Virga Alessandra, Urbini Milena, Polano Maurizio, Petracci Elisabetta, Tedaldi Gianluca, Gurioli Giorgia, Marisi Giorgia, Angeli Davide, Ambrosini-Spaltro Andrea, De Luca Giovanni, Cangini Ilaria, Zampiga Valentina, Cenacchi Giovanna, Toffoli Giuseppe, Casadei Chiara, Cursano Maria Concetta, Conteduca Vincenza, De Giorgi Ugo, Ulivi Paola
Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy.
Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy.
Sci Rep. 2025 Jul 1;15(1):21296. doi: 10.1038/s41598-025-05384-4.
PARP inhibitors (PARPi), recently introduced for treating metastatic castration-resistant prostate cancer (mCRPC), have heightened interest in molecular profiling for pathogenic aberrations in homologous recombination DNA repair (HRR) genes in all mCRPC patients. Liquid biopsy offers a viable alternative to archival tumor tissue for genetic analysis. In this study, we assessed the feasibility and utility of combining mutational panel sequencing with shallow whole genome sequencing (sWGS) to refine HRR status determination from plasma in prostate cancer (PCa) patients. The mutational profile of 16 HRR genes was assessed in 63 PCa patients: 28.6% of patients harbored putative pathogenic variants in HRR-related genes. A HRR-mutant status was defined for 10 patients (15.8%). Through the integration of sWGS data, plasma samples non-informative about somatic alterations were identified, and germline/somatic origin of HRR mutations was defined. Matched tumor tissue was available for 41 patients, with an 85.7% concordance rate between plasma and tissue mutational analyses. Additionally, we explored the copy number variation (CNV) profile using sWGS and it was found concordant with the literature PCa profiles. Our findings demonstrated that ctDNA analysis through liquid biopsy is a reliable alternative to tissue-based methods for identifying SNVs and CNVs. However, concordance was affected by ctDNA levels in plasma and clonal hematopoiesis. The data highlight the utility of integrating sWGS with targeted mutation analysis for comprehensive molecular profiling of PCa patients.
聚（ADP - 核糖）聚合酶抑制剂（PARPi）最近被用于治疗转移性去势抵抗性前列腺癌（mCRPC），这使得所有mCRPC患者对同源重组DNA修复（HRR）基因致病畸变的分子谱分析的关注度有所提高。液体活检为遗传分析提供了一种可行的替代存档肿瘤组织的方法。在本研究中，我们评估了将突变 panel 测序与浅层全基因组测序（sWGS）相结合以完善前列腺癌（PCa）患者血浆中HRR状态判定的可行性和实用性。在63例PCa患者中评估了16个HRR基因的突变谱：28.6%的患者在HRR相关基因中携带推定的致病变异。为10例患者（15.8%）定义了HRR突变状态。通过整合sWGS数据，鉴定出了关于体细胞改变无信息的血浆样本，并确定了HRR突变的种系/体细胞起源。41例患者可获得匹配的肿瘤组织，血浆和组织突变分析之间的一致率为85.7%。此外，我们使用sWGS探索了拷贝数变异（CNV）谱，发现其与文献中的PCa谱一致。我们的研究结果表明，通过液体活检进行的ctDNA分析是一种可靠的替代基于组织的方法来识别单核苷酸变异（SNV）和CNV。然而，一致性受到血浆中ctDNA水平和克隆性造血的影响。这些数据突出了将sWGS与靶向突变分析相结合用于PCa患者全面分子谱分析的实用性。
