肿瘤测序联合胚系基因检测提高晚期前列腺癌男性致病性胚系变异的检出率。
Addition of Germline Testing to Tumor-Only Sequencing Improves Detection of Pathogenic Germline Variants in Men With Advanced Prostate Cancer.
机构信息
Dana-Farber Cancer Institute, Boston, MA.
Brigham and Women's Hospital, Boston, MA.
出版信息
JCO Precis Oncol. 2022 Aug;6:e2200329. doi: 10.1200/PO.22.00329.
PURPOSE
Guidelines recommend somatic and germline testing for men with advanced prostate cancer (PCa). Barriers to widespread implementation result in underutilization of germline testing. Somatic testing alone risks missing pathogenic germline variants (PGVs). We sought to determine whether the addition of germline testing to tumor-only sequencing improves detection of PGVs in men with advanced PCa. Secondarily, we sought to define the added value of combining somatic and germline testing to optimize detection of clinically actionable alterations.
PATIENTS AND METHODS
We analyzed results of independent germline testing and tumor-only sequencing from 100 men with advanced PCa from a prospective clinical trial (ClinicalTrials.gov identifier: NCT03328091). The primary outcome was the proportion of PGVs not reported with tumor-only sequencing. The secondary outcome was the association of locus-specific loss of heterozygosity for PGVs in homologous recombination genes with clinical-genomic features.
RESULTS
In the 100 men who underwent germline testing and tumor-only sequencing, 24 PGVs were identified, 17 of which were clinically actionable, in 23 patients. Tumor-only sequencing failed to report four (17%) of the PGVs. One additional PGV (4.2%) had variant allele frequency on tumor-sequencing below the threshold for follow-up germline testing. When integrating tumor-only sequencing with germling testing results, 33% of patients harbored clinically actionable alterations. Rates of locus-specific loss of heterozygosity were higher for PGVs in castration-resistant PCa than PGVs in other homologous recombination genes in hormone-sensitive PCa ( = .029).
CONCLUSION
Tumor-only sequencing failed to report more than 20% of PGVs in men with advanced PCa. These findings strongly support guideline recommendations for universal germline and somatic testing in this population. Combining tumor and germline sequencing doubled the chance of detecting a clinically actionable alteration.
目的
指南建议对晚期前列腺癌（PCa）患者进行体细胞和种系检测。由于广泛实施的障碍，种系检测的利用率较低。单独进行体细胞检测有漏检致病性种系变异（PGV）的风险。我们旨在确定在晚期 PCa 男性中，增加种系检测是否能提高 PGV 的检出率。其次，我们试图确定将体细胞和种系检测相结合以优化检测具有临床意义的改变的附加价值。
患者和方法
我们分析了来自一项前瞻性临床试验（ClinicalTrials.gov 标识符：NCT03328091）的 100 名晚期 PCa 男性的独立种系检测和肿瘤仅测序结果。主要结局是肿瘤仅测序未报告的 PGV 比例。次要结局是同源重组基因中 PGV 的特异性杂合性缺失与临床基因组特征的相关性。
结果
在接受种系检测和肿瘤仅测序的 100 名男性中，23 名患者中有 24 个 PGV 被确定，其中 17 个为临床可操作的变异。肿瘤仅测序未能报告其中的 4 个（17%）PGV。另一个 PGV（4.2%）在肿瘤测序中的变异等位基因频率低于后续种系检测的阈值。当将肿瘤仅测序与种系检测结果整合时，33%的患者存在临床可操作的改变。在去势抵抗性 PCa 中，PGV 的特异性杂合性缺失率高于激素敏感性 PCa 中其他同源重组基因中的 PGV（=0.029）。
结论
肿瘤仅测序未能报告超过 20%的晚期 PCa 男性的 PGV。这些发现强烈支持指南建议对该人群进行普遍的种系和体细胞检测。肿瘤和种系测序的结合使检测到具有临床意义的改变的机会增加了一倍。
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