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Sub-clonal TP53 copy number is associated with prognosis in multiple myeloma

Vallari Shah, David C. Johnson, Amy L. Sherborne, Sidra Ellis, Frances M. Aldridge, Julie Howard-Reeves, Farzana Begum, Amy Price, Jack Kendall, Laura Chiecchio, Suvi Savola, Matthew W. Jenner, Mark T. Drayson, Roger G. Owen, Walter M. Gregory, Gareth J. Morgan, Faith E. Davies, Richard S. Houlston, Gordon Cook, David A. Cairns, Graham Jackson and Martin F. Kaiser

Key points

  • TP53 deletion of minor tumour sub-clones is independently prognostic in newly diagnosed multiple myeloma.

  • Assessment of sub-clonal TP53 deletions by MLPA is readily applicable in standard diagnostics, enabling stratified patient management.

Abstract

Multiple myeloma (MM) is a genetically heterogeneous cancer of bone marrow plasma cells with variable outcome. To assess the prognostic relevance of clonal heterogeneity of TP53 copy number, we profiled tumours from 1,777 newly diagnosed Myeloma XI trial patients with multiplex ligation-dependent probe amplification (MLPA). Sub-clonal TP53 deletions were independently associated with shorter overall survival with a hazard ratio of 1.8 (95% CI: 1.2-2.8; P=0.01). Clonal, but not sub-clonal, TP53 deletion were associated with clinical markers of advanced disease, specifically lower platelet counts (P<0.001) and increased LDH (P<0.001), and higher frequency of features indicative of genomic instability del(13q)(P=0.002) or del(1p)(P=0.006). Bi-allelic TP53 loss-of-function by mutation and deletion was rare (2.4%) and associated with advanced disease. We present a framework for identifying sub-clonal TP53 deletions by MLPA, to improve patient stratification in MM and tailor therapy, enabling management strategies.

  • Submitted June 12, 2018.
  • Accepted October 3, 2018.