Genome-wide screen for prostate cancer susceptibility genes in men with clinically significant disease.
BACKGROUND
One of the difficulties confronting genetic studies of prostate cancer is the complex and heterogeneous etiology. Given the high population frequency of lesions meeting the histological definition of prostate cancer, a significant portion of men with a positive family history may be diagnosed due to increased surveillance and associated higher likelihood of biopsy. Over diagnosis decreases power to detect genes that increase susceptibility to a clinically significant prostate cancer.


METHODS
We re-evaluated all 623 men with prostate cancer in our 188 hereditary prostate cancer families and identified a subset of 244 men with more aggressive disease based upon meeting at least one of the following clinical and/or pathologic criteria: tumor grade Gleason score > or = 7, tumor stage T2c or higher, pretreatment PSA > or = 20 ng/ml, rising PSA after treatment, evidence of metastasis, or death from prostate cancer.


RESULTS
Genome-wide screens were re-performed by defining men as affected only if they met the criteria for clinically significant disease. The new analyses identified stronger evidence for linkage in Xq27-28 and 22q, as well as several novel loci, including 3p and 9p.


CONCLUSIONS
Although, these results need to be confirmed in independent studies, our approach represents an important step to overcome the impact of over diagnosis in genetic studies of prostate cancer. Larger studies that incorporate this approach are needed.
Chang
Bao-Li
BL
Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Isaacs
Sarah D
SD
Wiley
Kathy E
KE
Gillanders
Elizabeth M
EM
Zheng
S Lilly
SL
Meyers
Deborah A
DA
Walsh
Patrick C
PC
Trent
Jeffrey M
JM
Xu
Jianfeng
J
Isaacs
William B
WB
D005192:Family Health; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D015894:Genome, Human; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D012307:Risk Factors; D012720:Severity of Illness Index