Genome-wide detection of recurring sites of uniparental disomy in follicular and transformed follicular lymphoma

Fitzgibbon, Jude; Iqbal, Sameena; Davies, Andrew; O’Shea, Derville; Carlotti, Emanuela; Chaplin, Tracy; Matthews, Janet; Raghavan, Manoj; Norton, A. J.; Lister, T. Andrew; Young, Bryan D.

doi:10.1038/sj.leu.2404696

Cited by 75 publications

(58 citation statements)

References 45 publications

(56 reference statements)

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“…6,14,16,17 A region of copy-number loss on 1p frequently had aUPD in FL and tFL (supplemental Figure 3B). A previous study 16 found 1p36 aUPD to negatively correlate with OS; however, we did not observe this, nor was aUPD at TNFRSF14 predictive of OS (data not shown).…”

Section: Acquired Uniparental Disomymentioning

confidence: 99%

Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma

Bouska

McKeithan

Deffenbacher

et al. 2014

Blood

116

122

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• Chromosome copy-number alterations that may affect immune surveillance and the NF-kB and p53 pathways are more frequent in tFL than FL.• Abnormalities involving chromosomes 6 and X are predictive of overall survival in FL.Follicular lymphoma (FL), the second most common type of non-Hodgkin lymphoma in the western world, is characterized by the t(14;18) translocation, which is present in up to 90% of cases. We studied 277 lymphoma samples (198 FL and 79 transformed FL [tFL]) using a single-nucleotide polymorphism array to identify the secondary chromosomal abnormalities that drive the development of FL and its transformation to diffuse large B-cell lymphoma. Common recurrent chromosomal abnormalities in FL included gains of 2, 5, 7, 6p, 8, 12, 17q, 18, 21, and X and losses on 6q and 17p. We also observed many frequent small abnormalities, including losses of 1p36.33-p36.31, 6q23.3-q24.1, and 10q23.1-q25.1 and gains of 2p16.1-p15, 8q24.13-q24.3, and 12q12-q13.13, and identified candidate genes that may be driving this selection. Recurrent abnormalities more frequent in tFL samples included gains of 3q27.3-q28 and chromosome 11 and losses of 9p21.3 and 15q. Four abnormalities, gain of X or Xp and losses of 6q23.2-24.1 or 6q13-15, predicted overall survival. Abnormalities associated with transformation of the disease likely impair immune surveillance, activate the nuclear factor-kB pathway, and deregulate p53 and B-cell transcription

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Section: Acquired Uniparental Disomymentioning

confidence: 99%

Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma

Bouska

McKeithan

Deffenbacher

et al. 2014

Blood

116

122

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“…23 UPD is considered to be one of the genetic mechanisms involved in tumor suppressor inactivation as mutated or deleted alleles of tumor suppressors could become homozygous through mitotic recombination. [75][76][77][78] Interestingly, studies of UPD in MPN and other myeloid malignancies showed that UPD is often involved in oncogene amplification. Semi-dominant oncogenic mutations present in neoplastic tissues in a heterozygous state can become homozygous due to mitotic recombination.…”

Section: Upd and Variability Of Mutational Burden In Mpnmentioning

confidence: 99%

Genetic complexity of myeloproliferative neoplasms

Královics

2008

Leukemia

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Oncogenic mutations in JAK2 and MPL genes have recently been identified in myeloproliferative neoplasms (MPNs). In addition to these mutations, cytogenetic aberrations are frequently present at diagnosis but their role in the pathogenesis remains unclear. Two models of MPN pathogenesis have recently emerged based on either a single-hit or a multi-hit concept. The first model proposes that the acquisition of JAK2 mutations is the disease-initiating event, causing both the onset of disease phenotype and establishment of clonal hematopoiesis. The second model postulates the existence of 'pre-JAK2' mutations that establish clonal hematopoiesis before acquisition of JAK2 mutations and onset of disease phenotype. In this review, the two models have been critically evaluated in the context of the latest findings. At present, neither of the two models can be universally applied to all MPN patients due to their genetic heterogeneity. It is likely that the disease pathogenesis in some patients follows the first, and in other patients, the second model. Thus, the somatic mutations in MPN do not seem to be acquired in a predetermined order as seen in other malignancies, but occur randomly. Furthermore, the role of uniparental disomy in MPN and certain aspects of MPN therapy are discussed.

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“…Transformation occurs by clonal evolution from a common mutated precursor, as shown by sequencing of rearranged VDJ sequences, 15 or whole exomes or genomes. 13,16 Recurrent genetic alterations that evolve during the process of transformation include: CDKN2A deletions and/or loss of heterozygosity 13,17 ; translocations, gains, amplifications, or mutations involving MYC 13,18,19 ; mutations, deletions, and loss of heterozygosity affecting TP53 13,[20][21][22][23][24] ; and mutations or deletions of B2M and CD58. 13 Increased proliferation resulting from cell cycle deregulation, defective DNA damage response, and escape from immune surveillance therefore emerge as critical elements of histologic progression of FL to an aggressive lymphoma.…”

Section: Introductionmentioning

confidence: 99%

Cell of origin of transformed follicular lymphoma

Kridel

Mottok

Farinha

et al. 2015

Blood

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Key Points• TFL is most commonly of the germinal center B-cell-like phenotype, but a significant minority of cases is of the ABC phenotype (16%).• The absence of BCL2 translocation in FL at diagnosis is associated with transformation into ABC-like large cell lymphoma.Follicular lymphoma (FL) is an indolent disease but transforms in 2% to 3% of patients per year into aggressive, large cell lymphoma, a critical event in the course of the disease associated with increased lymphoma-related mortality. Early transformation cannot be accurately predicted at the time of FL diagnosis and the biology of transformed FL (TFL) is poorly understood. Here, we assembled a cohort of 126 diagnostic FL specimens including 40 patients experiencing transformation (<5 years) and 86 patients not experiencing transformation for at least 5 years. In addition, we assembled an overlapping cohort of 155 TFL patients, including 114 cases for which paired samples were available, and assessed temporal changes of routinely available biomarkers, outcome after transformation, as well as molecular subtypes of TFL. We report that the expression of IRF4 is an independent predictor of early transformation (Hazard ratio, 13.3; P < .001). We also show that composite histology at the time of transformation predicts favorable prognosis. Moreover, applying the Lymph2Cx digital gene expression assay for diffuse large B-cell lymphoma (DLBCL) cell-of-origin determination to 110 patients with DLBCL-like TFL, we demonstrate that TFL is of the germinal-center B-cell-like subtype in the majority of cases (80%) but that a significant proportion of cases is of the activated B-cell-like (ABC) subtype (16%). These latter cases are commonly negative for BCL2 translocation and arise preferentially from BCL2 translocation-negative and/or IRF4-expressing FLs. Our study demonstrates the existence of molecular heterogeneity in TFL as well as its relationship to the antecedent FL. (Blood. 2015;126(18):2118-2127

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Genome-wide detection of recurring sites of uniparental disomy in follicular and transformed follicular lymphoma

Cited by 75 publications

References 45 publications

Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma

Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma

Genetic complexity of myeloproliferative neoplasms

Cell of origin of transformed follicular lymphoma

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