Genetic changes associated with relapse in favorable histology Wilms tumor: A Children’s Oncology Group AREN03B2 study

Summary

Over the last decade, sequencing of primary tumors has clarified the genetic underpinnings of Wilms tumor but has not affected therapy, outcome, or toxicity. We now sharpen our focus on relapse samples from the umbrella AREN03B2 study. We show that over 40% of relapse samples contain mutations in SIX1 or genes of the MYCN network, drivers of progenitor proliferation. Not previously seen in large studies of primary Wilms tumors, DIS3 and TERT are now identified as recurrently mutated. The analysis of primary-relapse tumor pairs suggests that 11p15 loss of heterozygosity (and other copy number changes) and mutations in WT1 and MLLT1 typically occur early, but mutations in SIX1, MYCN, and WTX are late developments in some individuals. Most strikingly, 75% of relapse samples had gain of 1q, providing strong conceptual support for studying circulating tumor DNA in clinical trials to better detect 1q gain earlier and monitor response.

Graphical abstract

Highlights

• •

  Methods for measuring 1q gain, seen in 75% of relapse samples, merit optimization

• •

  Drivers of progenitor proliferation ( SIX1 and MYCN) affect tumorigenesis and relapse

• •

  Mutations in DIS3 and in the TERT promoter are newly identified

• •

  Chromosomal gains and losses often occur prior to mutations in Wilms tumor

Abstract

Wilms tumors have many potential driver mutations. Gadd et al. focus on samples from relapse tumors revealing that over 40% contain mutations in SIX1 or in MYCN network genes, drivers of progenitor proliferation, and that 75% have 1q gain, supporting optimization of new tools for identifying 1q gain.