Two Genome-wide Association Studies of Aggressive Prostate Cancer Implicate Putative Prostate Tumor Suppressor Gene DAB2IP

• Published in: JNCI : Journal of the National Cancer Institute Vol. 99; no. 24; pp. 1836 - 1844
• Main Authors: Duggan, David, Zheng, Siqun L., Knowlton, Michele, Benitez, Debbie, Dimitrov, Latchezar, Wiklund, Fredrik, Robbins, Christiane, Isaacs, Sarah D., Cheng, Yu, Li, Ge, Sun, Jielin, Chang, Bao-Li, Marovich, Leslie, Wiley, Kathleen E., Bälter, Katarina, Stattin, Pär, Adami, Hans-Olov, Gielzak, Marta, Yan, Guifang, Sauvageot, Jurga, Liu, Wennuan, Kim, Jin Woo, Bleecker, Eugene R., Meyers, Deborah A., Trock, Bruce J., Partin, Alan W., Walsh, Patrick C., Isaacs, William B., Grönberg, Henrik, Xu, Jianfeng, Carpten, John D.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 19.12.2007; Oxford Publishing Limited (England)
• Subjects: adult; African American; African Americans; African Americans - genetics; Aged; allele; Biological; Biomarkers, Tumor - genetics; cancer risk; case control study; Case-Control Studies; Caucasian; controlled study; dab2ip gene; DAB2IP protein; European Continental Ancestry Group; European Continental Ancestry Group - genetics; gene; gene location; Genes; Genes, Tumor Suppressor; genetic association; genetic code; genetic marker; genetic model; genetic predisposition; Genetic Predisposition to Disease; Genetic research; genetic susceptibility; genetic variability; genetics; Genomics; Genotype; guanosine triphosphatase activating protein; human; Humans; major clinical study; Male; Middle Aged; Odds Ratio; Oncology; Polymorphism; Polymorphism, Single Nucleotide; population research; priority journal; Prostate cancer; prostate tumor; Prostatic Neoplasms; Prostatic Neoplasms - genetics; ras GTPase-Activating Proteins; ras GTPase-Activating Proteins - genetics; risk; Risk Assessment; risk factor; Risk Factors; Single Nucleotide; single nucleotide polymorphism; statistical significance; suppressor gene; Sweden; tumor marker; Tumor Markers; Tumor Suppressor; tumor suppressor gene; unclassified drug; Sweden; Biological/genetics; Tumor Markers; Genes; Single Nucleotide; Tumor Suppressor; Polymorphism
• ISSN: 0027-8874; 1460-2105; 1460-2105
• DOI: 10.1093/jnci/djm250

Background The consistent finding of a genetic susceptibility to prostate cancer suggests that there are germline sequence variants predisposing individuals to this disease. These variants could be useful in screening and treatment. Methods We performed an exploratory genome-wide association scan in 498 men with aggressive prostate cancer and 494 control subjects selected from a population-based case–control study in Sweden. We combined the results of this scan with those for aggressive prostate cancer from the publicly available Cancer Genetic Markers of Susceptibility (CGEMS) Study. Single-nucleotide polymorphisms (SNPs) that showed statistically significant associations with the risk of aggressive prostate cancer based on two-sided allele tests were tested for their association with aggressive prostate cancer in two independent study populations composed of individuals of European or African American descent using one-sided tests and the genetic model (dominant or additive) associated with the lowest value in the exploratory study. Results Among the approximately 60000 SNPs that were common to our study and CGEMS, we identified seven that had a similar (positive or negative) and statistically significant (P<.01) association with the risk of aggressive prostate cancer in both studies. Analysis of the distribution of these SNPs among 1032 prostate cancer patients and 571 control subjects of European descent indicated that one, rs1571801, located in the DAB2IP gene, which encodes a novel Ras GTPase-activating protein and putative prostate tumor suppressor, was associated with aggressive prostate cancer (one-sided P value = .004). The association was also statistically significant in an African American study population that included 210 prostate cancer patients and 346 control subjects (one-sided P value = .02). Conclusion A genetic variant in DAB2IP may be associated with the risk of aggressive prostate cancer and should be evaluated further.