Aberrations on TP53, either as deletions of chromosome 17p (del17p) or mutations, are associated with poor outcome in multiple myeloma (MM), but conventional detection methods currently in use underestimate their incidence, hindering an optimal risk assessment and prognostication of MM patients. We have investigated the altered status of TP53 gene by SNPs array and sequencing techniques in a homogenous cohort of 143 newly diagnosed MM patients, evaluated both at diagnosis and at first relapse: single-hit on TP53 gene, either deletion or mutation, detected both at clonal and sub-clonal level, had a minor effect on outcomes. Conversely, the coexistence of both TP53 deletion and mutation, which defined the so-called double-hit patients, was associated with the worst clinical outcome (PFS: HR 3.34 [95% CI: 1.37–8.12] p = 0.008; OS: HR 3.47 [95% CI: 1.18–10.24] p = 0.02). Moreover, the analysis of longitudinal samples pointed out that TP53 allelic status might increase during the disease course. Notably, the acquisition of TP53 alterations at relapse dramatically worsened the clinical course of patients. Overall, our analyses showed these techniques to be highly sensitive to identify TP53 aberrations at sub-clonal level, emphasizing the poor prognosis associated with double-hit MM patients.
TP53基因异常，无论是17号染色体短臂缺失（del17p）还是突变，均与多发性骨髓瘤的不良预后相关。然而，目前使用的常规检测方法低估了其发生率，阻碍了对多发性骨髓瘤患者进行最佳风险评估和预后判断。我们通过SNP芯片和测序技术，对143例新诊断多发性骨髓瘤患者的同质队列进行了TP53基因状态改变的研究，并在诊断时及首次复发时进行评估：在克隆和亚克隆水平检测到的TP53基因单次打击（缺失或突变）对患者结局影响较小。相反，同时存在TP53缺失和突变的所谓"双重打击"患者，其临床结局最差（无进展生存期：风险比3.34[95%置信区间：1.37–8.12]，p=0.008；总生存期：风险比3.47[95%置信区间：1.18–10.24]，p=0.02）。此外，纵向样本分析指出TP53等位基因状态可能在疾病进程中增强。值得注意的是，复发时获得TP53改变会显著恶化患者的临床病程。总体而言，我们的分析表明这些技术对亚克隆水平的TP53异常具有高度敏感性，并强调了与双重打击多发性骨髓瘤患者相关的不良预后。
肿瘤(癌症)患者之家