Single Nucleotide Polymorphism (SNP) Array Genomic Profiling Identified High Prevalence of Clonal Diversity Associated with Clinical Progress in Chronic Lymphocytic Leukemia.
Linsheng Zhang, Iya Znoyko, Sally E Self, Daynna J Wolff. Medical University of South Carolina, Charleston
Background: Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease; genomic aberrations are important prognostic factors. Acquisition of genetic mutations or clonal evolution, as shown by interphase fluorescent in situ hybridization (FISH), has been associated with disease progression. SNP microarray genomic profiling allows for interrogation of the entire genome at a high resolution to determine the amount of clonal heterogeneity in CLL.
Design: Whole genome analysis was performed in 14 CLL cases using the Illumina® HumanOmni1-Quad BeadChip SNP-array (Illumina, Inc. San Diego, California, USA). To identify clonal diversity, the percentage of cells in each clone was estimated from LogR and B-allele frequency data based on the SiDCon tool (Nancarrow, et. al. PLoS One. 2007; e1093). Concurrent FISH was also performed for each case. Clinical information, flow cytometry and conventional cytogenetics were reviewed from medical records. All studies were performed with institutional review board approval.
Results: Ten of the 14 cases had clonal diversity (more than one subclone as defined by percentage of cells containing specific genomic aberration). Cases with multiple clones were associated with late clinical stage, refractoriness to immunochemotherapy and disease progression (see table).
|Case #||Subclones||Clinical Stage||Clinical Status|
|1||No||I||Asymptomatic; WBC stable|
|2||No||I||Asymptomatic; WBC stable|
|3||No||IV||WBC stable; complicated hemolytic anemia and immune thrombocytopenia|
|4||No||II||Asymptomatic; WBC stable|
|5||Yes||I||Asymptomatic; WBC slowly increasing|
|6||Yes||II||At stage IV in 2007; WBC and platelet fluctuate over the years|
|7||Yes||I||WBC doubled twice in 4 months, progressed to stage III and platelet decreasing|
|8||Yes||IV||In clinical trial|
|9||Yes||IV||Relapsed, refractory to immunochemotherapy, recevied stem cell transplantation|
|11||Yes||IV||Refractory, transformed to prolymphocytic leukemia|
|12||Yes||IV||Relapsed after chemotherapy|
|13||Yes||III||TP53 clonal expansion; progress from stage I to III in less than 2 years|
|14||Yes||IV||Relapsed and refractory; WBC doubled in 2 months|