Inherited genetic variant predisposes to aggressive but not indolent prostate cancer.
Autopsy studies suggest that most aging men will develop lesions that, if detected clinically, would be diagnosed as prostate cancer (PCa). Most of these cancers are indolent and remain localized; however, a subset of PCa is aggressive and accounts for more than 27,000 deaths in the United States annually. Identification of factors specifically associated with risk for more aggressive PCa is urgently needed to reduce overdiagnosis and overtreatment of this common disease. To search for such factors, we compared the frequencies of SNPs among PCa patients who were defined as having either more aggressive or less aggressive disease in four populations examined in the Genetic Markers of Susceptibility (CGEMS) study performed by the National Cancer Institute. SNPs showing possible associations with disease severity were further evaluated in an additional three independent study populations from the United States and Sweden. In total, we studied 4,829 and 12,205 patients with more and less aggressive disease, respectively. We found that the frequency of the TT genotype of SNP rs4054823 at 17p12 was consistently higher among patients with more aggressive compared with less aggressive disease in each of the seven populations studied, with an overall P value of 2.1 x 10(-8) under a recessive model, exceeding the conservative genome-wide significance level. The difference in frequency was largest between patients with high-grade, non-organ-confined disease compared with those with low-grade, organ-confined disease. This study demonstrates that inherited variants predisposing to aggressive but not indolent PCa exist in the genome, and suggests that the clinical potential of such variants as potential early markers for risk of aggressive PCa should be evaluated.
Xu
Jianfeng
J
Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. jxu@wfubmc.edu
Zheng
Siqun Lilly
SL
Isaacs
Sarah D
SD
Wiley
Kathleen E
KE
Wiklund
Fredrik
F
Sun
Jielin
J
Kader
A Karim
AK
Li
Ge
G
Purcell
Lina D
LD
Kim
Seong-Tae
ST
Hsu
Fang-Chi
FC
Stattin
Pär
P
Hugosson
Jonas
J
Adolfsson
Jan
J
Walsh
Patrick C
PC
Trent
Jeffrey M
JM
Duggan
David
D
Carpten
John
J
Grönberg
Henrik
H
Isaacs
William B
WB
D014408:Biomarkers, Tumor / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012042:Registries; D013548:Sweden; D014481:United States
D014408:Biomarkers, Tumor