Gain of 1q is associated with inferior event‐free and overall survival in patients with favorable histology Wilms tumor: A report from the Children's Oncology Group

Abstract

Background Wilms tumor is the most common childhood renal tumor. While the majority of patients with favorable histology Wilms Tumor (FHWT) have good outcomes, some patients still experience recurrence and death from disease. This study’s goal was to determine if tumor-specific chromosome 1q gain is associated with event-free (EFS) and overall survival (OS) in FHWT. Methods Unilateral FHWT samples were obtained from patients enrolled on National Wilms Tumor Study-4 and Pediatric Oncology Group 9046, “A Molecular Genetic analysis of Wilms Tumor.” 1q gain, 1p loss, and 16q loss were determined using multiplex ligation-dependent probe amplification (MLPA). Results The eight-year EFS was 87% (95% CI 82%, 91%) for the entire cohort of 212 patients. Tumors of 58/212 patients (27%) displayed 1q gain. A strong relationship between 1q gain and 1p/16q loss was observed. The eight-year EFS was 76% (95% CI 63%, 85%) for those with 1q gain and 93% (95% CI 87%, 96%) for those lacking 1q gain (p=0.0024). The eight-year OS was 89% (95% CI 78%, 95%) for those with 1q gain, and 98% (95% CI 94%, 99%) for those lacking 1q gain (p=0.0075). Gain of 1q did not correlate with disease stage (p=0.16). After stratification for stage, 1q gain was associated with significantly increased risk of recurrence (risk ratio estimate: 2.72, p=0.0089). Conclusions Gain of 1q may provide a valuable prognostic marker to stratify therapy for patients with FHWT. A confirmatory study is necessary before this biomarker is incorporated into risk stratification schema of future therapeutic studies.

Outcome and Prognostic Factors in Stage III Favorable-Histology Wilms Tumor: A Report From the Children’s Oncology Group Study AREN0532

“…20 These findings are not immediately translatable to the COG experience for several There is strong evidence that 1q gain confers inferior survival. 4,[26][27][28][29]44 We did not attempt to replicate this in our study. There is also a strong correlation of LOH 1p/16q with 1q gain due to common genetic mechanisms (including isochromosome 1q and translocations involving chromosomes 1 and 16).…”

“…However, certain subgroups of patients have inferior survival estimates related to stage and biologic risk factors. [1][2][3][4][5] The National Wilms Tumor Study Group (NWTS), and subsequently the Children's Oncology Group (COG), have adopted an approach of upfront nephrectomy when feasible, followed by stageand biology-directed treatment. 6,7 This is distinct from the International Society of Pediatric Oncology (SIOP) approach, where chemotherapy is given before nephrectomy in most patients, which has been shown to alter the proportion designated as stage III.…”

“…Numerous studies have now demonstrated the adverse impact of 1q gain. 4,[26][27][28][29] In addition, a number of clinicopathologic markers have been identified in patients with NWTS-5 stage III disease, including tumor involvement of lymph nodes. 5 This latter finding requires validation.…”

Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer

“…In this case, independent mutation events, with different chromosomal breakpoints, led to repeated occurrence of both 1p and 16q loss of heterozygosity over time. This is particularly interesting as both these aberrations are strongly associated with high-risk morphology and poor outcome 22,23,33 . Genome profiles in metastases frequently derived from subclones that were part of a microdiversity landscape.…”

“…This protocol consists of both pre-and postoperative chemotherapy 21 , and all biopsies were obtained from tumournephrectomy specimens obtained B7 days after the last chemotherapy cycle. Our cohort was representative of nephroblastoma with regard to the panorama of genomic imbalances and had survival statistics that stratified according to established clinicopathological parameters (Supplementary Figs 5 and 6a-c) 22,23 . High-resolution genome array analysis showed microdiversity in 45% (20/44) of the tumours (Supplementary Fig.…”