title: Genomic characterization of high-count MBL cases indicates that early detection of driver mutations and subclonal expansion are predictors of adverse clinical outcome.
abstract: High-count monoclonal B-cell lymphocytosis (MBL) is an asymptomatic expansion of clonal B cells in the peripheral blood without other manifestations of chronic lymphocytic leukemia (CLL). Yearly, 1% of MBLs evolve to CLL requiring therapy; thus being critical to understand the biological events that determine which MBLs progress to intermediate/advanced CLL. In this study, we performed targeted deep sequencing on 48 high-count MBLs, 47 of them with 2-4 sequential samples analyzed, exploring the mutation status of 21 driver genes and evaluating clonal evolution. We found somatic non-synonymous mutations in 25 MBLs (52%) at the initial time point analyzed, including 12 (25%) with >1 mutated gene. In cases that subsequently progressed to CLL, mutations were detected 41 months (median) prior to progression. Excepting NOTCH1, TP53 and XPO1, which showed a lower incidence in MBL, genes were mutated with a similar prevalence to CLL, indicating the early origin of most driver mutations in the MBL/CLL continuum. MBLs with mutations at the initial time point analyzed were associated with shorter time-to-treatment (TTT). Furthermore, MBLs showing subclonal expansion of driver mutations on sequential evaluation had shorter progression time to CLL and shorter TTT. These findings support that clonal evolution has prognostic implications already at the pre-malignant MBL stage, anticipating which individuals will progress earlier to CLL.
authors.affiliation: Department of Hematology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: S
authors.initials: S
authors.lastname: Barrio
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: T D
authors.initials: TD
authors.lastname: Shanafelt
authors.affiliation: Department of Hematology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ojha
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: K G
authors.initials: KG
authors.lastname: Chaffee
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: C
authors.initials: C
authors.lastname: Secreto
authors.affiliation: Department of Hematology, Mayo Clinic, Scottsdale, AZ, USA.|Department of Hematology, University Hospital, Würzburg, Germany.
authors.forename: K M
authors.initials: KM
authors.lastname: Kortüm
authors.affiliation: Department of Hematology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: S
authors.initials: S
authors.lastname: Pathangey
authors.affiliation: Laboratory of Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Van-Dyke
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Slager
authors.affiliation: Department of Hematology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: R
authors.initials: R
authors.lastname: Fonseca
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: N E
authors.initials: NE
authors.lastname: Kay
authors.affiliation: Department of Hematology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: E
authors.initials: E
authors.lastname: Braggio
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D060965:Clonal Evolution; D002999:Clone Cells / Q000473:pathology; D018450:Disease Progression; D005260:Female; D023281:Genomics; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D018655:Lymphocyte Count; D008218:Lymphocytosis / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D061665:Time-to-Treatment