Prognostic significance of secondary cytogenetic alterations in follicular lymphomas

Abstract

Follicular lymphoma (FL) is an indolent lymphoma with a long median survival. Transformation to a more aggressive histology (TLy) is a major cause of mortality. The critical events leading to TLy are unknown. We assessed the prognostic significance of secondary cytogenetic alterations on overall survival (OS) and transformation from 210 diagnostic FL biopsies. We analyzed serial and transformed karyotypes for recurrent alterations that predict transformation. Over 10 years, 31% of cases developed TLy. The only alteration in diagnostic karyotypes that correlated with an inferior OS was an additional X chromosome in males only (P = 0.005) suggesting that other mechanisms including epigenetic factors and over-expression of genes on the X chromosome may play a role in FL pathogenesis. In transformed karyotypes, 8q24 (MYC) translocations were common (14/37) and resulted in a median survival of 3 months posttransformation (P = 0.01). In serially obtained biopsies (28 pts), 43% of the later biopsies lacked the cytogenetic alterations found in the original FL karyotype, suggesting that karyotypic progression of FL is not strictly linear in all cases. Consequently, studying clonal evolution in FL using serial biopsies may not represent the full complexity of genetic alterations leading to transformation.

Whole-genome integrative analysis reveals expression signatures predicting transformation in follicular lymphoma

“…Gain of X is associated with inferior outcome in FL. [1][2][3][4] Analysis of 131 FL-samples in the LLMPP data set 10,17 confirmed these results (supplemental Figures 2-5). Using Ingenuity Systems Pathway Analysis, the molecular network most enriched for cis-genes was identified ( Figure 1C).…”

“…[1][2][3][4] Most alterations span large genomic regions involving hundreds of genes, thus offering limited cues for identification of genes driving the development of FL. Elevated expression of c-MYC and other genes promoting proliferation, inactivation of TP53 and CDKN2A, dysregulation of p38-mitogen-activated protein kinase (MAPK), and mutations of BCL6 have been implicated in subsets of cases with transformation.…”

Pathogenesis of follicular lymphoma

“…Apart from the t(14;18), the most common chromosomal aberrations include non-random losses of 1p36 and 6q as well as gains of 7, 18, and X (39)(40)(41)(42). Recently, careful analysis of candidate genes within these regions has yielded insight into potential key players.…”

Genomic alterations reveal potential for higher grade transformation in follicular lymphoma and confirm parallel evolution of tumor cell clones

“…6 Some of these have been reported as independent prognostic factors in FL, including loss of 1p36, 6q21-26, 9p21, and 17p; gain of 12q, 18; and gain of the X chromosome in men, and some of these have been associated with transformation risk. [7][8][9][10][11][12][13] Although clinical and molecular parameters have been linked to survival and transformation, 4 the disease course cannot be reliably predicted. Indeed, it is not clear whether FLs that remain indolent and FLs that transform are biologically distinct.…”