PURPOSE DNA mismatch repair defects (MMRd) and tumor hypermutation are rare and under-characterized in metastatic prostate cancer (mPC). Furthermore, because hypermutated MMRd prostate cancers can respond to immune checkpoint inhibitors, there is an urgent need for practical detection tools. EXPERIMENTAL DESIGN We analyzed plasma cell-free DNA-targeted sequencing data from 433 patients with mPC with circulating tumor DNA (ctDNA) purity ≥2%. Samples with somatic hypermutation were subjected to 185 × whole-exome sequencing and capture of mismatch repair gene introns. Archival tissue was analyzed with targeted sequencing and IHC. RESULTS Sixteen patients (3.7%) had somatic hypermutation with MMRd etiology, evidenced by deleterious alterations in MSH2, MSH6, or MLH1, microsatellite instability, and characteristic trinucleotide signatures. ctDNA was concordant with mismatch repair protein IHC and DNA sequencing of tumor tissue. Tumor suppressors such as PTEN, RB1, and TP53 were inactivated by mutation rather than copy-number loss. Hotspot mutations in oncogenes such as AKT1, PIK3CA, and CTNNB1 were common, and the androgen receptor (AR)-ligand binding domain was mutated in 9 of 16 patients. We observed high intrapatient clonal diversity, evidenced by subclonal driver mutations and shifts in mutation allele frequency over time. Patients with hypermutation and MMRd etiology in ctDNA had a poor response to AR inhibition and inferior survival compared with a control cohort. CONCLUSIONS Hypermutated MMRd mPC is associated with oncogene activation and subclonal diversity, which may contribute to a clinically aggressive disposition in selected patients. In patients with detectable ctDNA, cell-free DNA sequencing is a practical tool to prioritize this subtype for immunotherapy.See related commentary by Schweizer and Yu, p. 981.

中文翻译：

---

来自转移性前列腺癌的ctDNA的超突变和缺陷错配修复的鉴定。

目的DNA错配修复缺陷（MMRd）和肿瘤过度突变在转移性前列腺癌（mPC）中很少见且特征不足。此外，由于超突变的MMRd前列腺癌可以对免疫检查点抑制剂产生反应，因此迫切需要实用的检测工具。实验设计我们分析了433例循环肿瘤DNA（ctDNA）纯度≥2％的mPC患者血浆无细胞DNA靶向测序数据。对具有体细胞高突变的样品进行185×全外显子组测序，并捕获错配修复基因内含子。用靶向测序和IHC分析档案组织。结果16名患者（3.7％）患有MMRd病因的体细胞超突变，由MSH2，MSH6或MLH1的有害改变，微卫星不稳定性和特征性三核苷酸特征证明。ctDNA与错配修复蛋白IHC和肿瘤组织的DNA测序一致。PTEN，RB1和TP53等肿瘤抑制因子是通过突变而不是拷贝数丢失而失活的。致癌基因（如AKT1，PIK3CA和CTNNB1）中的热点突变很常见，而雄激素受体（AR）-配体结合域在16例患者中的9例中发生了突变。我们观察到了较高的住院患者克隆多样性，这由亚克隆驱动子突变和突变等位基因频率随时间的变化所证明。与对照组相比，ctDNA中具有高突变和MMRd病因的患者对AR抑制的反应较差，生存期较差。结论高突变MMRd mPC与致癌基因激活和亚克隆多样性有关，这可能有助于某些患者的临床积极治疗。在可检测到ctDNA的患者中，无细胞DNA测序是区分该亚型进行免疫治疗的一种实用工具，请参见Schweizer和Yu，p。981。