Multiple recurrent chromosomal breakpoints in mantle cell lymphoma revealed by a combination of molecular cytogenetic techniques

Abstract

Mantle cell lymphoma (MCL) is genetically characterized by 11q13 translocations leading to the overexpression of CCND1, and additional secondary genomic alterations that may be important in the progression of this disease. We have analyzed 22 MCL cases and 10 MCL cell lines using multicolor fluorescence in situ hybridization (M-FISH), FISH, and comparative genomic hybridization (CGH). The 19 cases with abnormal karyotype showed the t(11;14)(q13;q32) translocation and, additionally, 89% of cases showed both numerical (n = 58) and structural (n = 77) aberrations. All but one MCL cell line showed t(11;14) and structural and numerical alterations in highly complex karyotypes. Besides 11 and 14, the most commonly rearranged chromosomes were 1, 8, and 10 in the tumors and 1, 8, and 9 in the cell lines. No recurrent translocations other than the t(11;14) were identified. However, we identified 17 recurrent breakpoints, the most frequent being 1p22 and 8p11, each observed in four cases and two cell lines. Interestingly, five tumors and four cell lines displayed a complex t(11;14), cryptic in one case and two cell lines, preferentially involving chromosome 8. In typical MCL, ATM gene deletions were significantly associated with a high number of structural and numerical alterations. In conclusion, MCL does not have recurrent translocations other than t(11;14), but shows recurrent chromosomal breakpoints. Furthermore, most MCL harbor complex karyotypes with a high number of both structural and numerical alterations affecting several common breakpoints, leading to various balanced and unbalanced translocations.

SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype

“…1,2 In addition to this primary genetic alteration, MCL also has a relatively specific profile of secondary genetic aberrations that include frequent losses, gains and recurrent chromosomal breakpoints. [3][4][5][6][7] In spite of the constant overexpression of cyclin D1 in MCL, some studies reported tumors with similar morphological and phenotypic characteristics but lacking the t(11;14) translocation and cyclin D1 expression. 8 However, it was controversial whether the apparent lack of cyclin D1 was a real biological phenomenon or was due to technical limitations in its detection.…”

Loss of MicroRNA Targets in the 3′ Untranslated Region as a Mechanism of Retroviral Insertional Activation of Growth Factor Independence 1

“…It is possible that such loss of regulatory regions in the 3ЈUTR of the human GFI1 gene might likewise contribute to human lymphomagenesis. The human GFI1 gene is carried in the chromosomal region 1p22 (58), a locus commonly affected in several cancers, including mantle cell lymphoma (60,61), mucosa-associated lymphoid tissue lymphoma (77), and neuroblastoma (46). Although there has been no direct correlation between translocations in this region and the effect on the GFI1 gene, our studies support the importance of this genomic region in tumor development.…”

Double-hit B-cell lymphomas

“…In most MCLs and in a substantial fraction of multiple myelomas 11q13 translocations are observed. [77][78][79][80] In addition to these malignancies, also hairy cell leukemia and some cells in the proliferation centers of chronic lymphocytic leukemia as well as extremely rare DLBCL cases may express CCND1, the mechanism being unknown. 81 Like the t(14;18), the t(11;14) in MCL is mediated by RAG1/2, probably in combination with low levels of AICDA as well as other mechanisms.…”