Combined genome-wide scan for prostate cancer susceptibility genes.
BACKGROUND
Prostate cancer represents a substantial public health burden worldwide. It is the second leading cause of cancer death among men in the United States. A family history of the disease is among the most well-established risk factors for prostate cancer. Efforts to localize prostate cancer susceptibility alleles by using genetic linkage analysis methods have been hindered by genetic heterogeneity, incomplete penetrance, disease phenocopies, and the lack of DNA samples from parents of individuals with late-onset prostate cancer.


METHODS
We performed a combined genome-wide linkage analysis among 426 families from four existing hereditary prostate cancer (HPC) study populations to systematically search for prostate cancer susceptibility genes. To decrease the degree of locus heterogeneity, we analyzed subsets of families with similar clinical and demographic characteristics. Nonparametric multipoint linkage was the primary method of analysis. Results are presented as allele-sharing logarithm of the odds (LOD) scores, and all reported P values are two-sided.


RESULTS
The strongest evidence for prostate cancer linkage was found at chromosome region 17q22 (nonparametric multipoint Kong and Cox allele-sharing LOD score = 3.16 at marker D17S787; P =.00007). Stratified analyses revealed several additional chromosomal regions that are likely to segregate prostate cancer susceptibility genes among specific subsets of HPC families, including 15q11 among families with late-onset disease (allele-sharing LOD = 5.57 at marker D15S128; P<.00001) and 4q35 among families with four or more affected family members (allele-sharing LOD = 3.10 at marker D4S1615; P =.00008).


CONCLUSIONS
Fine mapping studies to facilitate identification of prostate cancer susceptibility genes in these linked regions are warranted.
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Elizabeth M
EM
Gillanders
Jianfeng
J
Xu
Bao-li
BL
Chang
Ethan M
EM
Lange
Fredrik
F
Wiklund
Joan E
JE
Bailey-Wilson
Agnes
A
Baffoe-Bonnie
MaryPat
M
Jones
Derek
D
Gildea
Erica
E
Riedesel
Julie
J
Albertus
Sarah D
SD
Isaacs
Kathleen E
KE
Wiley
Caroline E
CE
Mohai
Mika P
MP
Matikainen
Teuvo L J
TL
Tammela
S Lilly
SL
Zheng
W Mark
WM
Brown
Annika
A
Rökman
John D
JD
Carpten
Deborah A
DA
Meyers
Patrick C
PC
Walsh
Johanna
J
Schleutker
Henrik
H
Gronberg
Kathleen A
KA
Cooney
William B
WB
Isaacs
Jeffrey M
JM
Trent
D014408:Biomarkers, Tumor / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D015986:Confounding Factors, Epidemiologic; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D011471:Prostatic Neoplasms / Q000453:epidemiology / Q000235:genetics*; D014481:United States / Q000453:epidemiology
D014408:Biomarkers, Tumor