Aspirin and the Risk of Colorectal Cancer in Relation to the Expression of 15-Hydroxyprostaglandin Dehydrogenase (HPGD)

Sci Transl Med 23 April 2014: 
Vol. 6, Issue 233, p. 233re2 
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3008481

• REPORTS

CANCER

Aspirin and the Risk of Colorectal Cancer in Relation to the Expression of 15-Hydroxyprostaglandin Dehydrogenase (HPGD)

1. Stephen P. Fink1,*, 
2. Mai Yamauchi2,*, 
3. Reiko Nishihara2,3,*,†, 
4. Seungyoun Jung4, 
5. Aya Kuchiba2,3,
6. Kana Wu3,4, 
7. Eunyoung Cho4,5, 
8. Edward Giovannucci3,4,6, 
9. Charles S. Fuchs2,4,‡, 
10. Shuji Ogino2,6,7,8,‡,
11. Sanford D. Markowitz1,†‡ and 
12. Andrew T. Chan4,9,†‡

+Author Affiliations

1. ¹Department of Medicine and Case Comprehensive Cancer Center, Case Western Reserve University and University Hospitals Case Medical Center, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
2. ²Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA.
3. ³Department of Nutrition, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA.
4. ⁴Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA.
5. ⁵Department of Dermatology, Warren Alpert Medical School of Brown University, 339 Eddy Street, Providence, RI 02903, USA.
6. ⁶Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA.
7. ⁷Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA.
8. ⁸Department of Pathology, Brigham and Women’s Hospital, Boston and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
9. ⁹Division of Gastroenterology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA.

+Author Notes

• ↵* S.P.F., M.Y., and R.N. contributed equally to this work.
• ↵‡ C.S.F., S.O., S.D.M., and A.T.C. contributed equally to this work.

1. ↵†Corresponding author. E-mail: rnishiha@hsph.harvard.edu (R.N.); sxm10@cwru.edu (S.D.M.);achan@mgh.harvard.edu (A.T.C.)

Abstract

Aspirin use reduces the risk of colorectal neoplasia, at least in part, through inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase 2)–related pathways. Hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide) (15-PGDH, HPGD) is down-regulated in colorectal cancers and functions as a metabolic antagonist of PTGS2. We hypothesized that the effect of aspirin may be antagonized by low 15-PGDH expression in the normal colon. In the Nurses’ Health Study and the Health Professionals Follow-Up Study, we collected data on aspirin use every 2 years and followed up participants for diagnoses of colorectal cancer. Duplication-method Cox proportional, multivariable-adjusted, cause-specific hazards regression for competing risks data was used to compute hazard ratios (HRs) for incident colorectal cancer according to 15-PGDH mRNA expression level measured in normal mucosa from colorectal cancer resections. Among 127,865 participants, we documented 270 colorectal cancer cases from which we could assess 15-PGDH expression. Compared with nonuse, regular aspirin use was associated with lower risk of colorectal cancer that developed within a background of colonic mucosa with high 15-PGDH expression [multivariable HR, 0.49; 95% confidence interval (CI), 0.34 to 0.71], but not with low 15-PGDH expression (multivariable HR, 0.90; 95% CI, 0.63 to 1.27) (P for heterogeneity = 0.018). Regular aspirin use was associated with lower incidence of colorectal cancers arising in association with high 15-PGDH expression, but not with low 15-PGDH expression in normal colon mucosa. This suggests that 15-PGDH expression level in normal colon mucosa may serve as a biomarker that may predict stronger benefit from aspirin chemoprevention.

• Copyright © 2014, American Association for the Advancement of Science

Citation: S. P. Fink, M. Yamauchi, R. Nishihara, S. Jung, A. Kuchiba, K. Wu, E. Cho, E. Giovannucci, C. S. Fuchs, S. Ogino, S. D. Markowitz, A. T. Chan, Aspirin and the Risk of Colorectal Cancer in Relation to the Expression of 15-Hydroxyprostaglandin Dehydrogenase (HPGD). Sci. Transl. Med. 6, 233re2 (2014).

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