Cyclin D1 is frequently overexpressed in microsatellite unstable colorectal cancer, independent of CpG island methylator phenotype

Authors

  • K Nosho,

    1. Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School
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    • *

      These authors contributed equally to this work.

  • T Kawasaki,

    1. Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School
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    • *

      These authors contributed equally to this work.

  • A T Chan,

    1. Department of Medicine, Channing Laboratory, Brigham and Women’s Hospital, and Harvard Medical School
    2. Gastrointestinal Unit, Massachusetts General Hospital
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  • M Ohnishi,

    1. Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School
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  • Y Suemoto,

    1. Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School
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  • G J Kirkner,

    1. Department of Medicine, Channing Laboratory, Brigham and Women’s Hospital, and Harvard Medical School
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  • C S Fuchs,

    1. Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School
    2. Department of Medicine, Channing Laboratory, Brigham and Women’s Hospital, and Harvard Medical School
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  • S Ogino

    1. Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School
    2. Department of Pathology, Brigham and Women’s Hospital, and Harvard Medical School
    3. Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
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Shuji Ogino, MD, PhD, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, 44 Binney St, Room JF-215C, Boston, MA 02115, USA. e-mail: shuji_ogino@dfci.harvard.edu

Abstract

Aims:  Cyclin D1 and cyclin-dependent kinases are commonly activated in colorectal cancer. Microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) are important molecular classifiers in colorectal cancer. The aim was to clarify the relationship between cyclin D1, MSI and CIMP.

Methods and results:  Among 865 colorectal cancers with MSI and CIMP data, 246 tumours (28.4%) showed cyclin D1 overexpression by immunohistochemistry. DNA methylation in p14 and eight CIMP-specific promoters (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) was quantified by real-time polymerase chain reaction (MethyLight). Both MSI-high and CIMP-high were associated with cyclin D1 overexpression (P < 0.0001). After tumours were stratified by MSI and CIMP status, the relationship between MSI-high and cyclin D1 persisted (P ≤ 0.02), whereas the relationship between CIMP-high and cyclin D1 did not. Cyclin D1 overexpression was correlated with BRAF mutation (P = 0.0001), p27 loss (P = 0.0007) and p16 loss (P = 0.02), and inversely with p53 expression (P = 0.0002) and p21 loss (P < 0.0001). After stratification by MSI status, the inverse relationship between cyclin D1 and p21 loss still persisted (P < 0.008).

Conclusions:  Cyclin D1 activation is associated with MSI and inversely with p21 loss in colorectal cancers. Cyclin D1 may play an important role in the development of MSI-high tumours, independent of CIMP status.

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