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DNA-Repair Gene Mutations Are Highly Prevalent in Circulating Tumour DNA from Multiple Myeloma Patients

1
Myeloma Research Group, Australian Centre for Blood Diseases, Alfred Hospital-Monash University, Melbourne 3004, Victoria, Australia
2
Malignant Hematology and Stem Cell Transplantation, Alfred Hospital, Melbourne 3004, Victoria, Australia
3
Epidemiology and Preventive Medicine, Alfred Health‐Monash University, Melbourne 3004, Australia
4
Department of Clinical Hematology, Monash University, Clayton 3800, Victoria, Australia
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(7), 917; https://doi.org/10.3390/cancers11070917
Received: 23 May 2019 / Revised: 8 June 2019 / Accepted: 25 June 2019 / Published: 29 June 2019
(This article belongs to the Special Issue Liquid Biopsy for Cancer)
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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. View Full-Text
Keywords: circulating tumour DNA; multiple myeloma; haematology; liquid biopsy; DNA-repair genes; TP53; RAS; prognosis circulating tumour DNA; multiple myeloma; haematology; liquid biopsy; DNA-repair genes; TP53; RAS; prognosis
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Mithraprabhu, S.; Hocking, J.; Ramachandran, M.; Choi, K.; Klarica, D.; Khong, T.; Reynolds, J.; Spencer, A. DNA-Repair Gene Mutations Are Highly Prevalent in Circulating Tumour DNA from Multiple Myeloma Patients. Cancers 2019, 11, 917.

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