High rate of TNFRSF14 gene alterations related to 1p36 region in de novo follicular lymphoma and impact on prognosis (original) (raw)

Leukemia volume 26, pages 559–562 (2012)Cite this article

Follicular lymphoma (FL) is characterized by the balanced chromosomal translocation t(14;18)(q32;q21) in about 80–90% of the cases. This primary event is not sufficient for emergence of FL, and acquisition of secondary genetic alterations is necessary to full disease manifestation. Genome-wide studies revealed recurring sites of copy number alterations and acquired uniparental disomies (aUPD).1, 2, 3 1p36 region alterations (deletions and aUPD) were described as one of the most frequent secondary genetic abnormality in FL,1 and del(1)(p36) was considered as a significant predictor of poor overall survival.2 In an initial prospective study based on 20 de novo and untreated FL, we performed a genome-wide approach using comparative genomic hybridization (CGH) and single-nucleotide polymorphism array technologies on cell-sorted tumor and microenvironment compartments to evaluate genetic changes involved in FL. We found that 25% of the cases presented a deletion of the region 1p36.32 and 40% of the cases presented an aUPD 1p36. Thus, 1p36.32 alterations were the most frequent additional genetic abnormality (67%) in our cohort, and our analysis delineated a minimum deleted region of ∼12 kb in band 1p36.32 comprising a unique candidate gene, TNFRSF14. This latter is a member of the tumor necrosis factor receptor (TNFR) superfamily and its stimulation in lymphoma cells via LIGHT ligand enhances Fas-induced apoptosis and could improve tumor immunogenicity.4 Additionally, TNFRSF14 activation by LIGHT inhibits proliferation of adenocarcinoma cells,5 both observations suggesting that TNFRSF14 signaling might have a tumor suppressor role.

To further investigate this gene, we designed a dedicated QMPSF (quantitative multiplex PCR of short fluorescent fragments) assay, targeting the eight exons of TNFRSF14 (Supplementary Table S1) to evaluate the deletion status of the gene in a larger cohort comprising 30 cell-sorted (FL1 to FL30, 20 of these cases were used for our initial study) and 51 additional non-sorted de novo FL (FL31 to FL81). Twenty patients presented a complete heterozygous deletion of TNFRSF14 and one patient presented a partial heterozygous deletion. Three patients had a complete (FL16) or partial (FL8, FL18) homozygous deletion. Array-CGH analyses showed that FL16 presented a large deletion 1p36.11–p36.33, comprising a homozygous deletion from PLCH2 to MMEL1, which are located in telomeric and centromeric position, respectively, with regard to TNFRSF14; FL8, with a homozygous deletion from exons 4 to 8, showed an isolated bi-allelic deletion of TNFRSF14 (array-CGH probe being located in exon 8; Supplementary Figure S1A), and FL18 homozygously deleted from exons 5 to 8 had a bi-allelic deletion in 1p36.32 associated with telomeric breakpoint in TNFRSF14 (Supplementary Figure S1B). QMPSF results were consistent with array-CGH data. Altogether, partial or complete deletion of TNFRSF14 was found in 30% of the FL (24 cases); the remaining 57 patients had two non-deleted copies of the TNFRSF14 gene.

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Acknowledgements

This study was supported by research fundings from the Institut National du Cancer (INCa libre 2005-PL070). We thank the ‘Centre de Ressources (CRB)-Santé’ of Rennes’ Hospital, Jean-Michel Picquenot and Patrick Tas for providing follicular lymphoma lymph nodes; Vinciane Rainville, Elodie Bohers and Françoise Parmentier for their technical assistance.

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Authors and Affiliations

  1. UMR INSERM U918, Centre Henri Becquerel, Université de Rouen, Rouen, France
    E Launay, P Bertrand, F Jardin, H Tilly & C Bastard
  2. CHU de Rennes, Laboratoire d’Hématologie, Rennes, France
    C Pangault & T Fest
  3. INSERM U917, IFR140, Université de Rennes 1, Rennes, France
    C Pangault, T Lamy, K Tarte & T Fest
  4. CHU de Rennes, Service d’Hématologie Clinique, Rennes, France
    T Lamy

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  1. E Launay
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  2. C Pangault
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  3. P Bertrand
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  4. F Jardin
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  5. T Lamy
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  6. H Tilly
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  7. K Tarte
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  8. C Bastard
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  9. T Fest
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Correspondence toT Fest.

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Launay, E., Pangault, C., Bertrand, P. et al. High rate of TNFRSF14 gene alterations related to 1p36 region in de novo follicular lymphoma and impact on prognosis.Leukemia 26, 559–562 (2012). https://doi.org/10.1038/leu.2011.266

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