Assessment of somatic mutations in urine and plasma of Wilms tumor patients

Abstract

Tumor DNA has been detected in body fluids of cancer patients. Somatic tumor mutations are being used as biomarkers in body fluids to monitor chemotherapy response as a minimally invasive tool. In this study, we evaluated the potential of tracking somatic mutations in free DNA of plasma and urine collected from Wilms tumor (WT) patients for monitoring treatment response. Wilms tumor is a pediatric renal tumor resulting from cell differentiation errors during nephrogenesis. Its mutational repertoire is not completely defined. Thus, for identifying somatic mutations from tumor tissue DNA, we screened matched tumor/leukocyte DNAs using either a panel containing 16 WT‐associated genes or whole‐exome sequencing (WES). The identified somatic tumor mutations were tracked in urine and plasma DNA collected before, during and after treatment. At least one somatic mutation was identified in five out of six WT tissue samples analyzed. Somatic mutations were detected in body fluids before treatment in all five patients (three patients in urine, three in plasma, and one in both body fluids). In all patients, a decrease of the variant allele fraction of somatic mutations was observed in body fluids during neoadjuvant chemotherapy. Interestingly, the persistence of somatic mutations in body fluids was in accordance with clinical parameters. For one patient who progressed to death, it persisted in high levels in serial body fluid samples during treatment. For three patients without disease progression, somatic mutations were not consistently detected in samples throughout monitoring. For one patient with bilateral disease, a somatic mutation was detected at low levels with no support of clinical manifestation. Our results demonstrated the potential of tracking somatic mutations in urine and plasma DNA as a minimally invasive tool for monitoring WT patients. Additional investigation is needed to check the clinical value of insistent somatic mutations in body fluids.

Circulating Tumor DNA as a Biomarker in Patients With Stage III and IV Wilms Tumor: Analysis From a Children's Oncology Group Trial, AREN0533

“…[11][12][13][14][15][16][17][18]24 Previous studies have demonstrated that the detection of ctDNA in the blood of patients with WT was feasible, but these studies were too small to demonstrate associations with other prognostic features or outcomes. 19,[21][22][23]25 In this study, we profiled samples collected from a cohort of 50 patients with matched tumor, serum, and urine who were treated on the COG study AREN0533 for patients with newly diagnosed stage III and IV disease. We found that the majority of these patients shed sufficient levels of ctDNA into their serum to be reliably detectable by a low-sensitivity nextgeneration sequencing approach that identifies segmental and chromosomal copy-number variants.…”

“…[11][12][13][14][15][16][17] Previous studies indicate that ctDNA is detectable in a range of pediatric solid tumors; however, those studies exploring ctDNA in patients with WT have been limited by sample size and cohorts of patients with a mix of risk-defining clinical features. 9,[18][19][20][21][22][23][24][25][26] Whether recently identified stratifying genomic features, namely 16q and 1p LOH and 1q copy gains, can be identified in the blood of patients with WT using liquid biopsy has yet to be explored.…”

Tracking the history of circulating nucleic acids for cancer research in Brazil: A systematic review

“…Miguez et al evaluated the somatic mutations using NGS platform in the cfDNA from plasma and urine of 6 female patients with Wilms tumor in SP. 28 Before treatment, 5 patients showed at least 1 somatic mutation in tumor samples and also in body fluids, being reduced after chemotherapy.…”

Liquid biopsies in pediatric oncology: opportunities and obstacles

“…Although larger validation studies are needed, these data suggest that ctDNA may predict prognostic postneoadjuvent percentage necrosis in osteosarcoma [78]. Similarly, dynamic changes in ctDNA have been shown to correlate with tumor burden in Wilms tumor [79], hepatoblastoma [80], retinoblastoma [81][82][83], EWS [51 && ,77,84], and neuroblastoma [61,62]. Additionally, circulating epigenetic signatures approximate tumor burden and response.…”