Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 60 Murray Street, Toronto, ON, M5T 3L9, Canada.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Medical Sciences Building (6th floor), 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
BMC Cancer. 2020 Oct 2;20(1):953. doi: 10.1186/s12885-020-07438-4.
Early treatment of patients at risk for developing aggressive prostate cancer is able to delay metastasis and reduce mortality; as such, up-front identification of these patients is critical. Several risk classification systems, including CAPRA-S, are currently used for disease prognostication. However, high-risk patients identified by these systems can still exhibit wide-ranging disease outcomes, leading to overtreatment of some patients in this group.
The master methylation regulator TET2 is downregulated in prostate cancer, where its loss is linked to aggressive disease and poor outcome. Using a random forest strategy, we developed a model based on the expression of 38 genes associated with TET2 utilizing 100 radical prostatectomy samples (training cohort) with a 49% biochemical recurrence rate. This 38-gene model was comprised of both upregulated and downregulated TET2-associated genes with a binary outcome, and was further assessed in an independent validation (n = 423) dataset for association with biochemical recurrence.
38-gene model status was able to correctly identify patients exhibiting recurrence with 81.4% sensitivity in the validation cohort, and added significant prognostic utility to the high-risk CAPRA-S classification group. Patients considered high-risk by CAPRA-S with negative 38-gene model status exhibited no statistically significant difference in time to recurrence from low-risk CAPRA-S patients, indicating that the expression of TET2-associated genes is able to separate truly high-risk cases from those which have a more benign disease course.
The 38-gene model may hold potential in determining which patients would truly benefit from aggressive treatment course, demonstrating a novel role for genes linked to TET2 in the prognostication of PCa and indicating the importance of TET2 dysregulation among high-risk patient groups.
早期治疗有发展为侵袭性前列腺癌风险的患者能够延迟转移并降低死亡率；因此，早期识别这些患者至关重要。目前有几种风险分类系统，包括 CAPRA-S，用于预测疾病预后。然而，这些系统识别的高危患者仍可能表现出广泛的疾病结局，导致该组中的一些患者过度治疗。
主甲基化调节剂 TET2 在前列腺癌中下调，其缺失与侵袭性疾病和不良结局相关。我们使用随机森林策略，基于与 TET2 相关的 38 个基因的表达，利用 100 例根治性前列腺切除术样本（训练队列），其中 49%的患者发生生化复发，开发了一种模型。该 38 个基因模型由上调和下调的与 TET2 相关的基因组成，具有二进制结果，并在独立验证（n=423）数据集进一步评估与生化复发的相关性。
38 个基因模型状态能够正确识别验证队列中具有复发的患者，敏感性为 81.4%，并为 CAPRA-S 高危分类组增加了显著的预后效用。CAPRA-S 高危且 38 个基因模型状态为阴性的患者与 CAPRA-S 低危患者相比，复发时间无统计学差异，表明 TET2 相关基因的表达能够将真正的高危病例与具有良性病程的病例区分开来。
38 个基因模型可能有助于确定哪些患者将真正受益于积极的治疗方案，为与 TET2 相关的基因在前列腺癌的预后中的作用提供了新的认识，并表明 TET2 失调在高危患者群体中的重要性。
