Cross-platform assessment of genomic imbalance confirms the clinical relevance of genomic complexity and reveals loci with potential pathogenic roles in diffuse large B-cell lymphoma

Dias, Lizalynn M.; Thodima, Venkata J.; Friedman, Julia; Ma, Charles; Guttapalli, Asha; Mendiratta, Geetu; Siddiqi, Imran; Syrbu, Sergei; Chaganti, R. S. K.; Houldsworth, Jane

doi:10.3109/10428194.2015.1080364

Cited by 6 publications

(10 citation statements)

References 49 publications

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“…For example, CNOT2 was generally hypomethylated, overexpressed, and observed CNA gains, which is a predicted scenario for a proto-oncogene. CNOT2 was also predicted to be an oncogene based on CNA and expression profiling data from 392 DLBCL patient samples (39). HIVEP2, a predicted TSG in our screen, had a similar level of methylation and CNAs as 3 known TSGs (TP53, CDKN2A, and TNFAIP3), suggesting HIVEP2 is a TSG in human DLBCL.…”

Section: Comparative Genomics Of Ciss In Cancer Including Lymphomamentioning

confidence: 63%

Sleeping Beauty Screen Identifies RREB1 and Other Genetic Drivers in Human B-cell Lymphoma

Rahrmann

Wolf

Otto

et al. 2019

Molecular Cancer Research

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Follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) are the most common non-Hodgkin lymphomas distinguishable by unique mutations, chromosomal rearrangements, and gene expression patterns. Here, it is demonstrated that early B-cell progenitors express 2 0 ,3 0-cyclicnucleotide 3 0 phosphodiesterase (CNP) and that when targeted with Sleeping Beauty (SB) mutagenesis, Trp53 R270H mutation or Pten loss gave rise to highly penetrant lymphoid diseases, predominantly follicular lymphoma and DLBCL. In efforts to identify the genetic drivers and signaling pathways that are functionally important in lymphomagenesis, SB transposon insertions were analyzed from splenomegaly specimens of SB-mutagenized mice (n ¼ 23) and SB-mutagenized mice on a Trp53 R270H background (n ¼ 7) and identified 48 and 12 sites with statistically recurrent transposon insertion events, respectively. Comparison with human data sets revealed novel and known driver genes for B-cell development, disease, and signaling pathways: PI3K-AKT-mTOR, MAPK, NFkB, and B-cell receptor (BCR). Finally, functional data indicate that modulating Rasresponsive element-binding protein 1 (RREB1) expression in human DLBCL cell lines in vitro alters KRAS expression, signaling, and proliferation; thus, suggesting that this protooncogene is a common mechanism of RAS/MAPK hyperactivation in human DLBCL. Implications: A forward genetic screen identified new genetic drivers of human B-cell lymphoma and uncovered a RAS/ MAPK-activating mechanism not previously appreciated in human lymphoid disease. Overall, these data support targeting the RAS/MAPK pathway as a viable therapeutic target in a subset of human patients with DLBCL.

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Section: Comparative Genomics Of Ciss In Cancer Including Lymphomamentioning

confidence: 63%

Sleeping Beauty Screen Identifies RREB1 and Other Genetic Drivers in Human B-cell Lymphoma

Rahrmann

Wolf

Otto

et al. 2019

Molecular Cancer Research

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“…We demonstrated a clear association between inferior clinical outcome and increased genomic complexity in FL. This was proposed previously in DLBCL, 16,17 although the criteria in calling aberration were different in each study. Monti et al specifically evaluated CNAs in genomic regions encompassing genes of the CDKN2A-TP53-RB-E2F axis and showed that any CNA in these regions predicted inferior OS in DLBCL.…”

Section: Discussionmentioning

confidence: 92%

“…16 Dias et al proposed that CNA in a panel of genomic regions predicts outcome. 17 Given the various criteria used to define "complex" genome, caution must be exercised when applying this parameter as a marker across different platforms and cohorts. We therefore focused on evaluating the prognostic significance of specific chromosome arms and subregions.…”

Section: Discussionmentioning

confidence: 99%

Genomic alterations important for the prognosis in patients with follicular lymphoma treated in SWOG study S0016

