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. 2023 Oct;37(10):2058-2065.
doi: 10.1038/s41375-023-01995-w. Epub 2023 Aug 10.

Novel insights into the pathogenesis of follicular lymphoma by molecular profiling of localized and systemic disease forms

Sabrina Kalmbach #  1   2   3 , Michael Grau #  4 , Myroslav Zapukhlyak  4 , Ellen Leich  5 , Vindi Jurinovic  6 , Eva Hoster  6 , Annette M Staiger  1   2   3 , Katrin S Kurz  1 , Oliver Weigert  6 , Erik Gaitzsch  6 , Verena Passerini  6 , Marianne Engelhard  7 , Klaus Herfarth  8 , Klaus Beiske  9   10 , Francesca Micci  11 , Peter Möller  12 , Heinz-Wolfram Bernd  13 , Alfred C Feller  13 , Wolfram Klapper  14 , Harald Stein  15 , Martin-Leo Hansmann  16 , Sylvia Hartmann  16 , Martin Dreyling  6 , Harald Holte  10 , Georg Lenz  4 , Andreas Rosenwald  5 , German Ott  17   18 , Heike Horn  1   2   3 ; German Lymphoma Alliance (GLA)
Affiliations

Novel insights into the pathogenesis of follicular lymphoma by molecular profiling of localized and systemic disease forms

Sabrina Kalmbach et al. Leukemia. 2023 Oct.

Abstract

Knowledge on the pathogenesis of FL is mainly based on data derived from advanced/systemic stages of FL (sFL) and only small cohorts of localized FL (lFL) have been characterized intensively so far. Comprehensive analysis with profiling of somatic copy number alterations (SCNA) and whole exome sequencing (WES) was performed in 147 lFL and 122 sFL. Putative targets were analyzed for gene and protein expression. Overall, lFL and sFL, as well as BCL2 translocation-positive (BCL2+) and -negative (BCL2-) FL showed overlapping features in SCNA and mutational profiles. Significant differences between lFL and sFL, however, were detected for SCNA frequencies, e.g., in 18q-gains (14% lFL vs. 36% sFL; p = 0.0003). Although rare in lFL, gains in 18q21 were associated with inferior progression-free survival (PFS). The mutational landscape of lFL and sFL included typical genetic lesions. However, ARID1A mutations were significantly more often detected in sFL (29%) compared to lFL (6%, p = 0.0001). In BCL2 + FL mutations in KMT2D, BCL2, ABL2, IGLL5 and ARID1A were enriched, while STAT6 mutations more frequently occurred in BCL2- FL. Although the landscape of lFL and sFL showed overlapping features, molecular profiling revealed novel insights and identified gains in 18q21 as prognostic marker in lFL.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Mutational landscape in lFL.
All called non-synonymous and synonymous mutations in significant genes according to MutSig2CV v3.11 (qM2CV < 0.1, cohort frequency ≥ 10% in lFL), but also non-significant biologically-relevant genes (e.g., BCL2) are color-coded and shown for sample per column, ranked by cohort frequency. Samples are ordered by waterfall sorting based on binary gene mutation status. The bar graph on the left shows the ratio of non-synonymous (blue) and synonymous (green) mutations per gene. At the top, the tumor mutational burden (TMB) per sample (mutations/sample/Mb) is depicted. On the right, occurring types of mutation, q values (M2CV) and cancer cell fractions (CCF) are shown per gene.
Fig. 2
Fig. 2. Comparative analysis of somatic copy number alterations (SCNA) in FL.
Frequency of SCNA in the entire cohort of localized FL (lFL) and systemic FL (sFL). Copy number gains along the genome are depicted in red (above); copy number losses are illustrated in blue (below). The dashed line indicates the threshold for recurrent SCNA ≥ 15%. Fisher’s exact test and Benjamini–Hochberg correction for multiple testing was applied to determine significant differences (q < 0.05) in the SCNA frequency of lFL and sFL. Significant differences between lFL and sFL are marked with a black frame and asterisk.
Fig. 3
Fig. 3. Identification of IKZF1 as significant alterated gene in 7p12.2 by GISTIC.
Chromosome 7 was affected by wide whole-arm gains. Applying the GISTIC algorithm enabled the identification of one single gene in chromosome 7p12.2, significantly (FDR q < 0.1) gained in lFL and sFL. Chromosomal gains of IKZF1 in 7p12.2 (A) was validated with locus-specific probes by fluorescence in situ hybridization (B). mRNA expression of IKZF1 (C) was significantly increased in FL samples with gains in 7p12.2 as measured by Mann–Whitney U-test. IKZF1 protein expression in tumor samples without (D) and with IKZF1 gain (E). An increased IKZF1 protein expression was observed in samples with IKZF1 gain, but to a lesser extent were also present in samples without IKZF1 gain (F).
Fig. 4
Fig. 4. Comparative mutational profiles in FL.
Most frequently mutated genes in lFL and sFL, indicating a significant difference (*) in ARID1A mutations in lFL and sFL (A). Wilcoxon rank sum test, followed by Benjamini–Hochberg correction for multiple hypothesis testing, were used to determine significant differences between lFL and sFL (q < 0.1). Comparing the mutation frequency in BCL2 translocation-negative (BLC2-) and –positive (BCL2+) FL revealed significant differences in mutation frequencies of BCL2, KMT2D, IGLL5 and ABL2 enriched in BCL2+, while STAT6 mutations more frequently occurred in BCL2− (B).
Fig. 5
Fig. 5. STAT6 mutations and 18q gains in BCL2 translocation-negative lFL.
mRNA expression of the anti-apoptotic genes BCL2 and BCL2L1 in relationship to the underlying STAT6 mutation status in BCL2 translocation-negative (BCL2-) lFL did not show any differences in STAT6 wildtype (WT) or mutant (MUT) samples (A). Gains in chromosome 18q21 (including the BCL2 locus) were associated with decreased progression-free survival (PFS) in the patient cohort of lFL as illustrated by Kaplan–Meier plot (B). Time to event variables were analysed with Cox proportional hazards regression. The p-values indicated in the Kaplan–Meier plots were calculated with the log-rank test.
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