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.

Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies

“…The use of circulating tumor DNA (ctDNA), an emerging field in multiple cancer types, allows the evolutionary dynamics of tumors such as early stage lung cancer [357] or in bladder cancer to be tracked to follow the development of resistance in real-time using a liquid biopsy [358]. DNA-repair gene mutations are highly prevalent in ctDNA from myeloma [359]. The pharmacodynamic activation of the DDR pathway can confirm target engagement in tumors following anticancer treatment.…”

Modulation of Apoptosis Pathways in the Biology and Treatment of Multiple Myeloma

“…60 p53 in multiple myeloma TP53 mutations are present in 5-6% of patients newly diagnosed with multiple myeloma and 21-26% in relapsed and/or refractory multiple myeloma patients. 62 The presence of TP53 mutations or del(17p) in the plasma cells is a poor prognostic factor and portends aggressive disease phenotype, a greater degree of extramedullary disease and shortened survival. 18,62 There is also overexpression of MDM2 in multiple myeloma, which results in rapid turnover of p53 and therefore constant low levels of p53.…”

“…62 The presence of TP53 mutations or del(17p) in the plasma cells is a poor prognostic factor and portends aggressive disease phenotype, a greater degree of extramedullary disease and shortened survival. 18,62 There is also overexpression of MDM2 in multiple myeloma, which results in rapid turnover of p53 and therefore constant low levels of p53. 63 MDM4, a homologue of MDM2, located on chromosome 1q is also implicated in p53 inactivation.…”

Human myeloma cell‐ and plasma‐derived extracellular vesicles contribute to functional regulation of stromal cells

“…Circulating extracellular vesicles (EVs) containing tumour-specific molecular signatures (oncoproteins, mRNAs, long noncoding RNAs and DNA fragments) have potential clinical utility as next-generation biomarkers for liquid biopsy in cancer diagnosis and management [12][13][14][15][16][17]. In the context of MM, liquid biopsies enable the characterisation of spatial heterogeneity and clonal evolution [18][19][20][21][22][23][24], and may represent an attractive alternative to the single-site tissue biopsies usually employed in the evaluation of MM [19,25,20,21,24,8]. Specifically in MM, a role for large EVs (plEV; EVs shed from the plasma membrane) as predictive or prognostic biomarkers has been demonstrated from patient blood [13,26,27,24], while several key studies have reported the diagnostic potential of small EVs (psEV; EVs with endosomal origin) for MM [26,[28][29][30][31].…”