A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics.
Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric (dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score >1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of < or = 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study.
Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Jianfeng
J
Xu
Latchezar
L
Dimitrov
Bao-Li
BL
Chang
Tamara S
TS
Adams
Aubrey R
AR
Turner
Deborah A
DA
Meyers
Rosalind A
RA
Eeles
Douglas F
DF
Easton
William D
WD
Foulkes
Jacques
J
Simard
Graham G
GG
Giles
John L
JL
Hopper
Lovise
L
Mahle
Pal
P
Moller
Tim
T
Bishop
Chris
C
Evans
Steve
S
Edwards
Julia
J
Meitz
Sarah
S
Bullock
Questa
Q
Hope
Chih-Lin
CL
Hsieh
Jerry
J
Halpern
Raymond N
RN
Balise
Ingrid
I
Oakley-Girvan
Alice S
AS
Whittemore
Charles M
CM
Ewing
Marta
M
Gielzak
Sarah D
SD
Isaacs
Patrick C
PC
Walsh
Kathleen E
KE
Wiley
William B
WB
Isaacs
Stephen N
SN
Thibodeau
Shannon K
SK
McDonnell
Julie M
JM
Cunningham
Katherine E
KE
Zarfas
Scott
S
Hebbring
Daniel J
DJ
Schaid
Danielle M
DM
Friedrichsen
Kerry
K
Deutsch
Suzanne
S
Kolb
Michael
M
Badzioch
Gail P
GP
Jarvik
Marta
M
Janer
Leroy
L
Hood
Elaine A
EA
Ostrander
Janet L
JL
Stanford
Ethan M
EM
Lange
Jennifer L
JL
Beebe-Dimmer
Caroline E
CE
Mohai
Kathleen A
KA
Cooney
Tarja
T
Ikonen
Agnes
A
Baffoe-Bonnie
Henna
H
Fredriksson
Mika P
MP
Matikainen
Teuvo Lj
TLj
Tammela
Joan
J
Bailey-Wilson
Johanna
J
Schleutker
Christiane
C
Maier
Kathleen
K
Herkommer
Josef J
JJ
Hoegel
Walther
W
Vogel
Thomas
T
Paiss
Fredrik
F
Wiklund
Monica
M
Emanuelsson
Elisabeth
E
Stenman
Bjorn-Anders
BA
Jonsson
Henrik
H
Gronberg
Nicola J
NJ
Camp
James
J
Farnham
Lisa A
LA
Cannon-Albright
Daniela
D
Seminara
D000368:Aged; D002874:Chromosome Mapping; D005192:Family Health; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D007391:International Cooperation; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D011471:Prostatic Neoplasms / Q000235:genetics*
D005819:Genetic Markers