1q gain is a frequent finding in preoperatively treated Wilms tumors, but of limited prognostic value for risk stratification in the SIOP2001/GPOH trial

Segers et al. recently reported in this journal that gain of chromosome arm 1q is a marker of poor prognosis in Wilms tumors (Segers et al., 2013). They performed a cytogenetic analysis of 331 Wilms tumors treated in the British UKW2, UKW3, and the international SIOP 2001 nephroblastoma studies. About half of the tumors were primary nephrectomy specimens and the other half were tumor samples received after preoperative chemotherapy. Nineteen percent of Wilms tumors showed gain of 1q. There was no difference in age at diagnosis, stage, or anaplasia in tumors with and without 1q gain. Multivariate analysis showed an independent association of 1q gain with an adverse outcome for both event-free survival (EFS; hazard ration (HR) 5 2.45, P 5 0.02) and overall survival (OS; HR 5 4.28, P 5 0.004). Gratias et al. (2013) reported on behalf of the Children’s Oncology Group in a study on chromosome arm 1q gain in primary resected Wilms tumors with favorable histology that gain of 1q was associated with inferior EFS and OS. In 212 analyzed tumors using the multiplex ligationdependent probe amplification (MLPA) technique, they found a 1q gain in 58 specimens (27%). Eightyear EFS rate of 76% for tumors with 1q gain was significantly lower as compared to tumors without 1q gain (93%, P 5 0.0024). Risk stratification of patients in the SIOP2001/ GPOH study, as part of the SIOP2001 trial, is mainly based on stage and tumor classification after preoperative chemotherapy. Based on histopathologic classification three risk groups exist: high-risk tumors including blastemal-type (preoperatively treated) and nephroblastomas with diffuse anaplasia; low risk tumors consisting of completely necrotic tumors; all other types of Wilms tumors (mixed, epithelial, stromal, and regressive tumors as well as tumors with focal anaplasia) are considered as intermediate risk tumors according to this classification (Vujanić et al., 2002). The goal of our study was to determine if the prognostic significance of chromosome 1q gain is still existent in a homogenous preoperatively treated cohort of patients from the SIOP2001/ GPOH study using macrodissected tissue with more than 90% viable tumor cells. In a first step, we analyzed a cohort of 98 tumors (test set) with predominance of high-risk tumors to study the prognostic value of chromosome arm 1q gain (patient characteristics, see Table 1). Chromosome 1q gain was studied using MLPA. MLPA analysis was performed using the SALSA MLPA-probemix P303 with four primers located on 1q (1q21.1, 1q32.1, 1q42.12, 1q44) according to the manufacturer’s protocol (MRC Holland, Amsterdam, The Netherlands). In the test set, a gain of chromosome arm 1q was found in 45% (44/98) of tumors, predominantly in blastemal-type (n 5 32; 53%) tumors and in tumors with diffuse anaplasia (n 5 21, 67%). The 5-year EFS was 71% for those with one 1q gain and 81% for those without gain of 1q (P 5 0.214; Fig. 1A). Evaluation of EFS data of this high-risk enriched cohort using histopathologic risk grouping showed a significant difference in survival [high-risk tumors 63% EFS, intermediate risk tumors 92% (P 5 0.001), Fig. 1B]. In the second step, all patients (n 5 81) registered in the SIOP2001/GPOH study within 1 year (2007) were investigated (validation set) with the same technique to demonstrate the incidence of 1q gain in a nationwide unbiased study and to validate the prognostic value found in the test set (patients characteristics in Table 1). In the validation set, we found a gain of 1q in 59% of tumors. In Kaplan–Meier analysis there was no statistically significant difference in EFS [tumors with 1q gain 80% EFS, without 1q gain 91% EFS (P 5 0.188), Fig. 1C]. Evaluation of EFS data of the same patients using histopathologic risk grouping showed a significant difference in survival [high-risk tumors 70% EFS, intermediate risk tumors 88% (P 5 0.048), Fig. 1D]. In contrast to the test set, we did not find a higher incidence of gain of 1q in blastemal-type or diffusely anaplastic Wilms tumors as compared to other