Liu

Braziel

et al. 2019

Blood

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K E Y P O I N T S l Assessing pretreatment genomic aberrations improves risk stratification of FL independent of clinical/ mutation markers. l Gain or cnLOH of 2p is correlated with 2-year progression; CDKN2A/B deletion with worse PFS; CREBBP and TP53 deletions predict worse OS.Although recent advances in molecular genetics have enabled improved risk classification of follicular lymphoma (FL) using, for example, the m7-FLIPI score, the impact on treatment has been limited. We aimed to assess the prognostic significance of copy-number aberrations (CNAs) and copy-neutral loss of heterozygosity (cnLOH) identified by chromosome genomic-array testing (CGAT) at FL diagnosis using prospectively collected clinical trial specimens from 255 patients enrolled in the SWOG study S0016. The impact of genomic aberrations was assessed for early progression (progressed or died within 2 years after registration), progression-free survival (PFS), and overall survival (OS). We showed that increased genomic complexity (ie, the total number of aberration calls) was associated with poor outcome in FL. Certain chromosome arms were critical for clinical outcome. Prognostic CNAs/cnLOH were identified: whereas early progression was correlated with 2p gain (P 5 .007; odds ratio [OR] 5 2.55 [1.29, 5.03]) and 2p cnLOH (P 5 .005; OR 5 10.9 [2.08, 57.2]), 2p gain specifically encompassing VRK2 and FANCL predicted PFS (P 5 .01; hazard ratio 5 1.80 [1.14, 2.68]) as well as OS (P 5 .005; 2.40 [1.30, 4.40]); CDKN2A/B (9p) deletion correlated with worse PFS (P 5 .004, 3.50 [1.51, 8.28]); whereas CREBBP (16p) (P < .001; 6.70 [2.52, 17.58]) and TP53 (17p) (P < .001; 3.90 [1.85, 8.31]) deletion predicted worse OS. An independent cohort from the m7-FLIPI study was explored, and the prognostic significance of aberration count, and TP53 and CDKN2A/B deletion were further validated. In conclusion, assessing genomic aberrations at FL diagnosis with CGAT improves risk stratification independent of known clinical parameters, and provides a framework for development of future rational targeted therapies. (Blood. 2019;133 (1):81-93) Follow-up for PFS, median (min, max), mo 89 (1, 173) 24 (11, 151) 86 (7, 173) 95 (1, 157) Follow-up for OS, median (min, max), mo 114 (2, 177) 135 (47, 177) 116 (12, 175) 111 (2, 175)*CHOP-R, 6 cycles of CHOP chemotherapy at 3-week intervals with 6 doses of rituximab; CHOP-RIT, 6 cycles of CHOP followed by consolidation with iodine 131 I tositumomab radioimmunotherapy. †LDH is not available from 5 patients, 4 on CHOP-R, and 1 on CHOP-RIT; FLIPI risk is not available from 11 patients, all on CHOP alone. ‡Early progression is defined as progression or death within 2 years after registration.

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“…Similarly treated reference DNA (normal male: female genomic DNA, Promega, Madison, WI, USA) and the tumor DNA were differentially labeled and hybridized to a targeted oligonucleotide array representing genomic regions commonly altered in mature B-cell neoplasms (Agilent Technologies Inc., Santa Clara, CA, USA) as previously described. 12,13 Data were extracted using Feature Extraction Version 10.7.3.1 (Agilent) and sites of gain/loss identified using the Rank segmentation algorithm within the Nexus Copy Number Analysis Software (Version 6.1, Biodiscovery Inc., Hawthorne, CA, USA) where an average log2 ratio change of ± 0.3 was considered acceptable for a minimum of eight consecutive probes. All gains/loss were visually confirmed by examining log ratio profiles and all genomic coordinates are given according to the NCBIbuild37/hg19 assembly.…”

Section: Fluorescence In Situ Hybridization and Array Comparative Genmentioning

confidence: 99%

“…12 Briefly, if the bulk of the DNA was greater than 800 bp in size, heat fragmentation was performed until the bulk DNA was 400-800 bp. Similarly treated reference DNA (normal male: female genomic DNA, Promega, Madison, WI, USA) and the tumor DNA were differentially labeled and hybridized to a targeted oligonucleotide array representing genomic regions commonly altered in mature B-cell neoplasms (Agilent Technologies Inc., Santa Clara, CA, USA) as previously described.…”

Section: Fluorescence In Situ Hybridization and Array Comparative Genmentioning

confidence: 99%

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

et al. 2016

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A predominantly diffuse growth pattern and CD23 co-expression are uncommon findings in nodal follicular lymphoma and can create diagnostic challenges. A single case series in 2009 (Katzenberger et al) proposed a unique morphologic variant of nodal follicular lymphoma, characterized by a predominantly diffuse architecture, lack of the t(14;18) IGH/BCL2 translocation, presence of 1p36 deletion, frequent inguinal lymph node involvement, CD23 co-expression, and low clinical stage. Other studies on CD23+ follicular lymphoma, while associating inguinal location, have not specifically described this architecture. In addition, no follow-up studies have correlated the histopathologic and cytogenetic/molecular features of these cases, and they remain a diagnostic problem. We identified 11 cases of diffuse, CD23+ follicular lymphoma with histopathologic features similar to those described by Katzenberger et al. Along with pertinent clinical information, we detail their histopathology, IGH/BCL2 translocation status, lymphoma-associated chromosomal gains/losses, and assessment of mutations in 220 lymphoma-associated genes by massively parallel sequencing. All cases showed a diffuse growth pattern around well-to ill-defined residual germinal centers, uniform CD23 expression, mixed centrocytic/centroblastic cytology, and expression of at least one germinal center marker. Ten of 11 involved inguinal lymph nodes, 5 solely. By fluorescence in situ hybridization analysis, the vast majority lacked IGH/BCL2 translocation (9/11). Deletion of 1p36 was observed in five cases and included TNFRSF14. Of the six cases lacking 1p36 deletion, TNFRSF14 mutations were identified in three, highlighting the strong association of 1p36/ TNFRSF14 abnormalities with this follicular lymphoma variant. In addition, 9 of the 11 cases tested (82%) had STAT6 mutations and nuclear P-STAT6 expression was detectable in the mutated cases by immunohistochemistry. The proportion of STAT6 mutations is higher than recently reported in conventional follicular lymphoma (11%). These findings lend support for a clinicopathologic variant of t(14;18) negative nodal follicular lymphoma and suggests importance of the interleukin (IL)-4/JAK/STAT6 pathway in this variant.

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Cross-platform assessment of genomic imbalance confirms the clinical relevance of genomic complexity and reveals loci with potential pathogenic roles in diffuse large B-cell lymphoma

Cited by 6 publications

References 49 publications

Sleeping Beauty Screen Identifies RREB1 and Other Genetic Drivers in Human B-cell Lymphoma

Sleeping Beauty Screen Identifies RREB1 and Other Genetic Drivers in Human B-cell Lymphoma

Genomic alterations important for the prognosis in patients with follicular lymphoma treated in SWOG study S0016

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

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