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
C2 - 31261969
AN - SCOPUS:85068683984
SN - 2072-6694
VL - 11
JO - Cancers
JF - Cancers
IS - 7
M1 - 917
ER -