title: Inherited genetic variant predisposes to aggressive but not indolent prostate cancer.
abstract: 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.
authors.affiliation: Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. jxu@wfubmc.edu
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.forename: Siqun Lilly
authors.initials: SL
authors.lastname: Zheng
authors.forename: Sarah D
authors.initials: SD
authors.lastname: Isaacs
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Wiley
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wiklund
authors.forename: Jielin
authors.initials: J
authors.lastname: Sun
authors.forename: A Karim
authors.initials: AK
authors.lastname: Kader
authors.forename: Ge
authors.initials: G
authors.lastname: Li
authors.forename: Lina D
authors.initials: LD
authors.lastname: Purcell
authors.forename: Seong-Tae
authors.initials: ST
authors.lastname: Kim
authors.forename: Fang-Chi
authors.initials: FC
authors.lastname: Hsu
authors.forename: Pär
authors.initials: P
authors.lastname: Stattin
authors.forename: Jonas
authors.initials: J
authors.lastname: Hugosson
authors.forename: Jan
authors.initials: J
authors.lastname: Adolfsson
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Walsh
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Trent
authors.forename: David
authors.initials: D
authors.lastname: Duggan
authors.forename: John
authors.initials: J
authors.lastname: Carpten
authors.forename: Henrik
authors.initials: H
authors.lastname: Grönberg
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
mesh_terms: 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
chemical_list: D014408:Biomarkers, Tumor