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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Germline predictors of androgen deprivation therapy response in advanced prostate cancer
Manish Kohli1, Shaun M Riska, Douglas W Mahoney
1Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. kohli.manish@mayo.edu
Objective:
To evaluate whether germline variations in genes involved in sex steroid biosynthesis and metabolic pathways predict time to treatment failure for patients with advanced prostate cancer undergoing androgen deprivation therapy (ADT), because there are few known clinical predictors of response.
Patients And Methods:
In a cohort of 304 patients with advanced prostate cancer undergoing ADT, we genotyped 746 single-nucleotide polymorphisms (SNPs) from 72 genes from germline DNA (680 tagSNPs from 58 genes and 66 candidate SNPs from 20 genes [6 genes common in both]). Association with the primary end point of time to ADT failure was assessed using proportional hazards regression models at the gene level (for genes with tagging SNPs) and at the SNP level. False discovery rates (FDRs) of 0.10 or less were considered noteworthy to account for multiple testing.
Results:
At the gene level, TRMT11 showed the strongest association with time to ADT failure (P<.001; FDR=0.008). Two of 4 TRMT11 tagSNPs were associated with time to ADT failure. Median time to ADT failure for rs1268121 (A>G) was 3.05 years for the AA, 4.27 years for the AG, and 6.22 years for the GG genotypes (P=.002), and for rs6900796 (G>A), it was 2.42 years for the GG, 3.52 years for the AG, and 4.18 years for the AA genotypes (P<.001). No other gene level or SNP level tests had an FDR of 0.10 or less.
Conclusion:
Genetic variation in TRMT11 was associated with time to ADT failure. Confirmation of these preliminary findings in an independent cohort is needed.
Insights
Genetic variations in the TRMT11 gene may predict treatment success for advanced prostate cancer patients undergoing androgen deprivation therapy (ADT). This finding could help personalize treatment strategies for better outcomes.
Area of Science:
- Oncology
- Genetics
- Pharmacogenomics
Background:
- Advanced prostate cancer treatment often relies on androgen deprivation therapy (ADT).
- Predicting treatment response to ADT is crucial for optimizing patient outcomes.
- Limited clinical predictors exist for ADT treatment failure.
Purpose of the Study:
- To investigate if germline genetic variations in sex steroid biosynthesis and metabolism genes can predict time to treatment failure in advanced prostate cancer patients receiving ADT.
- To identify potential genetic markers for ADT response.
Main Methods:
- A cohort of 304 advanced prostate cancer patients undergoing ADT was analyzed.
- Germline DNA was genotyped for 746 single-nucleotide polymorphisms (SNPs) across 72 genes.
- Association with time to ADT failure was assessed using proportional hazards regression models, with a false discovery rate (FDR) of 0.10 or less considered significant.
Main Results:
- The TRMT11 gene showed the strongest association with time to ADT failure (P<.001; FDR=0.008).
- Specific SNPs within TRMT11 (rs1268121 and rs6900796) were significantly associated with varying median times to ADT failure based on genotype.
- No other gene or SNP-level tests met the significance threshold.
Conclusions:
- Germline genetic variation in the TRMT11 gene is associated with time to treatment failure in patients with advanced prostate cancer undergoing ADT.
- These preliminary findings suggest TRMT11 as a potential predictive biomarker for ADT response.
- Further validation in an independent cohort is necessary to confirm these results.
