在标准诊断测序工作流程中检测 HLA 杂合性丢失，以获得预后和治疗机会。
Detecting HLA loss of heterozygosity within a standard diagnostic sequencing workflow for prognostic and therapeutic opportunities.
发表日期：2024 Aug 05
作者：
Ariane Lozac'hmeur, Tyler Danek, Qidi Yang, Mario G Rosasco, John S Welch, William Y Go, Eric W Ng, Armen Mardiros, David G Maloney, Edward B Garon, Kedar Kirtane, Diane M Simeone, Julian R Molina, Ameen A Salahudeen, Michelle M Stein, J Randolph Hecht
来源：
npj Precision Oncology
摘要：
为了能够将肿瘤 HLA LOH 询问作为精准肿瘤学的临床诊断，我们开发并验证了一种在 FDA 批准的临床诊断测试 Tempus xT CDx 背景下检测 HLA LOH 的检测方法。验证通过以下方式进行：(1) 对 17 个存档患者样本和 42 个细胞系混合物进行分析评估，以及 (2) 对 10,982 名患者的 HLA-A 基因 (HLA-A LOH) 的 LOH 患病率进行独立临床评估。为了评估 HLA-A LOH 的预后相关性，我们评估了 256 名接受免疫疗法治疗的非小细胞肺癌 (NSCLC) 患者。为了确定前瞻性识别 HLA-A LOH 患者并将其纳入临床试验的可行性，我们建立了 BASECAMP-1 (NCT04981119)。我们在肿瘤纯度≥40%的样本中观察到阳性预测一致性为97%，阴性预测一致性为100%。我们在 16.1% 的患者 (1771/10,982) 中观察到 HLA-A LOH，与之前的报告相当。 HLA-A LOH 与 NSCLC 腺癌患者的较长生存期相关（HR = 0.60，95% CI [0.37, 0.96]，p = 0.032），而鳞状细胞患者的生存期呈较短趋势（HR = 1.64，95% CI [0.37, 0.96]，p = 0.032）。 0.80, 3.41], p = 0.183)。在 20 个月内，我们使用 Tempus AWARE 计划前瞻性筛查了 1720 名受试者，在 8 个地点识别了 26 名 HLA-A*02 LOH 患者，其中 14 名 (54%) 纳入了 BASECAMP-1。总之，我们开发并验证了一种研究方法，可在 FDA 批准的临床诊断测试中检测肿瘤 HLA LOH，从而使 HLA LOH 在诊断、预后和治疗应用中得到利用。© 2024。作者。
To enable interrogation of tumor HLA LOH as a clinical diagnostic for precision oncology, we developed and validated an assay that detects HLA LOH within the context of an FDA-approved clinical diagnostic test, Tempus xT CDx. Validation was conducted via: (1) analytical evaluation of 17 archival patient samples and 42 cell line admixtures and (2) independent clinical evaluation of LOH prevalence in the HLA-A gene (HLA-A LOH) across 10,982 patients. To evaluate the prognostic relevance of HLA-A LOH we assessed 256 immunotherapy-treated non-small cell lung cancer (NSCLC) patients. To determine the feasibility of prospectively identifying and enrolling HLA-A LOH patients into a clinical trial, we established BASECAMP-1 (NCT04981119). We observed a positive predictive agreement of 97% and a negative predictive agreement of 100% in samples with ≥ 40% tumor purity. We observed HLA-A LOH in 16.1% of patients (1771/10,982), comparable to previous reports. HLA-A LOH was associated with longer survival among NSCLC adenocarcinoma patients (HR = 0.60, 95% CI [0.37, 0.96], p = 0.032) with a trend towards shorter survival among squamous cell patients (HR = 1.64, 95% CI [0.80, 3.41], p = 0.183). In 20 months, we prospectively screened 1720 subjects using the Tempus AWARE program, identifying 26 HLA-A*02 LOH patients at 8 sites, with 14 (54%) enrolled into BASECAMP-1. In conclusion, we developed and validated an investigational assay that detects tumor HLA LOH within an FDA-approved clinical diagnostic test, enabling HLA LOH utilization in diagnostic, prognostic, and therapeutic applications.© 2024. The Author(s).