The prognostic significance of various 13q14 deletions in CLL

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BlankThe prognostic significance of various 13q14 deletions in chronic

lymphocytic leukemia

1.. Ouillette1,

2.. Roxane 1,

3.. Sajid Shakhan1,

4.. Jinghui Li2,

5.. Chen Li3,

6.. Kerby Shedden4, and

7.. Sami N. Malek2,*

+ Author Affiliations

1.. 1Internal Medicine, University of Michigan

2.. 2Med-Hematology/ Oncology, University of Michigan

3.. 3Department of Biostatistics, Harvard School of Public Health (HSPH)

4.. 4Dept. of Biostatistics, University of Michigan

1.. ?* Corresponding Author:

Sami N. Malek, Med-Hematology/ Oncology, University of Michigan, 1500 E

Medical Center Drive, 4312 Cancer Center, Ann Arbor, MI, 48109, United States

smalek@...

Abstract

Purpose: To further our understanding of the biology and prognostic significance

of various chromosomal 13q14 deletions in CLL. Experimental Design: We have

analyzed data from SNP 6.0 arrays to define the anatomy of various 13q14

deletions in a cohort of 255 CLL patients and have correlated two subsets of

13q14 deletions (type I: exclusive of RB1 and type II: inclusive of RB1) with

patient survival. Further, we have measured the expression of the 13q14-resident

microRNAs by Q-PCR in 242 CLL patients and subsequently assessed their

prognostic significance. We have sequenced all coding exons of RB1 in patients

with monoallelic Rb1 deletion and have sequenced the 13q14-resident miR locus in

all patients. Results: Large 13q14 (type II) deletions were detected in ~20% of

all CLL patients and were associated with shortened survival. A strong

association between 13q14 type II deletions and elevated genomic complexity, as

measured through CLL-FISH or SNP 6.0 array profiling, was identified, suggesting

that these lesions may contribute to CLL disease evolution through genomic

destabilization. Sequence and copy number analysis of the RB1 gene identified a

small CLL subset that is RB1 null. Finally, neither the expression levels of the

13q14-resident microRNAs nor the degree of 13q14 deletion, as measured through

SNP 6.0 array-based copy number analysis, had significant prognostic importance.

Conclusions: Our data suggest that the clinical course of CLL is accelerated in

patients with large (type II) 13q14 deletions that span the RB1 gene, therefore

justifying routine identification of 13q14 subtypes in CLL management.

a.. Received March 23, 2011.