Oncogenic mutations in cervical cancer - Wright - 2013 - Cancer - Wiley Online Library

Oncogenic mutations in cervical cancer - Wright - 2013 - Cancer - Wiley Online Library

Oncogenic mutations in cervical cancer

Genomic differences between adenocarcinomas and squamous cell carcinomas of the cervix

1. Alexi A. Wright MD, MPH^1,2,3,*,
2. Brooke E. Howitt MD^2,4,†,
3. Andrea P. Myers MD, PhD^1,2,†,
4. Suzanne E. Dahlberg PhD^5,6,
5. Emanuele Palescandolo PhD^1,2,7,
6. Paul Van Hummelen PhD^1,2,7,8,
7. Laura E. MacConaill PhD^1,2,7,8,
8. Melina Shoni MD²,
9. Nikhil Wagle MD^1,2,8,
10. Robert T. Jones BSc⁷,
11. Charles M. Quick MD^2,4,
12. Anna Laury MD^2,4,
13. Ingrid T. Katz MD, MHS^2,9,
14. William C. Hahn MD, PhD^1,2,7,8,
15. Ursula A. Matulonis MD^1,2,†,
16. Michelle S. Hirsch MD, PhD^2,4,†

Article first published online: 23 AUG 2013

DOI: 10.1002/cncr.28288

© 2013 American Cancer Society

Issue

Cancer

Early View (Online Version of Record published before inclusion in an issue)

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How to CiteAuthor InformationPublication History

1. Ursula Matulonis and Michelle Hirsch contributed equally to this work and share last authorship.
2. 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.
3. 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.

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Keywords:

• cervical cancer;
• adenocarcinoma;
• squamous cell carcinoma;
• somatic mutations;
• PIK3CA;
• EGFR;
• KRAS;
• DNA mutational analysis;
• human papillomavirus;
• mutation

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. © 2013 American Cancer Society.

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