Journal of the National Cancer Institute Advance Access published online on December 11, 2007
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djm250
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© The Author 2007. Published by Oxford University Press.
ARTICLES |
Two Genome-wide Association Studies of Aggressive Prostate Cancer Implicate Putative Prostate Tumor Suppressor Gene DAB2IP
Affiliations of authors: Divisions of Genetic Basis of Human Disease (DD, MK, DB, LM) and Division of Integrative Cancer Genomics (CR, JC), Translational Genomics Research Institute, Phoenix, AZ; Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC (SZ, LD, YC, GL, JS, BC, WL, JWK, ERB, DAM, JX); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (FW, KB, HOA, HG); Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD (SDI, KEW, MG, GY, JS, BJT, AWP, PCW, WBI); Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University Hospital, Umeå, Sweden (PS); Department of Epidemiology, Harvard University, Boston, MA (HOA)
Correspondence to: Jianfeng Xu, MD, DrPH, Center for Human Genomics, Medical Center Blvd, Winston-Salem, NC 27157 (e-mail: jxu{at}wfubmc.edu), Henrik Grönberg, MD, PhD, Karolinska Institutet, Nobels väg 12 A, PO Box 281, Stockholm SE-171 77, Sweden (e-mail: henrik.gronberg{at}ki.se), or William B. Isaacs, PhD, Marburg 115, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287 (e-mail: wisaacs{at}jhmi.edu).
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.
| CONTEXT AND CAVEATS Prior knowledge The genetic variants that may predispose individuals to prostate cancer are largely unknown. Study design Single-nucleotide polymorphisms (SNPs) were tested for their association with aggressive prostate cancer in a population of case subjects and control subjects. SNPs that appeared to be strongly associated with the risk of aggressive prostate cancer in the exploratory analyses were then further tested in two independent populations. Contribution This study found evidence that a putative tumor suppressor gene may be associated with the risk of aggressive prostate cancer. Implications If confirmed, this work and previous studies that have associated genetic polymorphisms with prostate cancer may furnish a basis for improved screening and treatment. Limitations Possible effects of population stratification could not be fully controlled for in this study.
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Manuscript received May 9, 2007; revised September 27, 2007; accepted November 2, 2007.
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J Natl Cancer Inst 2007 99: 1823-1824.
J Natl Cancer Inst 2007 99: 1821.
J Natl Cancer Inst 2007 99: 1821.
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