Abstract:
This study aimed to re-evaluate the prognostic impact of TP53 mutations and to identify specific chromosomal aberrations as possible prognostic markers in WNT-activated medulloblastoma (WNT-MB). In a cohort of 191 patients with WNT-MBs, mutations in CTNNB1, APC, and TP53 were analyzed by DNA sequencing. Chromosomal copy-number aberrations were assessed by molecular inversion probe technology (MIP), SNP6, or 850k methylation array hybridization. Prognostic impact was evaluated in 120 patients with follow-up data from the HIT2000 medulloblastoma trial or HIT registries. CTNNB1 mutations were present in 92.2%, and APC mutations in 6.8% of samples. One CTNNB1 wild-type tumor gained WNT activation due to homozygous FBXW7 deletion. Monosomy 6 was present in 78.6%, and more frequent in children than adults. 16.1% of tumor samples showed TP53 mutations, of those 60% with nuclear positivity for the p53 protein. Loss of heterozygosity at the TP53 locus (chromosome 17p13.1) was found in 40.7% (11/27) of TP53 mutant tumor samples and in 12.6% of TP53 wild-type cases (13/103). Patients with tumors harboring TP53 mutations showed significant worse progression-free survival (PFS; 5-year-PFS 68% versus 93%, p = 0.001), and were enriched for chromosomes 17p (p = 0.001), 10, and 13 losses. Gains of OTX2 (14q22.3) occurred in 38.9% of samples and were associated with poor PFS and OS (5-year-PFS 72% versus 93%, p = 0.017 resp. 5-year-OS 83% versus 97%, p = 0.006). Multivariable Cox regression analysis for PFS/OS identified both genetic alterations as independent prognostic markers. Our data suggest that patients with WNT-MB carrying TP53 mutations or OTX2 gains (58.1%) are at higher risk of relapse. Eligibility of these patients for therapy de-escalation trials needs to be debated.
摘要:
这项研究旨在重新评估TP53突变的预后影响,并确定特定的染色体畸变作为WNT激活的髓母细胞瘤(WNT-MB)的可能预后标志物。在191名WNT-MBs患者的队列中,CTNNB1、APC、和TP53通过DNA测序进行分析。通过分子倒置探针技术(MIP)评估染色体拷贝数畸变,SNP6,或850k甲基化阵列杂交。对120例患者的预后影响进行了评估,随访数据来自HIT2000髓母细胞瘤试验或HIT注册。CTNNB1突变存在于92.2%,和APC突变在6.8%的样本中。一个CTNNB1野生型肿瘤由于纯合FBXW7缺失而获得WNT激活。单体6占78.6%,儿童比成人更频繁。16.1%的肿瘤样本显示TP53突变,其中60%对p53蛋白具有核阳性。在TP53突变肿瘤样品的40.7%(11/27)和TP53野生型病例的12.6%(13/103)中发现了TP53基因座(染色体17p13.1)的杂合性丧失。携带TP53突变的肿瘤患者的无进展生存期明显较差(PFS;5年PFS为68%对93%,p=0.001),并富集了染色体17p(p=0.001),10和13损失。OTX2(14q22.3)的收益发生在38.9%的样本中,并且与不良的PFS和OS相关(5年PFS为72%对93%,p=0.017。5年操作系统83%对97%,p=0.006)。PFS/OS的多变量Cox回归分析确定了两种遗传改变作为独立的预后标志物。我们的数据表明,携带TP53突变或OTX2增加的WNT-MB患者(58.1%)的复发风险较高。需要对这些患者进行治疗降级试验的资格进行辩论。