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Integrated Genomic Profiling of Chronic Lymphocytic Leukemia Identifies Subtypes of Deletion 13q14

¹ Department of Internal Medicine, Division of Hematology and Oncology and ² Department of Statistics, University of Michigan, Ann Arbor, Michigan

Requests for reprints: Sami N. Malek, Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0936. Phone: 734-763-2194; Fax: 734-647-9654; E-mail: smalek{at}med.umich.edu.

Key Words: CLL • 13q14 • LATS2 • PHLPP • microRNA

Chronic lymphocytic leukemia (CLL) is a biologically heterogeneous illness with a variable clinical course. Loss of chromosomal material on chromosome 13 at cytoband 13q14 is the most frequent genetic abnormality in CLL, but the molecular aberrations underlying del13q14 in CLL remain incompletely characterized. We analyzed 171 CLL cases for loss of heterozygosity and subchromosomal copy loss on chromosome 13 in DNA from fluorescence-activated cell sorting–sorted CD19⁺ cells and paired buccal cells using the Affymetrix XbaI 50k SNP array platform. The resulting high-resolution genomic maps, together with array-based measurements of expression levels of RNA in CLL cases with and without del13q14 and quantitative PCR–based expression analysis of selected genes, support the following conclusions: (a) del13q14 is heterogeneous and composed of multiple subtypes, with deletion of Rb or the miR15a/miR16 loci serving as anatomic landmarks, respectively; (b) del13q14 type Ia deletions are relatively uniform in length and extend from breakpoints close to the miR15a/miR16 cluster to a newly identified telomeric breakpoint cluster at the 50.2 to 50.5 Mb physical position; (c) LATS2 RNA levels are 2.6-fold to 2.8-fold lower in cases with del13q14 type I that do not delete Rb, as opposed to del13q14 type II or all other CLL cases; (d) PHLPP RNA is absent in 50% of CLL cases with del13q14; and (e) 15% of CLL cases display marked reductions in miR15a/miR16 expression that are often but not invariably associated with bi-allelic miR15a/miR16 loss. These data should aid future investigations into biological differences imparted on CLL by different del13q14 subtypes. [Cancer Res 2008;68(4):1012–21]

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