Identification of novel regions of amplification and deletion within mantle cell lymphoma DNA by comparative genomic hybridization

Abstract

Summary. We have carried out comparative genomic hybridization (CGH) analysis on archival biopsy material from a series of 30 UK mantle cell lymphomas. The most frequent aberrations were gains of 3q (21 cases), 6p (19 cases), 7q (8 cases), 12p (8 cases), 12q (9 cases) and 17q11q21 (8 cases), and losses of 1p13p32 (10 cases), 5p13p15.3 (9 cases), 6q14q27 (11 cases), 8p (7 cases), 11q13q23 (8 cases) and 13q (18 cases). Nineteen cases (63%) had a common region of amplification at 3q28q29, which was highly amplified in three cases, suggesting the presence of a mantle cell lymphoma (MCL)‐related oncogene in this region. There was a minimal common region of deletion at 6q25q26 in nine cases (30%). No MCL‐specific locus has previously been identified on chromosome 6 and this region may contain a tumour suppressor gene specifically implicated in the development of this subtype of lymphoma. An increased number of chromosome aberrations, gain of Xq and loss of 17p were all significantly associated with a worse prognosis. A greater understanding of the genetics of mantle cell lymphoma may allow the identification of prognostic factors which will aid the identification of appropriate treatment regimens.

Increased tumor cell proliferation in mantle cell lymphoma is associated with elevated insulin-like growth factor 2 mRNA-binding protein 3 expression

“…1,2 In recent years, several studies highlighted biological and prognostic implications of genetic gains and losses in the most commonly altered regions, leading to the hypothesis that variably affected target genes and associated pathways contribute to the highly divergent clinical behavior of mantle cell lymphoma ranging from very aggressive forms to more indolent clinical courses. 2 A gain of the chromosomal region 7p is frequent in mantle cell lymphoma [2][3][4][5] and is associated with a blastoid morphology. 4 A previous study using combined single-nucleotide polymorphism (SNP) and mRNA expression profiling directed our attention to the insulin-like growth factor (IGF) signaling pathway, as the IGF2 mRNA-binding protein 3 (IGF2BP3 aka IMP3) was the most strongly upregulated gene in cases harboring this alteration.…”

Mantle cell lymphomas with clonal immunoglobulin V3–21 gene rearrangements exhibit fewer genomic imbalances than mantle cell lymphomas utilizing other immunoglobulin V genes

“…Chromosome 9 deletions appeared to be a common finding, which is in agreement with other studies. [9][10][11][12] However, in our material, a dual pattern of losses was found in which the short arm was deleted only in the non-V H 3-21 mantle cell lymphoma, while losses of 9q were found in both V H 3-21 þ and non-V H 3-21 cases. Of note, the deletions on 9p encompass the INK4a/ARF locus at 9p21 that encodes two tumor suppressors, p16 INK4a and p14 ARF .…”

“…The deleted region recurrently identified encompassed 13q14-qter, which is in agreement with other studies. [9][10][11] Interestingly, deletions involving 13q14 are the most frequently occurring chromosomal changes in chronic lymphocytic leukemia, 16 a disease that has certain clinical and biological characteristics in common with mantle cell lymphoma. At present, a few candidate genes have been identified in the 13q14 region; however, it is not known if they are disease-related.…”

“…3 Characterization of variable heavy chain (V H ) gene usage has recently been performed in mantle cell lymphoma, revealing that two particular V H gene segments of the immunoglobulin (Ig) locus were preferentially used, namely V H 3-21 (18%) and V H 4-34 (16%). 2,6 Interestingly, the tumor samples with V H 3-21 gene usage almost exclusively expressed lambda light chains, and also in most cases utilized the same V l light chain gene (V l [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. 6 In addition, this group has been shown to have a significantly better prognosis in one report and in other studies displayed a clear tendency towards improved survival compared to mantle cell lymphomas utilizing other V H genes.…”

“…Earlier CGH studies indicate that mantle cell lymphoma constitutes a genetically homogeneous subgroup of lymphoma characterized by recurrent aberrations, in particular gains within 3q and 8q and losses in 6q, 9p, 11q and 13q. [9][10][11][12] An increased number of aberrations in addition to complex karyotypes have also been reported to be associated with poor prognosis in mantle cell lymphoma. 10 In the current series, we have applied the CGH technique to investigate whether the genomic architecture differs between the V H 3-21 þ group as compared to mantle cell lymphoma in general.…”