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

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Sarah Ouahoud1, Rutger J Jacobs1, Ludmilla L Kodach1

  • 1Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Utrecht, The Netherlands.

British Journal of Cancer
|October 27, 2021
PubMed
Abstract

Insights

Long-term statin use lowers colorectal cancer risk, particularly for SMAD4-positive tumors. This suggests statins may influence cancer development through the BMP pathway, not KRAS.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Long-term statin use shows a modest reduction in colorectal cancer (CRC) risk, but the underlying mechanisms remain unclear.
  • Previous research suggests statins may target the Bone Morphogenetic Protein (BMP) pathway, diverging from the commonly accepted KRAS pathway influence.
  • Understanding statin's molecular targets is crucial for elucidating their chemopreventive effects against CRC.

Purpose of the Study:

  • To investigate the association between statin use and the risk of developing specific molecular subtypes of colorectal cancer.
  • To explore the potential role of the BMP pathway in mediating statin's effect on CRC risk.
  • To determine if statin use is linked to CRC risk based on SMAD4 expression and KRAS/BRAF mutation status.

Main Methods:

  • A large-scale retrospective cohort study was conducted in the Netherlands, linking two unique population registries.
  • Identified 69,272 statin users and 94,753 controls, with colorectal cancer specimens traced for molecular subtyping.
  • Colorectal cancers were classified based on SMAD4 expression and the mutation status of KRAS and BRAF genes.

Main Results:

  • Statin use was associated with a reduced overall risk of developing colorectal cancer (Hazard Ratio: 0.77; 95% Confidence Interval: 0.66-0.89).
  • A significantly larger risk reduction was observed for SMAD4-positive colorectal cancer (Odds Ratio: 0.64; 95% Confidence Interval: 0.42-0.82).
  • No association was found between statin use and the risk of colorectal cancer with KRAS and/or BRAF mutations.

Conclusions:

  • Statin use is linked to a decreased risk of colorectal cancer, specifically in tumors exhibiting intact SMAD4 expression.
  • These findings support the hypothesis that statins may exert their chemopreventive effects on colorectal cancer through pathways involving SMAD4, potentially the BMP pathway.
  • Further research into the molecular mechanisms of statins in colorectal cancer prevention is warranted.

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