An integrated analysis of germline and somatic, genetic and epigenetic alterations at 9p21.3 in glioblastoma

Authors

  • Junjie Feng PhD,

    1. Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
    2. Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
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  • Seong-Tae Kim PhD,

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

    1. Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
    2. Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
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  • Jin Woo Kim PhD,

    1. Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
    2. Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
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  • Zheng Zhang MS,

    1. Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
    2. Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
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  • Yi Zhu MS,

    1. Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
    2. Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
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  • Michael Berens PhD,

    1. Van Andel Research Institute, Grand Rapids, Michigan
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  • Jielin Sun PhD,

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

    Corresponding author
    1. Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
    2. Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
    3. Van Andel Research Institute, Grand Rapids, Michigan
    • Center for Cancer Genomics, Medical Center Boulevard, Winston-Salem, NC 27157

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  • The results published here are in whole based upon data generated by The Cancer Genome Atlas pilot project established by the National Cancer Institute and the National Human Genome Research Institute. Information about The Cancer Genome Atlas (TCGA) and the investigators and institutions who constitute the TCGA research network can be found at http://cancergenome.nih.gov.

Abstract

BACKGROUND:

Glioblastoma multiforme (GBM) is the most prevalent and deadly brain tumor. A variety of germline and somatic, genetic and epigenetic alterations at 9p21.3, which encode CDKN2A/CDKN2B tumor suppressor genes, have been isolatedly reported to be associated with GBM risk and prognosis.

METHODS:

To obtain a comprehensive view of these events, we leveraged the wide-spectrum GBM data available from The Cancer Genome Atlas project and performed an integrated analysis by systematically evaluating 9p21.3-related germline single-nucleotide polymorphisms, somatic copy number alterations (CNAs), DNA methylation, and microRNAs (miRNAs) with regard to CDKN2A/CDKN2B expression and patient prognosis in GBM.

RESULTS:

Our multivariate analysis indicated that expression of CDKN2A and CDKN2B was both strongly affected by CNAs (P = 1.00 × 10−4 and 2.37 × 10−14). The miRNAs hsa-mir-126, hsa-mir-517a, and hsa-mir-125b exhibited significant negative correlations with CDKN2A expression (P = 0.003, 0.041, and 0.050). Survival analysis showed that complete 9p21.3 loss and low CDKN2B expression were associated with worse prognosis for both tumor progression/recurrence-free survival (P = .041 and .019) and patient overall survival (P = .043 and .021) after adjustment for age and treatment, and that higher methylation at cg17449661 predicted poorer overall survival (P = .048).

CONCLUSION:

Representing one of the first attempts to systematically integrate various levels of alterations associated with the often complex cancer genomes and phenotypes, our study provided a holistic view and a mechanistic explanation over the functional connections of multiple 9p21.3-related events in GBM, as well as clinically useful biomarker information for predicting disease outcomes. Cancer 2012;. © 2011 American Cancer Society.

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