Pearlman Alexander H, Wang Yuxuan, Kalluri Anita, Parker Megan, Cohen Joshua D, Dudley Jonathan, Rincon-Torroella Jordina, Xia Yuanxuan, Gensler Ryan, Alfonzo Horwitz Melanie, Theodore John, Dobbyn Lisa, Popoli Maria, Ptak Janine, Silliman Natalie, Judge Kathy, Groves Mari, Jackson Christopher M, Jackson Eric M, Jallo George I, Lim Michael, Luciano Mark, Mukherjee Debraj, Naidoo Jarushka, Rozati Sima, Sterling Cole H, Weingart Jon, Koschmann Carl, Mansouri Alireza, Glantz Michael, Kamson David, Schreck Karisa C, Pardo Carlos A, Holdhoff Matthias, Paul Suman, Kinzler Kenneth W, Papadopoulos Nickolas, Vogelstein Bert, Douville Christopher, Bettegowda Chetan
medRxiv. 2025 Feb 12:2024.12.02.24318303. doi: 10.1101/2024.12.02.24318303.
Patients who have radiographically detectable lesions in their brain or other symptoms compatible with brain tumors pose challenges for diagnosis. The only definitive way to diagnose such patients is through brain biopsy, an obviously invasive and dangerous procedure. Here we present a new workflow termed "CSF-BAM" that simultaneously identifies cell or T cell receptor rearrangements, neuploidy, and using PCR-mediated amplification of both strands of the DNA from CSF samples. We first describe the details of the molecular genetic assessments and then establish thresholds for positivity using training sets of libraries from patients with or without cancer. We then applied CSF-BAM to an independent set of 206 DNA samples from patients with common, aggressive cancer types as well as other forms of brain cancers. Among the 126 samples from patients with the most common aggressive cancer types (high grade gliomas, medulloblastomas, or metastatic cancers to the brain), the sensitivity of detection was >81%. None of 33 CSF-BAM assays (100% specificity, 90% to 100% credible interval) were positive in CSF samples from patients without brain cancers. The sensitivity of CSF-BAM was considerably higher than that achieved with cytology. CSF-BAM provides an integrated multi-analyte approach to identify neoplasia in the central nervous system, provides information about the immune environment in patients with or without cancer, and has the potential to inform the subsequent management of such patients.
There is a paucity of technologies beyond surgical biopsy that can accurately diagnose central nervous system neoplasms. We developed a novel, sensitive and highly specific assay that can detect brain cancers by comprehensively identifying somatic mutations, chromosomal copy number changes, and adaptive immunoreceptor repertoires from samples of cerebrospinal fluid.
脑部有影像学可检测病变或有与脑肿瘤相符的其他症状的患者在诊断方面存在挑战。诊断此类患者的唯一确定性方法是通过脑活检，这显然是一种侵入性且危险的程序。在此，我们提出一种名为“CSF - BAM”的新工作流程，该流程通过PCR介导的脑脊液样本DNA双链扩增，同时识别细胞或T细胞受体重排、非整倍体。我们首先描述分子遗传学评估的细节，然后使用来自有癌或无癌患者的文库训练集确定阳性阈值。然后，我们将CSF - BAM应用于来自常见侵袭性癌症类型患者以及其他形式脑癌患者的206个DNA样本的独立集合。在来自最常见侵袭性癌症类型（高级别胶质瘤、髓母细胞瘤或脑转移癌）患者的126个样本中，检测灵敏度>81%。在无脑癌患者的脑脊液样本中，33次CSF - BAM检测（100%特异性，90%至100%可信区间）均无阳性结果。CSF - BAM的灵敏度明显高于细胞学检测。CSF - BAM提供了一种综合多分析物方法来识别中枢神经系统肿瘤，提供有关有癌或无癌患者免疫环境的信息，并有可能为这类患者的后续管理提供依据。
除手术活检外，缺乏能够准确诊断中枢神经系统肿瘤的技术。我们开发了一种新颖、灵敏且高度特异的检测方法，该方法可通过全面识别脑脊液样本中的体细胞突变、染色体拷贝数变化和适应性免疫受体库来检测脑癌。
