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

Research output: Contribution to journalArticleResearchpeer-review

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

Cite this

@article{e8e82d453e2a4a2891cb1511223db78d,
title = "DNA-repair gene mutations are highly prevalent in circulating tumour dna from multiple myeloma patients",
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.",
keywords = "Circulating tumour DNA, DNA-repair genes, Haematology, Liquid biopsy, Multiple myeloma, Prognosis, RAS, TP53",
author = "Sridurga Mithraprabhu and Jay Hocking and Malarmathy Ramachandran and Kawa Choi and Daniela Klarica and Tiffany Khong and John Reynolds and Andrew Spencer",
year = "2019",
month = "6",
day = "29",
doi = "10.3390/cancers11070917",
language = "English",
volume = "11",
journal = "Cancers",
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DNA-repair gene mutations are highly prevalent in circulating tumour dna from multiple myeloma patients. / Mithraprabhu, Sridurga; Hocking, Jay; Ramachandran, Malarmathy; Choi, Kawa; Klarica, Daniela; Khong, Tiffany; Reynolds, John; Spencer, Andrew.

In: Cancers, Vol. 11, No. 7, 917, 29.06.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - DNA-repair gene mutations are highly prevalent in circulating tumour dna from multiple myeloma patients

AU - Mithraprabhu, Sridurga

AU - Hocking, Jay

AU - Ramachandran, Malarmathy

AU - Choi, Kawa

AU - Klarica, Daniela

AU - Khong, Tiffany

AU - Reynolds, John

AU - Spencer, Andrew

PY - 2019/6/29

Y1 - 2019/6/29

N2 - 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.

AB - 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.

KW - Circulating tumour DNA

KW - DNA-repair genes

KW - Haematology

KW - Liquid biopsy

KW - Multiple myeloma

KW - Prognosis

KW - RAS

KW - TP53

UR - http://www.scopus.com/inward/record.url?scp=85068683984&partnerID=8YFLogxK

U2 - 10.3390/cancers11070917

DO - 10.3390/cancers11070917

M3 - Article

VL - 11

JO - Cancers

JF - Cancers

SN - 2072-6694

IS - 7

M1 - 917

ER -