Genetic and epigenetic inactivation of LPL gene in human prostate cancer

Authors

  • Jin Woo Kim,

    1. Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC
    2. Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC
    3. Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC
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  • Yu Cheng,

    1. Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC
    2. Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC
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  • Wennuan Liu,

    1. Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC
    2. Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC
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  • Tao Li,

    1. Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC
    2. Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC
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  • Srinivasan Yegnasubramanian,

    1. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD
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  • Siqun L. Zheng,

    1. Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC
    2. Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC
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  • Jianfeng Xu,

    1. Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC
    2. Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC
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  • William B. Isaacs,

    Corresponding author
    1. Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD
    • Marburg 115, Johns Hopkins Hospital, 600 N. Wolfe Street, Baltimore, MD 21287, USA
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    • Fax: +410-955-0833.

  • Bao-Li Chang

    Corresponding author
    1. Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC
    2. Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC
    • Center for Cancer Genomics and Center for Human Genomics, Medical Center Blvd., Winston-Salem, NC 27157, USA
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    • Fax: +336-713-7566.


Abstract

Lipoprotein lipase (LPL) is in chromosome 8p22, site of one of the most common somatic deletions in prostate tumors. Additionally, a CpG island (CGI) was identified in the LPL promoter region. To test the hypothesis that LPL is a tumor suppressor gene, which is inactivated by somatic deletion and hypermethylation in prostate cancer, we evaluated somatic DNA deletion and methylation status at LPL in 56 pairs of DNA samples isolated from prostate cancer tissues and matching normal controls and 11 prostate cell lines. We found that the DNA in 21 of 56 primary cancers (38%) was methylated in the LPL promoter CGI, whereas no methylation was detected in any normal samples. In addition, we found a hemizygous deletion at LPL in 38 of the 56 tumors (68%). When the results of deletion and methylation were considered together, we found LPL promoter CGI methylation occurred in 45% of LPL deleted tumors and in 22% of LPL retained tumors. Within several clinical characteristics tested, the preoperative PSA levels were found to be significantly higher in subjects with LPL promoter CGI methylation compared with subjects without LPL promoter methylation (p = 0.0012). Additionally, demethylation of the LPL promoter CGI was accompanied by transcriptional reactivation of LPL in the prostate cancer cell lines DU145 and PC3. In summary, we report a novel finding that the LPL gene is commonly methylated in prostate tumors, and our results suggest that biallelic inactivation of LPL by chromosomal deletion and promoter hypermethylation may play a role in human prostate cancer. © 2008 Wiley-Liss, Inc.

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