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

Abstract

PurposeWilms tumor (WT) is the most common pediatric renal tumor. Treatment planning under International Society of Paediatric Oncology (SIOP) protocols is based on staging and histologic assessment of response to preoperative chemotherapy. Despite high overall survival (OS), many relapses occur in patients without specific risk factors, and many successfully treated patients are exposed to treatments with significant risks of late effects. To investigate whether molecular biomarkers could improve risk stratification, we assessed 1q status and other potential copy number biomarkers in a large WT series.Materials and MethodsWT nephrectomy samples from 586 SIOP WT 2001 patients were analyzed using a multiplex ligation-dependent probe amplification (MLPA) assay that measured the copy number of 1q and other regions of interest.ResultsOne hundred sixty-seven (28%) of 586 WTs had 1q gain. Five-year event-free survival (EFS) was 75.0% in patients with 1q gain (95% CI, 68.5% to 82.0%) and 88.2% in patients without gain (95% CI, 85.0% to 91.4%). OS was 88.4% with gain (95% CI, 83.5% to 93.6%) and 94.4% without gain (95% CI, 92.1% to 96.7%). In univariable analysis, 1q gain was associated with poorer EFS (P < .001; hazard ratio, 2.33) and OS (P = .01; hazard ratio, 2.16). The association of 1q gain with poorer EFS retained significance in multivariable analysis adjusted for 1p and 16q loss, sex, stage, age, and histologic risk group. Gain of 1q remained associated with poorer EFS in tumor subsets limited to either intermediate-risk localized disease or nonanaplastic localized disease. Other notable aberrations associated with poorer EFS included MYCN gain and TP53 loss.ConclusionGain of 1q is a potentially valuable prognostic biomarker in WT, in addition to histologic response to preoperative chemotherapy and tumor stage.

Chromosomal gains of 12p and 1q are not associated with inferior outcome of pediatric and adolescent germ cell tumors

“…Therefore, prognostic biomarkers may help to improve risk‐adapted therapy. We studied gains of 1q in GCT since this chromosomal aberration has been reported to be associated with unfavorable prognosis in other pediatric neoplasms such as Wilms tumors and brain tumors and is a known genetic alteration in Type I GCT. However, in our cohort of pediatric GCT, this alteration is not associated with inferior outcome.…”

“…Gains of 12p have recently also been detected in prepubertal testicular teratomas, which represent Type I GCT in children . Furthermore, gain of chromosome 1q, which is known to be associated with poor prognosis in a variety of malignancies of the childhood (eg, Wilms tumor or pediatric brain tumors), was examined for its prognostic relevance in pediatric GCT …”

“…17 Furthermore, gain of chromosome 1q, which is known to be associated with poor prognosis in a variety of malignancies of the childhood (eg, Wilms tumor or pediatric brain tumors), was examined for its prognostic relevance in pediatric GCT. [18][19][20][21][22]…”

Outcome of Wilms tumor patients with bone metastasis enrolled on National Wilms Tumor Studies 1‐5: A report from the Children's Oncology Group

“…[13][14][15] Prognostic features include stage, tumor weight, histology at baseline and following preoperative chemotherapy, 16 and genetic markers such as 1q gain and loss of heterozygosity at 1p and 16q. 17,18 The most common sites of metastasis in patients with stage IV WT are the lung followed by the liver. 13,16,19 Other sites are rare, but bone and brain have been reported more often at relapse rather than at primary diagnosis.…”

Wilms tumor: “State-of-the-art” update, 2016

“…The most recent series of unilateral WT studies have just been completed and the 4 year EFS and OS outcomes are shown in Table 2 .SIOP protocol uses stage and histological risk group assigned by assessment of the tumour's response to neoadjuvant chemotherapy to stratify patients but the recent emergence of 1q gain as a new biomarker of recurrence risk is likely to change the future consideration of biomarkers in the determination of subsequent therapeutic regimens . 45,46 Before considering 1q gain for clinical use, the heterogeneity of its expression within the tumor needs to be fully assessed and its prognostic significance needs to be validated in an independent sample set. 47 Recently, several new Wilms tumour genes have been discovered .…”