DNA-repair gene mutations are highly prevalent in circulating tumour dna from multiple myeloma patients

Sridurga Mithraprabhu, Jay Hocking, Malarmathy Ramachandran, Kawa Choi, Daniela Klarica, Tiffany Khong, John Reynolds, Andrew Spencer

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19 Citations (Scopus)

Abstract

Mutational characterisation utilising plasma (PL)-derived circulating tumour DNA (ctDNA) in multiple myeloma (MM) has been recently described. Mutational analyses of paired bone marrow (BM) MM cell DNA and ctDNA from 76 patients (n = 24, new diagnosis (ND), n = 52, relapsed/refractory (RR)) for (ras/raf signaling pathway) and tumour protein p53 (TP53) mutations using the OnTarget™ Mutation Detection (OMD) platform was performed. The total number and proportions of mutations in each of the compartments (BM-specific, PL-specific or shared) was significantly higher in RR patients compared to ND patients (p = 0.0002 and p < 0.0001, respectively). Patients with > 2 mutations or > 1% fractional abundance (FA) in the PL had significantly shorter overall survival (OS) (p = 0.04 and p = 0.0006, respectively). Patients with PL-specific TP53 mutations had significantly shorter OS compared to patients with no PL-TP53 mutations (p = 0.003), while no differences were observed in patients with (K-ras) KRAS mutations. Targeted deep amplicon sequencing (TAS) of matched PL and BM samples from 36 MM patients for DNA-repair and RAS-RAF pathway genes found that DNA-repair genes were present at significantly higher levels in the PL when compared to RAS-RAF mutations (p = 0.0095). We conclude that ctDNA analysis identifies a higher prevalence of potentially actionable DNA-repair gene mutated subclones than BM analysis.

Original languageEnglish
Article number917
Number of pages14
JournalCancers
Volume11
Issue number7
DOIs
Publication statusPublished - 29 Jun 2019

Keywords

  • Circulating tumour DNA
  • DNA-repair genes
  • Haematology
  • Liquid biopsy
  • Multiple myeloma
  • Prognosis
  • RAS
  • TP53

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