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Deletion of a Small Consensus Region at 6q15, Including the MAP3K7 Gene, Is Significantly Associated with High-Grade Prostate Cancers

Authors' Affiliations: ¹ Center for Human Genomics, Departments of ² Cancer Biology and ³ Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina; ⁴ Department of Pathology, University of California at Los Angeles, Los Angeles, California; and ⁵ Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland

Requests for reprints: Jianfeng Xu, Center for Human Genomics, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. Phone: 336-713-7500; Fax: 336-713-7566; E-mail: jxu{at}wfubmc.edu or William B. Isaacs, Department of Urology, Johns Hopkins Medical Institutions, Marburg 115, 600 North Wolfe Street, Baltimore, MD 21287. Phone: 410-955-2518; Fax: 336-502-9336; E-mail: wisaacs{at}jhmi.edu.

Purpose: Chromosome 6q14-21 is commonly deleted in prostate cancers, occurring in 22% of all tumors and 40% of metastatic tumors. However, candidate prostate tumor suppressor genes in this region have not been identified, in part due to the large and broad nature of the deleted region implicated in previous studies.

Experimental Design: We first used high-resolution Affymetrix single nucleotide polymorphism arrays to examine DNA from malignant and matched nonmalignant cells from 55 prostate cancer patients. We identified a small consensus region on 6q14-21 and evaluated the deletion status within the region among additional 40 tumors and normal pairs using quantitative PCR and fluorescence in situ hybridization. We finally tested the association between the deletion and Gleason score using the Fisher's exact test.

Results: Tumors with small, interstitial deletions at 6q14-21 defined an 817-kb consensus region that is affected in 20 of 21 tumors. The MAP3K7 gene is one of five genes located in this region. In total, MAP3K7 was deleted in 32% of 95 tumors. Importantly, deletion of MAP3K7 was highly associated with higher-grade disease, occurring in 61% of tumors with Gleason score 8 compared with only 22% of tumors with Gleason score 7. The difference was highly significant (P = 0.001).

Conclusion: Our study provides strong evidence for the first time that a small deletion at 6q15, including the MAP3K7 gene and four other genes, is associated with high-grade prostate cancers. Although the deletion may be a marker for high-grade prostate cancer, additional studies are needed to understand its molecular mechanisms.

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