title: Monitoring multiple myeloma by quantification of recurrent mutations in serum.
abstract: Circulating tumor DNA is a promising biomarker to monitor tumor load and genome alterations. We explored the presence of circulating tumor DNA in multiple myeloma patients and its relation to disease activity during long-term follow-up. We used digital droplet polymerase chain reaction analysis to monitor recurrent mutations, mainly in mitogen activated protein kinase pathway genesNRAS,KRASandBRAFMutations were identified by next-generation sequencing or polymerase chain reaction analysis of bone marrow plasma cells, and their presence analyzed in 251 archived serum samples obtained from 20 patients during a period of up to 7 years. In 17 of 18 patients, mutations identified in bone marrow during active disease were also found in a time-matched serum sample. The concentration of mutated alleles in serum correlated with the fraction in bone marrow plasma cells (r=0.507, n=34,P<0.002). There was a striking covariation between circulating mutation levels and M protein in ten out of 11 patients with sequential samples. When relapse evaluation by circulating tumor DNA and M protein could be directly compared, the circulating tumor DNA showed relapse earlier in two patients (3 and 9 months), later in one patient (4 months) and in three patients there was no difference. In three patients with transformation to aggressive disease, the concentrations of mutations in serum increased up to 400 times, an increase that was not seen for the M protein. In conclusion, circulating tumor DNA in myeloma is a multi-faceted biomarker reflecting mutated cells, total tumor mass and transformation to a more aggressive disease. Its properties are both similar and complementary to M protein.
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.
authors.forename: Even Holth
authors.initials: EH
authors.lastname: Rustad
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.|Norwegian Cancer Genomics Consortium, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.
authors.forename: Eivind
authors.initials: E
authors.lastname: Coward
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.
authors.forename: Emilie R
authors.initials: ER
authors.lastname: Skytøen
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.
authors.forename: Kristine
authors.initials: K
authors.lastname: Misund
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.
authors.forename: Toril
authors.initials: T
authors.lastname: Holien
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.|CEMIR - Center for Molecular Inflammation Research, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.
authors.forename: Therese
authors.initials: T
authors.lastname: Standal
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.
authors.forename: Magne
authors.initials: M
authors.lastname: Børset
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.
authors.forename: Vidar
authors.initials: V
authors.lastname: Beisvag
authors.affiliation: Norwegian Cancer Genomics Consortium, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.|Institute for Clinical Science, University of Bergen, Trondheim, Norway.|Institute for Cancer Research, Oslo University Hospital, Trondheim, Norway.
authors.forename: Ola
authors.initials: O
authors.lastname: Myklebost
authors.affiliation: Norwegian Cancer Genomics Consortium, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.|Institute for Cancer Research, Oslo University Hospital, Trondheim, Norway.
authors.forename: Leonardo A
authors.initials: LA
authors.lastname: Meza-Zepeda
authors.affiliation: Department of Pathology and Medical Genetics, St. Olav's University Hospital, Trondheim, Norway.
authors.forename: Hong Yan
authors.initials: HY
authors.lastname: Dai
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.|CEMIR - Center for Molecular Inflammation Research, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Sundan
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway anders.waage@ntnu.no.|Norwegian Cancer Genomics Consortium, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.|Department of Hematology, St. Olav's University Hospital, Trondheim, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Waage
mesh_terms: D000368:Aged; D015415:Biomarkers; D014408:Biomarkers, Tumor; D000073888:Cell-Free Nucleic Acids; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm; D018450:Disease Progression; D005260:Female; D006801:Humans; D000073890:Liquid Biopsy; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D009154:Mutation; D009194:Myeloma Proteins; D009367:Neoplasm Staging; D012189:Retrospective Studies; D000073359:Exome Sequencing
chemical_list: D015415:Biomarkers; D014408:Biomarkers, Tumor; D000073888:Cell-Free Nucleic Acids; D004273:DNA, Neoplasm; D009194:Myeloma Proteins; C085016:multiple myeloma M-proteins