A combination of molecular cytogenetic analyses reveals novel recurrent breakpoints in Mantle cell lymphoma

Proc Amer Assoc Cancer Res, Volume 47, 2006 4206 Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm genetically characterized by chromosomal translocations involving the 11q13 region and its molecular counterpart BCL-1 rearrangement, leading to the overepression of CCND1 gene. experimental studies have shown that CCND1 can function as an oncogene but its tumorigenic and transforming properties seem to be less effective than other oncogenes, suggesting that other mechanisms may participate in the development and progression of MCLs. These other mechanisms presumably are secondary genomic alterations, usually affecting large chromosomal regions that may contain many candidate genes. In this study, we have analysed 29 MCL obtained at diagnosis, 19 men, 10 women, mean age 75 years (range 50-90 years), four relapsed samples obtained between 1 and 4 years after diagnosis, and five MCL cell lines (JVM-2, GRANTA-519, REC-1, JEKO-1 and NCEB-1) using G-Banding technique, multicolour-FISH (M-FISH) in 17 samples, and comparative genomic hybridization (CGH). Clinical data of all cases was available. Combined cytogenetic analysis detected the MCL-hallmark t(11;14) in all cases and was found as a single abnormality in 4 of these cases. M-FISH revealed new alterations not detected by G- Banding in 59% of the analyzed cases. Thirty-six numerical (range 1-19, mean 2.7 imbalances/case), and 51 structural aberrations (range 1-7, mean 3 imbalances/case) were observed. Furthermore, no other recurrent translocations were detected in this series. All five cell lines carried structural, including t(11;14) and numerical (except JVM-2) alterations and display different patterns of instability. Three cases and JEKO-1 cell line displayed complex translocations involving the IGH and CCND1 loci rearrangement and other chromosomes including chromosomes 8 (two cases), 10 and 17. Cytogenetic formulas were corrected using breakpoints detected by CGH. Recurrent breakpoints were identified at 1p32, 1p36, 3q25, 10p14, 11q13, 11q21, 11q23, 13q11, 13q21, 14q32, and 15q22 (two cases each, except 11q13 and 14q32). Breakpoints located at 1p32, 1p36 and 15q22 were also detected in JEKO-1, REC-1 and JVM-2 respectively. Breakpoints 1p36, 3q25, 10p14, 13q11, 13q21 and 15q22 are described for the first time in MCL. Besides 11 and 14, the most involved chromosomes in rearrangements were 1, 8, and 10 (6, 5, and 5 rearrangements, respectively). Comparison between the four sequential samples detected the same chromosomal alterations in three of them and gains of 3q24-qter and 7p in the second sample of the fourth case. In conclusion, the combination of M-FISH and CGH analysis gives a more specific approach to the genetic imbalances in MCL pathogenesis delineating several frequent regions of gain and loss and new recurrent breakpoints.