Related Experiment Video
Updated: Jun 4, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
GWAS from a multicenter prospective study of radium-223 in bone-metastatic castration-resistant prostate cancer
Tokiyoshi Tanegashima1, Masaki Shiota2, Atsushi Doi3
1Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Background:
Radium-223 dichloride improves survival and delays symptomatic skeletal events in patients with bone-metastatic castration-resistant prostate cancer; however, therapeutic responses vary considerably among individuals, and predictive germline biomarkers remain undefined. We conducted a prospective multicenter genome-wide association study within the KYUCOG-1901 cohort to identify germline single-nucleotide polymorphisms associated with the clinical efficacy of radium-223.
Results:
Among 93 patients with bone-predominant castration-resistant prostate cancer treated with up to six cycles of radium-223, the intronic variant rs1568679 in MEIS2 reached genome-wide significance for association with ≥ 30% decline in prostate-specific antigen (P < 5.0 × 10⁻⁸). Patients carrying the rs1568679 CC genotype exhibited significantly greater prostate-specific antigen decline and significantly longer symptomatic skeletal event-free survival, radiographic progression-free survival, and overall survival compared with those with TT/TC genotypes. In multivariate analyses adjusting for established clinical prognostic factors, the rs1568679 CC genotype remained independently associated with favorable clinical outcomes. Although rs1568679 showed no significant expression quantitative trait loci effect on MEIS2 expression, pathway enrichment analysis of MEIS2-associated regulatory networks revealed strong enrichment of genes involved in DNA repair and genomic stability.
Conclusions:
The germline variant rs1568679 in MEIS2 may represent a potential biomarker associated with favorable response to radium-223 in metastatic castration-resistant prostate cancer. These findings suggest that MEIS2-related DNA repair regulation may influence susceptibility to α-particle-induced cytotoxicity and may facilitate biomarker-driven treatment strategies for optimizing Ra-223 therapy.
Trial Registration:
University Hospital Medical Information Network (UMIN), UMIN000040358, registered 11 May 2020, https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000045641 .
Insights
A specific gene variant, rs1568679 in MEIS2, is linked to better outcomes in patients with metastatic castration-resistant prostate cancer treated with radium-223. This finding may lead to new biomarker-driven strategies for optimizing prostate cancer therapy.
Area of Science:
- Genetics and Oncology
- Pharmacogenomics
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) treatment with radium-223 dichloride improves survival but shows variable patient responses.
- Predictive germline biomarkers for radium-223 efficacy are currently undefined.
- Identifying genetic factors influencing treatment response is crucial for personalized medicine in mCRPC.
Purpose of the Study:
- To identify germline single-nucleotide polymorphisms (SNPs) associated with the clinical efficacy of radium-223 in patients with bone-metastatic castration-resistant prostate cancer.
- To explore the potential of germline genetic variations as predictive biomarkers for radium-223 therapy.
Main Methods:
- A prospective, multicenter genome-wide association study (GWAS) was conducted on the KYUCOG-1901 cohort.
- 93 patients with bone-predominant mCRPC treated with radium-223 were analyzed.
- Statistical analyses, including multivariate regression and pathway enrichment, were performed to assess the association between SNPs and clinical outcomes.
Main Results:
- The intronic variant rs1568679 in the MEIS2 gene reached genome-wide significance for association with a ≥30% decline in prostate-specific antigen (PSA).
- Patients with the rs1568679 CC genotype demonstrated significantly improved PSA decline, symptomatic skeletal event-free survival, radiographic progression-free survival, and overall survival compared to TT/TC genotypes.
- The rs1568679 CC genotype remained an independent predictor of favorable outcomes in multivariate analyses, and MEIS2-associated networks were enriched for DNA repair genes.
Conclusions:
- The germline variant rs1568679 in MEIS2 may serve as a predictive biomarker for favorable response to radium-223 in mCRPC.
- MEIS2-related DNA repair regulation might influence sensitivity to alpha-particle therapy, suggesting potential for biomarker-driven treatment optimization.
- These findings support the development of personalized therapeutic strategies for radium-223 in prostate cancer patients.
