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Statin use is associated with a reduced incidence of colorectal cancer expressing SMAD4



Long-term use of statins is associated with a small reduced risk of colorectal cancer but their mechanism of action is not well understood. While they are generally believed to act on KRAS, we have previously proposed that they act via influencing the BMP pathway. The objective of this study was to look for associations between statin use and the risk of developing colorectal cancer of a particular molecular subtype.


By linking two registries unique to the Netherlands, 69,272 statin users and 94,753 controls were identified and, if they developed colorectal cancer, their specimens traced. Colorectal cancers were molecularly subtyped according to the expression of SMAD4 and the mutation status of KRAS and BRAF.


Statin use was associated with a reduction in the risk of developing colorectal cancer regardless of molecular subtype (HR 0.77; 95% CI 0.66–0.89) and a larger reduction in the risk of developing SMAD4-positive colorectal cancer (OR 0.64; 95% CI 0.42–0.82). There was no relationship between statin use and the risk of developing colorectal cancer with a mutation in KRAS and/or BRAF.


Statin use is associated with a reduced risk of developing colorectal cancer with intact SMAD4 expression.

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Fig. 1: Colorectal cancer incidence and duration of statin use.
Fig. 2: SMAD4 expression in immunohistochemical assays of colorectal cancer tissue.

Data availability

The data included in this study are available directly from the PHARMO database network (


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This work was funded by the Dutch Digestive Foundation—Grant number WO 09-32.

Author information




SO, RJ, LRAB and PV performed experiments and wrote the manuscript. NW, BW and TW performed experiments. EB and HP performed the statistical analyses. RH, LJACH, LK and HM designed the study. MS critically assessed the manuscript. JH conceived the study, acquired funding, wrote the manuscript.

Corresponding author

Correspondence to James C. H. Hardwick.

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Formal Medical Ethical permission for this study was deemed unnecessary after consultation with the Medical Ethical Committee of the Leiden University Medical Centre as it was retrospective and anonymous and complied with the ethical requirements of the 2 databases used, PALGA and PHARMO.

Competing interests

The authors declare no competing interests.

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Ouahoud, S., Jacobs, R.J., Kodach, L.L. et al. Statin use is associated with a reduced incidence of colorectal cancer expressing SMAD4. Br J Cancer (2021).

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