Whereas 90% of patients with Wilms tumor (WT) reach cure, approximately half of patients developing a recurrent tumor die of the disease. Therefore, to disclose events leading to recurrence represents a clinical need. To study paired primary/recurrent tumor samples, being aware of the intra-tumoral heterogeneity, might help finding these answers. We previously suggested that mutations in SIX1 and DROSHA underlie WT recurrence. With the aim to better investigate this scenario, we collected 19 paired primary/recurrent tumors and 10 primary tumors from relapsing patients and searched for mutations in the SIX1/2 genes and microRNA processing genes (miRNAPGs). We found SIX1 mutation in one case, miRNAPGs mutations in seven cases, and the co-occurrence of SIX1 and miRNAPG mutations in one case. We could observe that, whereas in primary tumors the mutations could be heterogeneously present, in all cases they were positively selected and homogeneously present in the recurrent disease, as also indicated by a “moderate” and “almost perfect” agreement (according to the Landis and Koch classification criteria) between paired samples. Analysis of SIX1/2 genes and miRNAPGs in 50 non-relapsing WTs disclosed SIX2 mutation in one case and miRNAPGs mutations in seven. A borderline statistically significant association was observed between miRNAPGs mutations and the occurrence of relapse (p value: 0.05). These data suggest that SIX1 and miRNAPGs mutations may provide an advantage during tumor progression to recurrence and can represent oncogenic drivers in WT development.

尽管 90% 的肾母细胞瘤 (WT) 患者能够治愈，但大约一半的肿瘤复发患者死于该病。因此，披露导致复发的事件代表了临床需要。研究成对的原发性/复发性肿瘤样本，了解肿瘤内的异质性，可能有助于找到这些答案。我们之前提出SIX1和DROSHA中的突变是 WT 复发的基础。为了更好地研究这种情况，我们从复发患者中收集了 19 个成对的原发/复发肿瘤和 10 个原发肿瘤，并搜索了SIX1/2基因和 microRNA 加工基因 (miRNAPG) 的突变。我们找到了 SIX1突变1例，miRNAPGs突变7例，SIX1与miRNAPG突变共存1例。我们可以观察到，虽然在原发性肿瘤中突变可能异质存在，但在所有情况下，它们都被积极选择并均匀存在于复发性疾病中，正如“适度”和“几乎完美”的一致性所表明的那样（根据 Landis和科赫分类标准）配对样本之间。对50 例非复发 WT中的SIX1/2基因和 miRNAPG 的分析揭示了 1 例SIX2突变和 7 例 miRNAPG 突变。在 miRNAPGs 突变与复发的发生之间观察到具有统计学意义的临界关联（p值：0.05）。这些数据表明，SIX1和 miRNAPGs 突变可能在肿瘤进展到复发期间提供优势，并且可以代表 WT 发展中的致癌驱动因素。