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SMO Expression in Colorectal Cancer: Associations with Clinical, Pathological, and Molecular Features

  • Colorectal Cancer
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Smoothened, frizzled family receptor (SMO) is an important component of the hedgehog signaling pathway, which has been implicated in various human carcinomas. However, clinical, molecular, and prognostic associations of SMO expression in colorectal cancer remain unclear.

Methods

Using a database of 735 colon and rectal cancers in the Nurse’s Health Study and the Health Professionals Follow-up Study, we examined the relationship of tumor SMO expression (assessed by immunohistochemistry) to prognosis, and to clinical, pathological, and tumor molecular features, including mutations of KRAS, BRAF, and PIK3CA, microsatellite instability, CpG island methylator phenotype (CIMP), LINE-1 methylation, and expression of phosphorylated AKT and CTNNB1.

Results

SMO expression was detected in 370 tumors (50 %). In multivariate logistic regression analysis, SMO expression was independently inversely associated with phosphorylated AKT expression [odds ratio (OR) 0.48; 95 % confidence interval (CI) 0.34–0.67] and CTNNB1 nuclear localization (OR 0.48; 95 % CI 0.35–0.67). SMO expression was not significantly associated with colorectal cancer-specific or overall survival. However, in CIMP-high tumors, but not CIMP-low/0 tumors, SMO expression was significantly associated with better colorectal cancer-specific survival (log-rank P = 0.012; multivariate hazard ratio, 0.36; 95 % CI 0.13–0.95; P interaction = 0.035, for SMO and CIMP status).

Conclusions

Our data reveal novel potential associations between the hedgehog, the WNT/CTNNB1, and the PI3K (phosphatidylinositol-4,5-bisphosphonate 3-kinase)/AKT pathways, supporting pivotal roles of SMO and hedgehog signaling in pathway networking. SMO expression in colorectal cancer may interact with tumor CIMP status to affect patient prognosis, although confirmation by future studies is needed.

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Acknowledgment

Supported in part by USA National Institute of Health (NIH) [P01 CA87969 (to S. E. Hankinson), UM1 CA167552 and P01 CA55075 (to W. C. Willett), R01 CA137178 (to A.T.C.), P50 CA127003 (to C.S.F.), and R01 CA151993 (to S.O.)]; the Bennett Family Fund for Targeted Therapies Research; and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. PL was supported by a Harvard University Frank Knox Memorial Fellowship and a fellowship from the Chief Scientist Office, Scotland. A.T.C is a Damon Runyon Clinical Investigator. We would like to thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-Up Study for their valuable contributions, as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR PA, RI, SC, TN, TX, VA, WA, and WY. In addition, this study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. Certain data used in this publication were obtained from the DPH. The authors assume full responsibility for analyses and interpretation of these data. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. Funding agencies did not have any role in the design of the study; the collection, analysis, or interpretation of the data; the decision to submit the article for publication; or the writing of the article.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    Tingting Li MD, PhD, Xiaoyun Liao MD, PhD, Paul Lochhead MB, ChB, Mai Yamauchi PhD, Reiko Nishihara PhD, Kentaro Inamura MD, PhD, Sun A. Kim MD, PhD, Kosuke Mima MD, PhD, Yasutaka Sukawa MD, PhD, Aya Kuchiba PhD, Yu Imamura MD, PhD, Jeffrey A. Meyerhardt MD, MPH, Charles S. Fuchs MD, MPH, Shuji Ogino MD, PhD, MS & Zhi Rong Qian MD, PhD

  2. Department of Geriatric Gastroenterology, Chinese PLA General Hospital, Beijing, China

    Tingting Li MD, PhD

  3. Department of Pathology, University of Tokyo Hospital, Tokyo, Japan

    Teppei Morikawa MD, PhD

  4. Department of Nutrition, Harvard School of Public Health, Boston, MA, USA

    Reiko Nishihara PhD & Aya Kuchiba PhD

  5. Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Kentaro Inamura MD, PhD

  6. Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan

    Yoshifumi Baba MD, PhD

  7. Department of Oral Pathology, Kagoshima University, Kagoshima, Japan

    Kaori Shima DDS, PhD

  8. Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA

    Andrew T. Chan MD, MPH

  9. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Charles S. Fuchs MD, MPH

  10. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    Shuji Ogino MD, PhD, MS

  11. Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA

    Shuji Ogino MD, PhD, MS

Authors
  1. Tingting Li MD, PhD
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  2. Xiaoyun Liao MD, PhD
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  3. Paul Lochhead MB, ChB
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  4. Teppei Morikawa MD, PhD
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  5. Mai Yamauchi PhD
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  6. Reiko Nishihara PhD
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  7. Kentaro Inamura MD, PhD
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  8. Sun A. Kim MD, PhD
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  9. Kosuke Mima MD, PhD
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  10. Yasutaka Sukawa MD, PhD
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  11. Aya Kuchiba PhD
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  12. Yu Imamura MD, PhD
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  13. Yoshifumi Baba MD, PhD
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  14. Kaori Shima DDS, PhD
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  15. Jeffrey A. Meyerhardt MD, MPH
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  16. Andrew T. Chan MD, MPH
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  17. Charles S. Fuchs MD, MPH
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  18. Shuji Ogino MD, PhD, MS
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  19. Zhi Rong Qian MD, PhD
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Corresponding authors

Correspondence to Shuji Ogino MD, PhD, MS or Zhi Rong Qian MD, PhD.

Additional information

Tingting Li, Xiaoyun Liao, Paul Lochhead, Teppei Morikawa, Shuji Ogino, and Zhi Rong Qian contributed equally.

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Li, T., Liao, X., Lochhead, P. et al. SMO Expression in Colorectal Cancer: Associations with Clinical, Pathological, and Molecular Features. Ann Surg Oncol 21, 4164–4173 (2014). https://doi.org/10.1245/s10434-014-3888-y

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