B-cell clones as early markers for chronic lymphocytic leukemia.
BACKGROUND
Otherwise healthy persons with a small number of B-cell clones circulating in the peripheral blood have been designated as having monoclonal B-cell lymphocytosis (MBL). Hospital-based series indicate an excess risk of progression from MBL to chronic lymphocytic leukemia (CLL). In this prospective cohort study, we tested the hypothesis that CLL is always preceded by MBL.


METHODS
Among 77,469 healthy adults who were enrolled in the nationwide, population-based Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, we identified 45 subjects in whom CLL was subsequently diagnosed (up to 6.4 years later) through the collection of a peripheral-blood sample. Using six-color flow cytometry (with antibodies CD45, CD19, CD5, CD10, kappa, and lambda) and immunoglobulin heavy-chain gene rearrangement by reverse-transcriptase-polymerase-chain-reaction assay, we determined the association between MBL and subsequent CLL and characterized the immunoglobulin gene repertoire of the prediagnostic B-cell clones.


RESULTS
On the basis of either flow-cytometric or molecular analysis, 44 of 45 patients with CLL (98%; 95% confidence interval [CI], 88 to 100) had a prediagnostic B-cell clone; in 41 patients (91%; 95% CI, 79 to 98), the presence of the B-cell clone was confirmed by both methods. The presence of immunoglobulin heavy-chain variable (IGHV) genes was determined in 35 of 45 prediagnostic clones (78%). Of these clones, 16 (46%) were IGHV3 subgroup genes (including 6 [17%] IGHV3-23 genes) and 9 (26%) were IGHV4 subgroup genes (including 4 [11%] IGHV4-34 genes). Furthermore, 27 of 35 of the IGHV sequences (77%) had mutations, with similar distributions after stratification either below or above the median time between the collection of the prediagnostic blood sample and the subsequent CLL diagnosis.


CONCLUSIONS
In peripheral blood obtained up to 77 months before a CLL diagnosis, prediagnostic B-cell clones were present in 44 of 45 patients with CLL.
Landgren
Ola
O
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. landgreo@mail.nih.gov
Albitar
Maher
M
Ma
Wanlong
W
Abbasi
Fatima
F
Hayes
Richard B
RB
Ghia
Paolo
P
Marti
Gerald E
GE
Caporaso
Neil E
NE
D000368:Aged; D015703:Antigens, CD; D001402:B-Lymphocytes / Q000276:immunology*; D014408:Biomarkers, Tumor / Q000097:blood*; D002999:Clone Cells; D005260:Female; D005434:Flow Cytometry; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007147:Immunoglobulin Light Chains / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000175:diagnosis* / Q000276:immunology; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015703:Antigens, CD; D014408:Biomarkers, Tumor; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D012333:RNA, Messenger