Multicolor Fluorescence In Situ Hybridization (M-FISH) in Highly Aggressive B-Cell Lymphomas with 8q24/MYC Involvement Revealed the Heterogeneity of 13q Abnormalities with Unexpected Partial Gains.

Chromosomal translocations involving the MYC oncogene (8q24) are known to occur in Burkitt lymphomas/leukemias (BL) but also in 5–30% of diffuse large B-cell lymphomas which are usually highly aggressive (8q24 DLBCL). Two recent conventional cytogenetics (CC) studies showed that secondary chromosomal abnormalities have a negative prognostic impact, especially13q abnormalities (frequently described as a deletion and usually associated with a complex karyotype, i.e. > 3 chromosomal alterations), mainly in childhood mature B-cell lymphomas, and in a less extent 7q, 3q, 22q and chromosome 17. M-FISH was applied to 120 (74% adults and 26% children) high grade B-cell non-Hodgkin lymphomas (86% BL, 14% 8q24 DLBCL) carrying MYC rearrangement and complex karyotype and/or 13q abnormality in order to find recurrent and/or cryptic chromosomal alterations. Abnormal metaphases were available in 96 (80%) cases. We described ‘new’ (not seen in CC) chromosomal rearrangements in 50 (52%) cases, refined those seen by CC in 28 (29%) cases and confirmed CC abnormalities in 18 (19%) cases.

M-FISH allowed to characterize 55 structural 13q abnormalities in 42 patients (21 ‘new’ alterations): 24 der(13q) leading to partial del(13q) and partial gain of different partner chromosomes [mainly 1q or 7q], 15 del(13q) [of 2 minimal regions : q14 & q31q34], 13 gains (only 2 seen by CC) and 3 balanced translocations.

Combined results of CC and M-FISH showed that the most frequent abnormalities among patients with complex karyotype involved 1q, 7q, Xq, 3q, 18q, 6q, 17p and chromosome 22 (excluding 8q24 translocations). 79 1q abnormalities were detected in 54 patients (26 % ‘new’): mostly gains (minimal amplified region: q22q31) due to unbalanced translocations with chromosomes 13, 22, 7 (59%) or duplications (25%). 55 partial 7q gains were observed in 42 patients (22% ‘new’), mostly +7 or unbalanced translocations with 13q, 6q or 1q. The other most common abnormalities were: t(14;18) in 8q24 DLBCL, del(6q), der(3q) with various partners leading to partial loss of 3q, monosomy 17 or del(17p) and numerical changes of chromosomes 22 (monosomy) and X.

In conclusion, this study confirms the contribution of M-FISH in refining CC results in highly aggressive 8q24 B-cell lymphomas:

1. ‘new’ rearrangements were identified especially in 1q (leading to partial 1q gains), 18q, 6q (leading to partial 6q deletions), 13q ;

2. partial 13q gains were underestimated by CC and both 13q deletions and gains were more heterogeneous than expected.

We are characterizing these prognostic additional chromosomal abnormalities with SNP-CHIPS 50K array (Affymetrix) to look for candidate genes and/or cellular pathways involved in Burkitt lymphomagenesis in cooperation with oncogenic effect of MYC. °on behalf of the GFCH (Groupe Francophone de Cytogénétique Hématologique) and the BCG-Ho (Belgian Cytogenetic Group of Hematology and Oncology).