Genetics-Driven, Intensity-Modulated Adaptive Management of Patients With Metastatic Prostate Cancer.

IF 2.5 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Prostate Pub Date : 2025-10-05 DOI:10.1002/pros.70070

Reynier D Rodriguez Rosales, Arjun Venkatesh, Jean-Pierre Kanumuambidi, Yudai Ishiyama, Mohammed Al-Toubat, Hunter Sceats, Thomas D Metzner, Shelby Sparks, Nicole Murray, Mark Bandyk, K C Balaji

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引用次数: 0

Abstract

Background: Survival differs markedly between men with metastatic prostate cancer (mPC) confined to lymph nodes (LNM) versus bone (BM). We examined whether site-specific genomic alterations-and their combinations-explain this disparity and could inform intensity-modulated follow-up or therapy.

Methods: Clinical and targeted-sequencing data for 1011 men with mPC in the cBioPortal for Cancer Genomics registry were analyzed (LNM-only = 622; BM-only = 389). Genes altered in > 5% of tumors (two-sided p < 0.05) were assessed individually and in every possible multigene cluster for associations with overall survival (OS). Survival was evaluated with Kaplan-Meier curves and the difference in restricted mean survival time (dRMST) to pinpoint the first significant curve divergence. Synthetic-lethal (SL) interactions were explored via the SLOAD database.

Results: In total, 18 of 184 profiled genes (9.8%) exceeded the 5% alteration threshold. FOXA1 was enriched in BM, whereas TMPRSS2, ERG, PTEN, ZFHX3, CDK12, and KMT2C were enriched in LNM (p < 0.05). Among 9143 tested gene clusters, 65 were associated with inferior OS; 48 occurred in the LNM subgroup, 17 in the combined cohort, and none in the BM alone. High-risk clusters showed first OS divergence 10-60 months after diagnosis of metastasis. SLOAD identified 615 putative SL pairs involving these genes.

Conclusions: We identified 65 site-specific multigene clusters-chiefly in lymph node-only mPC-that underlie the survival gap between nodal and bone metastases. These signatures suggest a 10-60-month interval that may lend itself for intensity-modulated follow-up. We also discovered hundreds of synthetic-lethal gene-alteration pairs, opening future research opportunities in combinatorial therapeutic targeting.

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转移性前列腺癌患者的遗传驱动、强度调节适应性管理。

背景：转移性前列腺癌（mPC）局限于淋巴结（LNM）和骨（BM）患者的生存率明显不同。我们研究了特定位点的基因组改变及其组合是否解释了这种差异，并可以为强度调节的随访或治疗提供信息。方法：对cbiopportal for Cancer Genomics registry中1011例mPC男性患者的临床和靶向测序数据进行分析（lnm = 622; bm = 389）。结果：184个分析基因中有18个（9.8%）超过了5%的改变阈值。FOXA1在BM中富集，而TMPRSS2、ERG、PTEN、ZFHX3、CDK12和KMT2C在LNM中富集(p)。结论：我们鉴定了65个位点特异性多基因簇，主要存在于仅淋巴结的mpc中，这些多基因簇决定了淋巴结和骨转移之间的生存差距。这些特征表明，10-60个月的间隔可能适合进行强度调节的随访。我们还发现了数百个合成致死性基因改变对，为组合治疗靶向开辟了未来的研究机会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Prostate 医学-泌尿学与肾脏学

CiteScore

5.10

自引率

3.60%

发文量

180

审稿时长

1.5 months

期刊介绍： The Prostate is a peer-reviewed journal dedicated to original studies of this organ and the male accessory glands. It serves as an international medium for these studies, presenting comprehensive coverage of clinical, anatomic, embryologic, physiologic, endocrinologic, and biochemical studies.