Oncogenic mutations in cervical cancer

Genomic differences between adenocarcinomas and squamous cell carcinomas of the cervix

Authors

  • Alexi A. Wright MD, MPH,

    Corresponding author
    1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
    3. Centers for Outcomes and Policy Research and Psychosocial Epidemiology and Outcomes Research, Dana-Farber Cancer Institute, Boston, Massachusetts
    • Corresponding author: Alexi A. Wright, MD, MPH, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215; Fax: (617) 632-3479; alexi_wright@dfci.harvard.edu

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  • Brooke E. Howitt MD,

    1. Harvard Medical School, Boston, Massachusetts
    2. Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Boston, Massachusetts
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    • Brooke Howitt and Andrea Myers contributed equally to this work and share second authorship.

  • Andrea P. Myers MD, PhD,

    1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
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    • Brooke Howitt and Andrea Myers contributed equally to this work and share second authorship.

  • Suzanne E. Dahlberg PhD,

    1. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
    2. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts
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  • Emanuele Palescandolo PhD,

    1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
    3. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts
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  • Paul Van Hummelen PhD,

    1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
    3. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts
    4. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts
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  • Laura E. MacConaill PhD,

    1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
    3. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts
    4. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts
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  • Melina Shoni MD,

    1. Harvard Medical School, Boston, Massachusetts
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  • Nikhil Wagle MD,

    1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
    3. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts
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  • Robert T. Jones BSc,

    1. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts
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  • Charles M. Quick MD,

    1. Harvard Medical School, Boston, Massachusetts
    2. Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Boston, Massachusetts
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  • Anna Laury MD,

    1. Harvard Medical School, Boston, Massachusetts
    2. Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Boston, Massachusetts
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  • Ingrid T. Katz MD, MHS,

    1. Harvard Medical School, Boston, Massachusetts
    2. Department of Medicine, Divisions of Women's Health and Infectious Disease, Brigham and Women's Hospital, Boston, Massachusetts
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  • William C. Hahn MD, PhD,

    1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
    3. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts
    4. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts
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  • Ursula A. Matulonis MD,

    1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
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    • Brooke Howitt and Andrea Myers contributed equally to this work and share second authorship.

  • Michelle S. Hirsch MD, PhD

    1. Harvard Medical School, Boston, Massachusetts
    2. Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Boston, Massachusetts
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    • Brooke Howitt and Andrea Myers contributed equally to this work and share second authorship.


  • Ursula Matulonis and Michelle Hirsch contributed equally to this work and share last authorship.

  • We thank Courtney Doyle, BA; Christina Go, BSc; Christina Roden, BSc; Aaron Thorner, PhD; Zachary Herbert, MSc; Matthew Ducar, BSc; and Ravali Adusimilli, BSc for additional administrative, technical, and analytic support.

  • The funding organizations had no role in the design or conduct of the study; the collection, analysis, or preparation of the data; or the preparation, review, or approval of the article. Any opinions, findings, or conclusions expressed in this material are those of the authors and do not necessarily reflect those of the American Cancer Society, the American Society of Clinical Oncology, or the Conquer Cancer Foundation.

Abstract

BACKGROUND

Cervical cancer is the second leading cause of cancer deaths among women worldwide. The objective of this study was to describe the most common oncogenic mutations in cervical cancers and to explore genomic differences between the 2 most common histologic subtypes: adenocarcinoma and squamous cell carcinoma.

METHODS

A high-throughput genotyping platform, termed Oncomap, was used to interrogate 80 cervical tumors for 1250 known mutations in 139 cancer genes. Samples were analyzed using a mass spectrometry-based genotyping platform and were validated using orthogonal chemistry. Epidermal growth factor receptor (EGFR) mutations were further validated by massive parallel sequencing. Human papilloma virus (HPV) genotyping also was performed.

RESULTS

Validated mutations were detected in 48 of 80 tumors (60%) examined. The highest mutation rates were in the genes phosphatidylinositol 3-kinase, catalytic subunit α (PIK3CA) (31.3%); Kirsten rat sarcoma viral oncogene homolog (KRAS) (8.8%); and EGFR (3.8%). PIK3CA mutation rates did not differ significantly between adenocarcinomas and squamous cell carcinomas (25% vs 37.5%, respectively; P = .33). In contrast, KRAS mutations were identified only in adenocarcinomas (17.5% vs 0%; P = .01), and a novel EGFR mutation was detected only in squamous cell carcinomas (0% vs 7.5%; P = .24). There were no associations between HPV-16 or HPV-18 and somatic mutations or overall survival. In adjusted analyses, PIK3CA mutations were associated with shorter survival (67.1 months vs 90.3 months; hazard ratio, 9.1; 95% confidence interval, 2.8-29.5 months; P < .001).

CONCLUSIONS

Cervical cancers harbor high rates of potentially targetable oncogenic mutations. In addition, cervical squamous cell carcinoma and adenocarcinoma have distinct molecular profiles, suggesting that clinical outcomes may be improved with the use of more tailored treatment strategies, including PI3K and MEK inhibitors. Cancer 2013;119:3776–3783. © 2013 American Cancer Society.

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