Identification and validation of biomarkers of IgV(H) mutation status in chronic lymphocytic leukemia using microfluidics quantitative real-time polymerase chain reaction technology.
To develop a model incorporating relevant prognostic biomarkers for untreated chronic lymphocytic leukemia patients, we re-analyzed the raw data from four published gene expression profiling studies. We selected 88 candidate biomarkers linked to immunoglobulin heavy-chain variable region gene (IgV(H)) mutation status and produced a reliable and reproducible microfluidics quantitative real-time polymerase chain reaction array. We applied this array to a training set of 29 purified samples from previously untreated patients. In an unsupervised analysis, the samples clustered into two groups. Using a cutoff point of 2% homology to the germline IgV(H) sequence, one group contained all 14 IgV(H)-unmutated samples; the other contained all 15 mutated samples. We confirmed the differential expression of 37 of the candidate biomarkers using two-sample t-tests. Next, we constructed 16 different models to predict IgV(H) mutation status and evaluated their performance on an independent test set of 20 new samples. Nine models correctly classified 11 of 11 IgV(H)-mutated cases and eight of nine IgV(H)-unmutated cases, with some models using three to seven genes. Thus, we can classify cases with 95% accuracy based on the expression of as few as three genes.
Abruzzo
Lynne V
LV
University of Texas M.D. Anderson Cancer Center, Department of Hematopathology, Box 72, 1515 Holcombe Blvd., Houston, TX 77030, USA. labruzzo@mdanderson.org
Barron
Lynn L
LL
Anderson
Keith
K
Newman
Rachel J
RJ
Wierda
William G
WG
O'brien
Susan
S
Ferrajoli
Alessandra
A
Luthra
Madan
M
Talwalkar
Sameer
S
Luthra
Rajyalakshmi
R
Jones
Dan
D
Keating
Michael J
MJ
Coombes
Kevin R
KR
D014408:Biomarkers, Tumor / Q000235:genetics*; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D005819:Genetic Markers; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D044085:Microfluidics / Q000379:methods*; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods*; D015203:Reproducibility of Results
D014408:Biomarkers, Tumor; D005819:Genetic Markers; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region
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