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.
Xu
Jianfeng
J
Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Dimitrov
Latchezar
L
Chang
Bao-Li
BL
Adams
Tamara S
TS
Turner
Aubrey R
AR
Meyers
Deborah A
DA
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
Bishop
Tim
T
Evans
Chris
C
Edwards
Steve
S
Meitz
Julia
J
Bullock
Sarah
S
Hope
Questa
Q
Hsieh
Chih-Lin
CL
Halpern
Jerry
J
Balise
Raymond N
RN
Oakley-Girvan
Ingrid
I
Whittemore
Alice S
AS
Ewing
Charles M
CM
Gielzak
Marta
M
Isaacs
Sarah D
SD
Walsh
Patrick C
PC
Wiley
Kathleen E
KE
Isaacs
William B
WB
Thibodeau
Stephen N
SN
McDonnell
Shannon K
SK
Cunningham
Julie M
JM
Zarfas
Katherine E
KE
Hebbring
Scott
S
Schaid
Daniel J
DJ
Friedrichsen
Danielle M
DM
Deutsch
Kerry
K
Kolb
Suzanne
S
Badzioch
Michael
M
Jarvik
Gail P
GP
Janer
Marta
M
Hood
Leroy
L
Ostrander
Elaine A
EA
Stanford
Janet L
JL
Lange
Ethan M
EM
Beebe-Dimmer
Jennifer L
JL
Mohai
Caroline E
CE
Cooney
Kathleen A
KA
Ikonen
Tarja
T
Baffoe-Bonnie
Agnes
A
Fredriksson
Henna
H
Matikainen
Mika P
MP
Tammela
Teuvo Lj
TLj
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
Bjorn-Anders
BA
Gronberg
Henrik
H
Camp
Nicola J
NJ
Farnham
James
J
Cannon-Albright
Lisa A
LA
Seminara
Daniela
D
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