA
Stanford
Janet L
JL
Ewing
Charles M
CM
Gielzak
Marta
M
Isaacs
Sarah D
SD
Walsh
Patrick C
PC
Wiley
Kathleen E
KE
Isaacs
William B
WB
Lange
Ethan M
EM
Ho
Lindsey A
LA
Beebe-Dimmer
Jennifer L
JL
Wood
David P
DP
Cooney
Kathleen A
KA
Seminara
Daniela
D
Ikonen
Tarja
T
Baffoe-Bonnie
Agnes
A
Fredriksson
Henna
H
Matikainen
Mika P
MP
Tammela
Teuvo L J
TL
Bailey-Wilson
Joan
J
Schleutker
Johanna
J
Maier
Christiane
C
Herkommer
Kathleen
K
Hoegel
Josef J
JJ
Vogel
Walther
W
Paiss
Thomas
T
Wiklund
Fredrik
F
Emanuelsson
Monica
M
Stenman
Elisabeth
E
Jonsson
Björn-Anders
BA
Grönberg
Henrik
H
Camp
Nicola J
NJ
Farnham
James
J
Cannon-Albright
Lisa A
LA
Catalona
William J
WJ
Suarez
Brian K
BK
Roehl
Kimberly A
KA
D001741:Black or African American / Q000235:genetics; D000368:Aged; D002874:Chromosome Mapping; D005192:Family Health; D005260:Female; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D007391:International Cooperation; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D010375:Pedigree; D011471:Prostatic Neoplasms / Q000208:ethnology / Q000235:genetics*; D044465:White People / Q000235:genetics