Array Comparative Genomic Hybridization: A Better Alternative for Genomic Profiling and Prognosis of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Abstract 4572

Traditional cytogenetic techniques such as chromosome analysis and fluorescence in situ hybridization (FISH) have provided valuable genetic information in the evaluation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). However, many genomic abnormalities remain undetected due to the limitations intrinsic to these techniques. We designed, validated, and clinically applied a combined targeted-whole genome custom oligonucleotide microarray for the evaluation of hematological malignancies. Incorporation of array comparative genomic hybridization (aCGH) analysis has enabled us to identify previously undetected copy number changes with an increased resolution and sensitivity and more precisely determine genomic breakpoints and gene content with diagnostic and prognostic relevance in CLL/SLL. A cohort of 300 patients diagnosed with CLL/SLL was studied using concurrent cytogenetics, FISH and aCGH analyses on either peripheral blood or bone marrow aspirate samples. Array CGH identified clinically significant genomic alterations in 75% of the cases compared to 57% and 47% by cytogenetics and FISH analyses, respectively. There were no statistically significant differences detected between peripheral blood and bone marrow samples. Recurrent alterations such as deletions in chromosomes 11q (ATM, adverse prognosis), 13q (RB1, DLEU1, 2, and 7, MIR15A and 16–1, favorable prognosis in general), 17p (TP53, adverse prognosis) and gain of one copy of the entire chromosome 12 (ETV6, KLRK1, CD27, KRAS, MDM2, HIP1R, KITLG, intermediate prognosis) were identified in 55% of cases by aCGH. Of these cases, chromosome and/or FISH analyses did not detect these abnormalities in 42% and 27% of cases respectively. In addition, aCGH study more fully characterized the interstitial deletion in chromosome 13q recently suggested to have different outcomes based on size and gene content. Important findings exclusively by aCGH analysis in 7% of cases include loss of genetic material in chromosomes 3p (KAT2B, FHIT, clonal evolution), 6q (MAP3K7, PRDM1, AIM1, TNFAIP3, intermediate prognosis), 8p (TNFRSF10D, disease progression), 9q (JAK2, MLLT3, CDKN2A and B, DAPK1) and gain of genetic material in chromosome 2p (ACP1, MYCN, ALK, REL, BCL11A) associated with unmutated IGHV status, advanced disease stage and adverse prognosis. The results obtained in this study demonstrate the superior resolution and detection rate of aCGH technology as well as the importance of incorporating this methodology into current algorithms for the diagnosis and prognosis of CLL/SLL.