Genomic imbalances during transformation from follicular lymphoma to diffuse large B-cell lymphoma

Abstract

Follicular lymphoma is commonly transformed to a more aggressive diffuse large B-cell lymphoma (DLBCL). In order to molecularely characterize this histiological and clinical transformation, comparative genomic hybridization was applied on 23 follicular lymphoma and 35 transformed DLBCL tumors from a total of 30 patients. The results were also compared with our published findings in de novo DLBCL. Copy number changes were detected in 70% of follicular lymphoma and in 97% of transformed DLBCL. In follicular lymphoma, the most common alterations were þ 18q21 (33%), þ Xq25-26 (28%), þ 1q31-32 (23%), and À17p (23%), whereas transformed DLBCL most frequently exhibited þ Xq25-26 (36%), þ 12q15 (29%), þ 7pter-q22 (25%), þ 8q21 (21%), and À6q16-21(25%). Transformed DLBCL showed significantly more alterations as compared to follicular lymphoma (P ¼ 0.0001), and the alterations À6q16-21 and þ 7pter-q22 were only found in transformed DLBCL but not in follicular lymphoma (P ¼ 0.02). Alterations involving þ 13q22 were significantly less frequent, whereas À4q13-21 was more common in transformed as compared to de novo DLBCL (P ¼ 0.01 and P ¼ 0.02, respectively). Clinical progression from follicular lymphoma to transformed DLBCL is on the genetic level associated with acquirement of increasing number of genomic copy number changes, with non-random involvement of specific target regions. The findings support diverse genetic background between transformed and de novo DLBCL.

Microarray‐based genomic profiling reveals novel genomic aberrations in follicular lymphoma which associate with patient survival and gene expression status

“…The deletion 9p21 might also identify cases which have a propensity for transformation. In this context, a second recurrent aberration on 6q16 affecting the RNAH gene might have relevance for the function of CDKN2A/ CDKN2B by a hampered positive regulation of its transcription (Henderson et al, 2004;Berglund et al, 2007). Summarizing, one must keep in mind that the prognostic significance of aberrations on 9p and 6q refers to a cohort assembled over a time period of more than 20 years which was treated according to heterogeneous regimens.…”

“…However, the sole presence of this translocation is not sufficient for emergence of FL (McDonnell and Korsmeyer 1991). In this context, a large number of genomic gains and losses were described using chromosome banding analysis, conventional comparative genomic hybridization (CGH), or single nucleotide polymorphism chip technologies (Tilly et al, 1994;Bentz et al, 1996;Avet-Loiseau et al, 1997;Horsman et al, 2001;Neat et al, 2001;Viardot et al, 2001Viardot et al, , 2002Ott et al, 2002;Hö glund et al, 2004;Berglund et al, 2007;Ross et al, 2007). Because of the restricted spatial resolution of most of these techniques, it can be speculated that a large number of aberrations have not been identified so far.…”

Genome-wide profiling of follicular lymphoma by array comparative genomic hybridization reveals prognostically significant DNA copy number imbalances

“…For instance, the cytochrome gene CYP51 on 7q has been found overexpressed in lymphomas. 16 In 8q, 4 candidate genes have been suggested: a potassium channel protein KCNK9, NF-KB-activating protein NIBP, the protein tyrosine kinase PTK2/FAK, and the protein tyrosine phosphatise PTP4A3. 22 The PTEN phosphatase tumor suppressor at 10q23.1-q25.1 has been of constant interest.…”

“…The reported recurrent copy number alterations have consistently included losses of 1p32-36, 6q, 10q, and 17p, and gains of 1q, 2p, 7, 9p, 12, 17q, 18q, and X. [14][15][16][17][18][19][20][21][22][23][24][25] The analysis by Hoglund et al utilized computational analysis of a large number of published G-banded FL karyotypes to define early from late accruing genetic imbalances and demonstrated 4 putative pathways of clonal evolution in FL. 26 This karyotype-based study was hampered by the inherent inaccuracies of G-banding analysis and excluded from consideration all marker chromosomes and unbalanced chromosomal additions that are common features of FL karyotypes.…”

Patterns of spectrin expression in B-cell lymphomas: loss of spectrin isoforms is associated with nodule-forming and germinal center-related lymphomas

“…25,26 Furthermore, genomic instability is considered rare in B-cell malignant lymphomas. Even microsatellite instability, a type of genomic instability secondary to defective DNA mismatch repair, has only occasionally been detected during progression or histologic transformation of B-cell malignant lymphomas.…”