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Background <p>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.</p> Results <p>Among 93 patients with bone-predominant castration-resistant prostate cancer treated with up to six cycles of radium-223, the intronic variant rs1568679 in <i>MEIS2</i> reached genome-wide significance for association with ≥ 30% decline in prostate-specific antigen (<i>P</i> &lt; 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 <i>MEIS2</i> expression, pathway enrichment analysis of <i>MEIS2</i>-associated regulatory networks revealed strong enrichment of genes involved in DNA repair and genomic stability.</p> Conclusions <p>The germline variant rs1568679 in <i>MEIS2</i> may represent a potential biomarker associated with favorable response to radium-223 in metastatic castration-resistant prostate cancer. These findings suggest that <i>MEIS2</i>-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, <a href="https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000045641">https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000045641</a>.</p>

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GWAS from a multicenter prospective study of radium-223 in bone-metastatic castration-resistant prostate cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月2日

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  • Tokiyoshi Tanegashima,
  • Masaki Shiota,
  • Atsushi Doi,
  • Shuichi Tatarano,
  • Tomomi Kamba,
  • Tsukasa Igawa,
  • Naoya Masumori,
  • Hirotsugu Uemura,
  • Toshiyuki Kamoto,
  • Katsuyoshi Higashijima,
  • Kensuke Mitsunari,
  • Hiroji Uemura,
  • Takayuki Sumiyoshi,
  • Takuro Isoda,
  • Kousei Ishigami,
  • Shoji Tokunaga,
  • Masatoshi Eto

摘要

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.