Somatic TP53 Mutations Are Detectable in Circulating Tumor DNA from Children with Anaplastic Wilms Tumors

Taryn D Treger,Tasnim Chagtai,Robert Butcher,George D Cresswell,Reem Al-Saadi,Jesper Brok,Richard D Williams,Chrissy Roberts,Nicholas M Luscombe,Kathy Pritchard Jones,William Mifsud

doi:10.1016/j.tranon.2018.08.006

Abstract

BACKGROUND: Diffuse anaplastic Wilms tumor (DAWT) is a rare, high-risk subtype that is often missed on diagnostic needle biopsy. Somatic mutations in TP53 are associated with the development of anaplasia and with poorer survival, particularly in advanced-stage disease. Early identification of DAWT harboring TP53 abnormalities could improve risk stratification of initial therapy and monitoring for recurrence. METHODS: Droplet digital polymerase chain reaction (ddPCR) was used to evaluate 21 samples from 4 patients with DAWT. For each patient, we assessed TP53 status in frozen tumor, matched germline DNA, and circulating tumor DNA (ctDNA) from plasma, serum, and urine collected throughout treatment. RESULTS: Mutant TP53 was detectable in ctDNA from plasma and serum in all patients. We did not detect variant TP53 in the same volume (200 μl) of urine. One patient displayed heterogeneity of TP53 in the tumor despite both histological sections displaying anaplasia. Concentration of ctDNA from plasma/serum taken prenephrectomy varied significantly between patients, ranging from 0.44 (0.05-0.90) to 125.25 (109.75-140.25) copies/μl. We observed variation in ctDNA throughout treatment, and in all but one patient, ctDNA levels fell significantly following nephrectomy. CONCLUSION: We demonstrate for the first time that ddPCR is an effective method for detection of mutant TP53 in ctDNA from children with DAWT even when there is intratumoral somatic heterogeneity. This should be further explored in a larger cohort of patients, as early detection of circulating variant TP53 may have significant clinical impact on future risk stratification and surveillance.

Highlights

Wilms tumor (WT) or nephroblastoma is the most common childhood renal cancer, with 1 in 100,000 children diagnosed annually [1]
Mutant TP53 is detectable in circulating tumor DNA (ctDNA) from plasma and serum in patients with Diffuse anaplastic Wilms tumor (DAWT), though not from the same volume of urine
There are over 200 Single nucleotide polymorphisms (SNPs) in the gene, with some of these variants likely predisposing to cancer [21]

Summary

Introduction

Wilms tumor (WT) or nephroblastoma is the most common childhood renal cancer, with 1 in 100,000 children diagnosed annually [1]. In North America, children undergo immediate surgery prior to chemotherapy in accordance with the Children's Oncology Group (COG) For both groups, tumor histology and stage dictate the intensity of postoperative treatment, with chemotherapy and sometimes radiotherapy. CONCLUSION: We demonstrate for the first time that ddPCR is an effective method for detection of mutant TP53 in ctDNA from children with DAWT even when there is intratumoral somatic heterogeneity. This should be further explored in a larger cohort of patients, as early detection of circulating variant TP53 may have significant clinical impact on future risk stratification and surveillance

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