Circulating tumour DNA sequence analysis as an alternative to multiple myeloma bone marrow aspirates

Olena Kis, Rayan Kaedbey, Signy Chow, Arnavaz Danesh, Mark Dowar, Tiantian Li, Zhihua Li, Jessica Liu, Mark Mansour, Esther Masih-Khan, Tong Zhang, Scott V. Bratman, Amit M. Oza, Suzanne Kamel-Reid, Suzanne Trudel () and Trevor J. Pugh ()
Additional contact information
Olena Kis: Princess Margaret Cancer Centre, University Health Network
Rayan Kaedbey: Princess Margaret Cancer Centre, University Health Network
Signy Chow: Princess Margaret Cancer Centre, University Health Network
Arnavaz Danesh: Princess Margaret Cancer Centre, University Health Network
Mark Dowar: Princess Margaret Cancer Centre, University Health Network
Tiantian Li: Princess Margaret Cancer Centre, University Health Network
Zhihua Li: Princess Margaret Cancer Centre, University Health Network
Jessica Liu: Princess Margaret Cancer Centre, University Health Network
Mark Mansour: Princess Margaret Cancer Centre, University Health Network
Esther Masih-Khan: Princess Margaret Cancer Centre, University Health Network
Tong Zhang: Princess Margaret Cancer Centre, University Health Network
Scott V. Bratman: Princess Margaret Cancer Centre, University Health Network
Amit M. Oza: Princess Margaret Cancer Centre, University Health Network
Suzanne Kamel-Reid: Princess Margaret Cancer Centre, University Health Network
Suzanne Trudel: Princess Margaret Cancer Centre, University Health Network
Trevor J. Pugh: Princess Margaret Cancer Centre, University Health Network

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract The requirement for bone-marrow aspirates for genomic profiling of multiple myeloma poses an obstacle to enrolment and retention of patients in clinical trials. We evaluated whether circulating cell-free DNA (cfDNA) analysis is comparable to molecular profiling of myeloma using bone-marrow tumour cells. We report here a hybrid-capture-based Liquid Biopsy Sequencing (LB-Seq) method used to sequence all protein-coding exons of KRAS, NRAS, BRAF, EGFR and PIK3CA in 64 cfDNA specimens from 53 myeloma patients to >20,000 × median coverage. This method includes a variant filtering algorithm that enables detection of tumour-derived fragments present in cfDNA at allele frequencies as low as 0.25% (median 3.2%, range 0.25–46%). Using LB-Seq analysis of 48 cfDNA specimens with matched bone-marrow data, we detect 49/51 likely somatic mutations, with subclonal hierarchies reflecting tumour profiling (96% concordance), and four additional mutations likely missed by bone-marrow testing (>98% specificity). Overall, LB-Seq is a high fidelity adjunct to genetic profiling of bone-marrow in multiple myeloma.

Date: 2017
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DOI: 10.1038/ncomms15086

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