Circulating tumour DNA analysis demonstrates spatial mutational heterogeneity that coincides with disease relapse in myeloma

S Mithraprabhu, T Khong, M Ramachandran, A Chow, D Klarica, L Mai, S Walsh, D Broemeling, A Marziali, M Wiggin, J Hocking, A Kalff, B Durie, A Spencer

Research output: Research - peer-reviewArticle

Abstract

Mutational characterisation in multiple myeloma (MM) currently relies on bone marrow (BM) biopsy, which fails to capture the putative spatial and genetic heterogeneity of this multifocal disease. Analysis of plasma (PL)-derived circulating free tumour DNA (ctDNA) as an adjunct to BM biopsy, for mutational characterisation and tracking disease progression, was evaluated. Paired BM MM cell DNA and ctDNA from 33 relapsed/refractory (RR) and 15 newly diagnosed (ND) patients were analysed for KRAS, NRAS, BRAF and TP53 mutations using the OnTarget Mutation Detection (OMD) platform. OMD detected 128 mutations (PL=31, BM=59, both=38) indicating the presence of PL mutations (54%). A higher frequency of PL-only mutations was detected in RR patients than ND (27.2% vs 6.6%, respectively), authenticating the existence of spatial and genetic heterogeneity in advanced disease. Activating RAS mutations were more highly prevalent than previously described with 69% harboring at least one RAS mutation. Sequential ctDNA quantitation with droplet digital PCR through longitudinal PL tracking of specific clones in seven patients demonstrated changes in fractional abundance of certain clones reflective of the disease status. We conclude that ctDNA analysis as an adjunct to BM biopsy represents a noninvasive and holistic strategy for improved mutational characterisation and therapeutic monitoring of MM.

LanguageEnglish
Pages1695-1705
Number of pages11
JournalLeukemia
Volume31
Issue number8
DOIs
StatePublished - 1 Aug 2017

Cite this

Mithraprabhu, S ; Khong, T ; Ramachandran, M ; Chow, A ; Klarica, D ; Mai, L ; Walsh, S ; Broemeling, D ; Marziali, A ; Wiggin, M ; Hocking, J ; Kalff, A ; Durie, B ; Spencer, A. / Circulating tumour DNA analysis demonstrates spatial mutational heterogeneity that coincides with disease relapse in myeloma. In: Leukemia. 2017 ; Vol. 31, No. 8. pp. 1695-1705
@article{09001981e60c482d903253f637e15b02,
title = "Circulating tumour DNA analysis demonstrates spatial mutational heterogeneity that coincides with disease relapse in myeloma",
abstract = "Mutational characterisation in multiple myeloma (MM) currently relies on bone marrow (BM) biopsy, which fails to capture the putative spatial and genetic heterogeneity of this multifocal disease. Analysis of plasma (PL)-derived circulating free tumour DNA (ctDNA) as an adjunct to BM biopsy, for mutational characterisation and tracking disease progression, was evaluated. Paired BM MM cell DNA and ctDNA from 33 relapsed/refractory (RR) and 15 newly diagnosed (ND) patients were analysed for KRAS, NRAS, BRAF and TP53 mutations using the OnTarget Mutation Detection (OMD) platform. OMD detected 128 mutations (PL=31, BM=59, both=38) indicating the presence of PL mutations (54%). A higher frequency of PL-only mutations was detected in RR patients than ND (27.2% vs 6.6%, respectively), authenticating the existence of spatial and genetic heterogeneity in advanced disease. Activating RAS mutations were more highly prevalent than previously described with 69% harboring at least one RAS mutation. Sequential ctDNA quantitation with droplet digital PCR through longitudinal PL tracking of specific clones in seven patients demonstrated changes in fractional abundance of certain clones reflective of the disease status. We conclude that ctDNA analysis as an adjunct to BM biopsy represents a noninvasive and holistic strategy for improved mutational characterisation and therapeutic monitoring of MM.",
author = "S Mithraprabhu and T Khong and M Ramachandran and A Chow and D Klarica and L Mai and S Walsh and D Broemeling and A Marziali and M Wiggin and J Hocking and A Kalff and B Durie and A Spencer",
year = "2017",
month = "8",
doi = "10.1038/leu.2016.366",
volume = "31",
pages = "1695--1705",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Macmillan Publishers",
number = "8",

