Genomic profiling reveals spatial intra-tumor heterogeneity in follicular lymphoma

Araf, Shamzah; Wang, Jun; Korfi, Koorosh; Pangault, Céline; Kotsiou, Eleni; Río-Machín, Ana; Rahim, T.; Heward, James A.; Clear, Andrew; Iqbal, Sameena; Davies, Jeff; Johnson, Peter; Calaminici, Maria; Montoto, Silvia; Auer, Rebecca; Chelala, Claude; Gribben, John G.; Graham, Trevor A.; Fest, Thierry; Fitzgibbon, Jude; Okosun, Jessica

doi:10.1038/s41375-018-0043-y

Cited by 94 publications

(74 citation statements)

References 16 publications

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“…25,30 CD79B was also 1 of the NF-kB/BCR-signaling genes with recurrent mutations documented in FL. 31 The overexpression of CD79B in vitro correlated with decreased susceptibility to Bruton tyrosine kinase and SYK inhibitors in mantle cell lymphoma cells. 32 The 9p deletion (CDKN2A/B) was reported to predict inferior OS in FL.…”

Section: Discussionmentioning

confidence: 96%

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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Section: Discussionmentioning

confidence: 96%

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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“…Intratumor heterogeneity (ITH) refers to the recently described phenomenon of the distribution of somatic mutations in subsets of malignant cells (subclones) rather than being found in all malignant cells ("clonal" mutations). ITH has been documented in solid tumors 16,35 and in non-Hodgkin lymphomas [36][37][38] and is considered to be a genomic manifestation of tumor evolution. ITH arises due to differences in the proliferation and survival between cells bearing different mutations and enhances the evolution by providing material for natural selection where the fittest subclones determine prognosis and resistance to therapy.…”

Section: Discussionmentioning

confidence: 99%

Branched evolution and genomic intratumor heterogeneity in the pathogenesis of cutaneous T-cell lymphoma

Iyer

Hennessey

OʼKeefe

et al. 2019

Preprint

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Mycosis fungoides (MF) is a slowly progressive cutaneous T-cell lymphoma (CTCL) for which there is no cure. In the early plaque stage the disease is indolent, but development of tumors heralds an increased risk of metastasis and death. Previous research into the genomic landscape of CTCL revealed a complex pattern of >50 driver mutations implicated in more than a dozen of signaling pathways. However, the genomic mechanisms governing disease progression and treatment resistance remain unknown. Building on our previous discovery of the clonotypic heterogeneity of MF, we hypothesized that this lymphoma does not progress in a linear fashion as currently thought, but comprises heterogeneous mutational subclones. We sequenced exomes of 49 cases of MF and identified 28 previously unreported putative driver genes. MF exhibited extensive intratumoral heterogeneity (ITH) of a median of six subclones showing branched pattern of phylogenetic relationships. Stage progression was correlated with an increase in ITH and redistribution of mutations from the stem to the clades. The pattern of clonal driver mutations was highly variable with no consistent mutations between patients. A similar intratumoral heterogeneity was detected in leukemic CTCL (Sézary syndrome). Based on these findings we propose a model of the pathogenesis of MF comprising neutral, divergent evolution of cancer subclones and discuss how ITH impacts the efficacy of targeted drug therapies and immunotherapies of CTCL.

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“…Predominantly diffuse FLs are usually BCL2-negative and often carry a 1p36 deletion including HVEM but tumor B cells produce very low amounts of LT and mature FDCs are poorly detectable [62]. Another important issue is the level of tumor cell intratumoral their localization with LN versus BM, suggesting that trafficking within various microenvironments could differentially impact FL pathogenesis and clonal selection [76][77][78][79]. In this context, the nature of the specific stromal niches supporting FL proliferative cells versus the FL ancestral common precursor clone responsible for disease relapse and transformation remains to be explored.…”

Section: How To Study Stromal Cell/ Fl B Cell Interactions?mentioning

confidence: 99%

Impact of B cell/lymphoid stromal cell crosstalk in B-cell physiology and malignancy

Lamaison

Tarte

2019

Immunology Letters

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Highlights-Lymphoid stromal cells form a heterogeneous and plastic cell compartment -Follicular and extrafollicular stromal cells contribute to normal B-cell activation -FL-CAFs exhibit specific phenotypic and transcriptomic features -FL B cells and their immune microenvironment trigger FL-CAF differentiation -FL-CAFs support directly malignant B-cell growth and organize tumor cell niche Abstract Stromal cells have been considered for a long time essentially as a structural component organizing tissue architecture, including those of secondary lymphoid organs. More recently, highly specialized stromal cell subsets were shown to differentially organize immune cell recruitment, survival, and differentiation within lymph nodes. In particular, mature B cells interact with different lymphoid stromal cell networks through bidirectional interactions involving cell-cell contact and soluble factors. Follicular lymphoma (FL) is the paradigm of a B-cell malignancy dependent on a lymphoid-like microenvironment supporting tumor cell growth, drug resistance, and clonal evolution. This review provides an overview of our current knowledge of lymphoid stromal cell heterogeneity and functions in normal B-cell activation. In addition, we also depict the dynamic and plasticity of FL cancer-associated fibroblasts, the mechanisms underlying their key role within FL permissive niches, and their potential as therapeutic targets in this still fatal malignancy.

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Genomic profiling reveals spatial intra-tumor heterogeneity in follicular lymphoma

Cited by 94 publications

References 16 publications

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

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

Branched evolution and genomic intratumor heterogeneity in the pathogenesis of cutaneous T-cell lymphoma

Impact of B cell/lymphoid stromal cell crosstalk in B-cell physiology and malignancy

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