Abstract
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.
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References
Brok J, Lopez-Yurda M, Tinteren HV, Treger TD, Furtwängler R, Graf N, et al. Relapse of Wilms’ tumour and detection methods: a retrospective analysis of the 2001 Renal Tumour Study Group-International Society of Paediatric Oncology Wilms’ tumour protocol database. Lancet Oncol. 2018;19:1072–81.
Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol. 2018;15:81–94.
Cresswell GD, Apps JR, Chagtai T, Misfud B, Bentley CC, Maschietto M, et al. Intra-tumor genetic heterogeneity in Wilms tumor: clonal evolution and clinical implications. EBioMedicine. 2016;9:120–9.
Williams RD, Chagtai T, Alcaide-German M, Apps J, Wegert J, Popov S, et al. Multiple mechanisms of MYCN dysregulation in Wilms tumour. Oncotarget. 2015;6:7232–43.
Wegert J, Vokuhl C, Ziegler B, Ernestus K, Leuschner I, Furtwängler R, et al. TP53 alterations in Wilms tumour represent progression events with strong intratumour heterogeneity that are closely linked but not limited to anaplasia. J Pathol Clin Res. 2017;34:234–48.
Spreafico F, Ciceri S, Gamba B, Torri F, Terenziani M, Collini P, et al. Chromosomal anomalies at 1q, 3, 16q, and mutations of SIX1 and DROSHA genes underlie Wilms tumor recurrences. Oncotarget. 2016;7:8908–15.
Walz AL, Ooms A, Gadd S, Gerhard DS, Smith MA, Guidry Auvil JM, et al. Recurrent DGCR8, DROSHA, and SIX homeodomain mutations in favorable histology Wilms tumors. Cancer Cell. 2015;27:286–97.
Wegert J, Ishaque N, Vardapour R, Geörg C, Gu Z, Bieg M, et al. Mutations in the SIX1/2 pathway and the DROSHA/DGCR8 miRNA microprocessor complex underlie high-risk blastemal type Wilms tumors. Cancer Cell. 2015;27:298–311.
Natrajan R, Little SE, Sodha N, Reis-Filho JS, Mackay A, Fenwick K, et al. Analysis by array CGH of genomic changes associated with the progression or relapse of Wilms’ tumour. J Pathol. 2007;211:52–9.
Fleiss JL. Statistical methods for rates and proportions. 2nd ed. New York, USA: Wiley; 1981.
Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33:159–74.
Byrt T, Bishop J, Carlin JB. Bias, prevalence and kappa. J Clin Epidemiol. 1993;46:423–9.
Paradiso A, Ellis IO, Zito FA, Marubini E, Pizzamiglio S, Verderio P. Short- and long-term effects of a training session on pathologists’ performance: the INQAT experience for histological grading in breast cancer. J Clin Pathol. 2009;62:279–81.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457e81.
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science. 2013;339:1546–58.
Perotti D, Spreafico F, Torri F, Gamba B, D’Adamo P, Pizzamiglio S, et al. Genomic profiling by whole-genome single nucleotide polymorphism arrays in Wilms tumor and association with relapse. Genes Chromosomes Cancer. 2012;51:644–53.
Gratias EJ, Dome JS, Jennings LJ, Chi YY, Tian J, Anderson J, et al. Association of chromosome 1q gain with inferior survival in favorable-histology wilms tumor: a report from the Children’s Oncology Group. J Clin Oncol. 2016;34:3189–94.
Chagtai T, Zill C, Dainese L, Wegert J, Savola S, Popov S, et al. Gain of 1q as a prognostic biomarker in Wilms tumors (WTs) treated with preoperative chemotherapy in the International Society of Paediatric Oncology (SIOP) WT 2001 Trial: a SIOP Renal Tumours Biology Consortium Study. J Clin Oncol. 2016;34:3195–203.
Grundy PE, Breslow NE, Li S, Perlman E, Beckwith JB, Ritchey ML, et al. Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorable-histology Wilms tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol. 2005;23:7312–21.
Acknowledgements
Authors wish to thank all AIEOP Clinicians and Pathologists for their collaboration.
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Partially supported by Associazione Bianca Garavaglia ONLUS, Busto A. (VA), Italy, Italian Association for Cancer Research (AIRC), Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
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Ciceri, S., Montalvão-de-Azevedo, R., Tajbakhsh, A. et al. Analysis of the mutational status of SIX1/2 and microRNA processing genes in paired primary and relapsed Wilms tumors and association with relapse. Cancer Gene Ther 28, 1016–1024 (2021). https://doi.org/10.1038/s41417-020-00268-3
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DOI: https://doi.org/10.1038/s41417-020-00268-3
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