}

Mithraprabhu, S, Khong, T, Ramachandran, M, Chow, A, Klarica, D, Mai, L, Walsh, S, Broemeling, D, Marziali, A, Wiggin, M, Hocking, J, Kalff, A, Durie, B & Spencer, A 2017, 'Circulating tumour DNA analysis demonstrates spatial mutational heterogeneity that coincides with disease relapse in myeloma' Leukemia, vol 31, no. 8, pp. 1695-1705. DOI: 10.1038/leu.2016.366

Circulating tumour DNA analysis demonstrates spatial mutational heterogeneity that coincides with disease relapse in myeloma. / Mithraprabhu, S; Khong, T; Ramachandran, M; Chow, A; Klarica, D; Mai, L; Walsh, S; Broemeling, D; Marziali, A; Wiggin, M; Hocking, J; Kalff, A; Durie, B; Spencer, A.

In: Leukemia, Vol. 31, No. 8, 01.08.2017, p. 1695-1705.

Research output: Research - peer-reviewArticle

TY - JOUR

T1 - Circulating tumour DNA analysis demonstrates spatial mutational heterogeneity that coincides with disease relapse in myeloma

AU - Mithraprabhu,S

AU - Khong,T

AU - Ramachandran,M

AU - Chow,A

AU - Klarica,D

AU - Mai,L

AU - Walsh,S

AU - Broemeling,D

AU - Marziali,A

AU - Wiggin,M

AU - Hocking,J

AU - Kalff,A

AU - Durie,B

AU - Spencer,A

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Mutational characterisation in multiple myeloma (MM) currently relies on bone marrow (BM) biopsy, which fails to capture the putative spatial and genetic heterogeneity of this multifocal disease. Analysis of plasma (PL)-derived circulating free tumour DNA (ctDNA) as an adjunct to BM biopsy, for mutational characterisation and tracking disease progression, was evaluated. Paired BM MM cell DNA and ctDNA from 33 relapsed/refractory (RR) and 15 newly diagnosed (ND) patients were analysed for KRAS, NRAS, BRAF and TP53 mutations using the OnTarget Mutation Detection (OMD) platform. OMD detected 128 mutations (PL=31, BM=59, both=38) indicating the presence of PL mutations (54%). A higher frequency of PL-only mutations was detected in RR patients than ND (27.2% vs 6.6%, respectively), authenticating the existence of spatial and genetic heterogeneity in advanced disease. Activating RAS mutations were more highly prevalent than previously described with 69% harboring at least one RAS mutation. Sequential ctDNA quantitation with droplet digital PCR through longitudinal PL tracking of specific clones in seven patients demonstrated changes in fractional abundance of certain clones reflective of the disease status. We conclude that ctDNA analysis as an adjunct to BM biopsy represents a noninvasive and holistic strategy for improved mutational characterisation and therapeutic monitoring of MM.

AB - Mutational characterisation in multiple myeloma (MM) currently relies on bone marrow (BM) biopsy, which fails to capture the putative spatial and genetic heterogeneity of this multifocal disease. Analysis of plasma (PL)-derived circulating free tumour DNA (ctDNA) as an adjunct to BM biopsy, for mutational characterisation and tracking disease progression, was evaluated. Paired BM MM cell DNA and ctDNA from 33 relapsed/refractory (RR) and 15 newly diagnosed (ND) patients were analysed for KRAS, NRAS, BRAF and TP53 mutations using the OnTarget Mutation Detection (OMD) platform. OMD detected 128 mutations (PL=31, BM=59, both=38) indicating the presence of PL mutations (54%). A higher frequency of PL-only mutations was detected in RR patients than ND (27.2% vs 6.6%, respectively), authenticating the existence of spatial and genetic heterogeneity in advanced disease. Activating RAS mutations were more highly prevalent than previously described with 69% harboring at least one RAS mutation. Sequential ctDNA quantitation with droplet digital PCR through longitudinal PL tracking of specific clones in seven patients demonstrated changes in fractional abundance of certain clones reflective of the disease status. We conclude that ctDNA analysis as an adjunct to BM biopsy represents a noninvasive and holistic strategy for improved mutational characterisation and therapeutic monitoring of MM.

UR - http://www.scopus.com/inward/record.url?scp=85007551377&partnerID=8YFLogxK

U2 - 10.1038/leu.2016.366

DO - 10.1038/leu.2016.366

M3 - Article

VL - 31

SP - 1695

EP - 1705

JO - Leukemia

T2 - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 8

ER -