Secondary genomic alterations in follicular lymphomas

Abstract

Follicular lymphoma (FL) is the second most common subtype of B-cell non-Hodgkin lymphoma (NHL) in the Western world. It is genetically characterized by t(14;18)(q32;q21) translocation that determines the juxtaposition of BCL2 gene in 18q21.3 with the immunoglobulin in heavy chain (IGH) gene at 14q32.33. This translocation is observed in 70%-80% of cases and, by itself is not sufficient to explain either FL biology or clinical outcome. Additional changes are necessary to generate a fully malignant clonal proliferation. Many of these secondary genetic aberrations are visible in the clonal karyotype, but the sequence by which they arise and their influence on clinical behaviour has not been determined yet. In the present study, we analyzed 12 cases with diagnosis of FL with abnormal karyotypes in order to identify secondary genetic alterations associated with t(14;18)(q32;q21)-positive and negative subsets. Cytogenetic, FISH (fluorescence in situ hybridization) and molecular studies were used to a more accurate definition of these rearrangements. By classical cytogenetics, translocation t(14;18)(q32;q21) was observed in 7 (58.3%) cases. FISH and molecular studies demonstrated that BCL2/IGH rearrangements were also present in other 2 (16,7%) cases and the remainder 3 (25%) were negative patients. Seventy five percent of secondary alterations of this series were unbalanced rearrangements with loss of chromosome regions. As a whole, chromosome 1 was the most frequently involved in structural rearrangements followed by chromosomes 3 and 6. Overall, t(3;14)(q27;q32), dup(1)(q21q32), del(6)(q21) and del(6)(q23) were recurrent in our series. Translocations at 3q27 and genomic gains on 1q21-q32 were more frequent in t(14;18)(q32;q211) positive subset. The most common breakpoints were 3q27, 1q21 and 1q32 other than 14q32 and 18q21. Fourteen novel rearrangements associated and non associated to t(14;18)(q32;q21) translocation were described. Trisomies 21, 2, 20, 12 and 9 and monosomy 13 were recurrent in our series. According to the literature, our patients showed a great karyotypic instability with different types of chromosome aberrations that appeared to be involved in tumor development and disease progression. These genomic abnormalities reflect the heterogeneity of this pathology. They do not occur randomly and some of them target genes important for the survival and tumor progression. So, it is important to go on with this type of studies in order to know the biological basis of clinical heterogeneity among FL patients that could lead to development of novel therapeutics.