lunes, 28 de abril de 2014

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

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



Sci Transl Med
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. 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.
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. 6233re2 (2014).


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