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A Germline DNA Polymorphism Enhances Alternative Splicing of the KLF6 Tumor Suppressor Gene and Is Associated with Increased Prostate Cancer Risk

Departments of ¹ Medicine and ² Human Genetics, Mount Sinai School of Medicine, New York, New York; ³ Departments of Health Sciences Research and ⁴ Laboratory Medicine and Pathology, Mayo Clinic Foundation, Rochester, Minnesota; ⁵ Brady Urological Institute, Johns Hopkins Medical Institution, Baltimore, Maryland; ⁶ Divisions of Clinical Human Biology and ⁷ Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington; ⁸ Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan; ⁹ Department of Pathology, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts; and ¹⁰ Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Requests for reprints: John A. Martignetti, Department of Human Genetics, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, NY 10029. Phone: 212-659-6744; Fax: 212-849-2638; E-mail: john.martignetti{at}mssm.edu.

Prostate cancer is a leading and increasingly prevalent cause of cancer death in men. Whereas family history of disease is one of the strongest prostate cancer risk factors and suggests a hereditary component, the predisposing genetic factors remain unknown. We first showed that KLF6 is a tumor suppressor somatically inactivated in prostate cancer and since then, its functional loss has been further established in prostate cancer cell lines and other human cancers. Wild-type KLF6, but not patient-derived mutants, suppresses cell growth through p53-independent transactivation of p21. Here we show that a germline KLF6 single nucleotide polymorphism, confirmed in a tri-institutional study of 3,411 men, is significantly associated with an increased relative risk of prostate cancer in men, regardless of family history of disease. This prostate cancer–associated allele generates a novel functional SRp40 DNA binding site and increases transcription of three alternatively spliced KLF6 isoforms. The KLF6 variant proteins KLF6-SV1 and KLF6-SV2 are mislocalized to the cytoplasm, antagonize wtKLF6 function, leading to decreased p21 expression and increased cell growth, and are up-regulated in tumor versus normal prostatic tissue. Thus, these results are the first to identify a novel mechanism of self-encoded tumor suppressor gene inactivation and link a relatively common single nucleotide polymorphism to both regulation of alternative splicing and an increased risk in a major human cancer.

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