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Published on: July 25, 2017
Genetically predicted TTK inhibition and its association with reduced breast cancer risk: a two-step Mendelian
Jia Liu1, Mohan Liu1, Ying Xu1
1Department of Breast Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Background:
BOS172722, a selective TTK inhibitor, shows promise for Breast Cancer (BC) treatment. The role of gut microbiota as a potential mediator in this process has not been established. This Mendelian Randomization (MR) study investigated the causal effect of TTK inhibition on BC and conducted an exploratory analysis of potential mediation by gut microbiota.
Methods:
A two-step, two-sample drug target MR analysis used IEU Open GWAS project datasets. The inverse-variance-weighted method estimated causal effects, with sensitivity tests confirming robustness. False Discovery Rate (FDR) correction was applied to analyses for all microbial taxa.
Results:
Genetically predicted TTK inhibition significantly reduced BC risk (OR = 0.667, 95 % CI 0.543-0.819; FDR-adjusted p < 0.001). In secondary analyses, initial uncorrected results indicated nominal associations between TTK inhibition and 20 gut microbial taxa, and between 6 taxa and BC risk. However, none of these microbiota-related associations remained statistically significant after FDR correction (all q-values >0.1). An exploratory mediation analysis on Genus Anaerostipes id.1991, which showed the strongest nominal signals (TTK inhibition on Anaerostipes: uncorrected p = 0.003; Anaerostipes on BC: uncorrected p = 0.025), was performed for hypothesis generation only; no statistically significant mediation was observed.
Conclusion:
This study provides robust genetic evidence that TTK inhibition is causally associated with a decreased risk of breast cancer. The exploratory analysis of gut microbiota as a mediator did not yield statistically significant results after correction for multiple testing. The potential role of specific microbes, such as Genus Anaerostipes, remains inconclusive and requires further dedicated investigation.
Insights
TTK inhibition causally reduces breast cancer risk. Exploratory analysis did not find significant mediation by gut microbiota, suggesting further research is needed for specific microbes.
Area of Science:
- Genetics
- Oncology
- Microbiome Research
Background:
- Breast cancer (BC) treatment is an active area of research.
- BOS172722, a selective TTK inhibitor, shows therapeutic potential for BC.
- The influence of gut microbiota on BC and TTK inhibitor efficacy is not well understood.
Purpose of the Study:
- To investigate the causal relationship between TTK inhibition and breast cancer risk.
- To explore the potential mediating role of gut microbiota in this association.
Main Methods:
- A two-sample Mendelian Randomization (MR) study design was employed.
- Data from the IEU Open GWAS project was utilized.
- Inverse-variance-weighted (IVW) method and False Discovery Rate (FDR) correction were applied.
Main Results:
- Genetically predicted TTK inhibition was robustly associated with a reduced risk of breast cancer (OR = 0.667, p < 0.001).
- No statistically significant mediation effects of gut microbial taxa on the TTK inhibition-BC risk association were found after FDR correction.
- Exploratory analyses suggested nominal associations that did not withstand multiple testing adjustments.
Conclusions:
- TTK inhibition demonstrates a causal protective effect against breast cancer.
- The gut microbiota does not appear to be a significant mediator in the TTK inhibition-BC pathway based on current data.
- Further dedicated studies are required to elucidate the role of specific gut microbes, like Genus Anaerostipes, in breast cancer.
