High resolution analysis of follicular lymphoma genomes reveals somatic recurrent sites of copy‐neutral loss of heterozygosity and copy number alterations that target single genes

Abstract

A multiplatform approach, including conventional cytogenetic techniques, BAC array comparative genomic hybridization, and Affymetrix 500K SNP arrays, was applied to the study of the tumor genomes of 25 follicular lymphoma biopsy samples with paired normal DNA samples to characterize balanced translocations, copy number imbalances, and copy-neutral loss of heterozygosity (cnLOH). In addition to the t(14;18), eight unique balanced translocations were found. Commonly reported FL-associated copy number regions were revealed including losses of 1p32-36, 6q, and 10q, and gains of 1q, 6p, 7, 12, 18, and X. The most frequent regions affected by copy-neutral loss of heterozygosity were 1p36.33 (28%), 6p21.3 (20%), 12q21.2-q24.33 (16%), and 16p13.3 (24%). We also identified by SNP analysis, 45 aberrant regions that each affected one gene, including CDKN2A, CDKN2B, FHIT, KIT, PEX14, and PTPRD, which were associated with canonical pathways involved in tumor development. This study illustrates the power of using complementary high-resolution platforms on paired tumor/normal specimens and computational analysis to provide potential insights into the significance of single-gene somatic aberrations in FL tumorigenesis.

Early lesions of follicular lymphoma: a genetic perspective

“…As expected, no major genomic alterations (>700 kb) were found in normal cells (RFH and FLIS background); in contrast, numerous lesions could be found in positive controls (FL grade 1-2 and 3A). Despite the low sampling, the alterations in FL grade 1-2 and 3A (Table 1 and Online Supplementary Figure S2) were overall comparable to those previously reported, [18][19][20] further validating our technological approach. Likewise, chromosomes most frequently affected in early-FL groups were overall similar to those recurrently observed in overt FL, including chromosomes 1 and 18 (accounting for 17% and 33% of alterations, respectively).…”

Characterization of a variant of t(14;18) negative nodal diffuse follicular lymphoma with CD23 expression, 1p36/TNFRSF14 abnormalities, and STAT6 mutations

“…This comprised the detection of other recurrent genomic structural aberrations including the loss of 4q34-q35, gain of 3p, 3q, and 12q, all of which can be seen in conventional follicular lymphoma, [23][24][25][26] but are detected at higher frequencies in nodal marginal zone lymphomas. 27,28 Gains of 2p (four cases with three as focal gains of REL, at higher frequency than observed in follicular lymphoma), 9q, and 11p were also recurrently observed.…”

Recurrent loss of heterozygosity in 1p36 associated with TNFRSF14 mutations in IRF4 translocation negative pediatric follicular lymphomas

“…Of note, IRF4 translocation positive cases presented more frequently gains of 11q and deletions of 17p arm including the TP53 gene. Furthermore, one of the cases showed a deletion at 1pter-p35.2 with a transition mutation in the TNFRSF14 gene (g.343C>T, T15I) (data not shown).Both the gain in 6p as well as CNN-LOH/loss of 1p seem not to be exclusive to pediatric FL, since they have also been described in adult FL independently of the presence of t(14;18) translocation.14 In fact, deletions and CNN-LOH of 1p36 have been described as one of the most frequent secondary genetic aberrations in adult FL 15 and are considered a significant predictor of poor overall survival. 17 The minimal region of loss/CNN-LOH in 1p36 contains the candidate gene TNFRSF14, encoding a member of the tumor necrosis factor receptor (TNFR) superfamily which has been shown to be recurrently mutated in adult FL.…”

“…14 In fact, deletions and CNN-LOH of 1p36 have been described as one of the most frequent secondary genetic aberrations in adult FL 15 and are considered a significant predictor of poor overall survival. 17 The minimal region of loss/CNN-LOH in 1p36 contains the candidate gene TNFRSF14, encoding a member of the tumor necrosis factor receptor (TNFR) superfamily which has been shown to be recurrently mutated in adult FL.…”