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The Transition between Telomerase and ALT Mechanisms in Hodgkin Lymphoma and Its Predictive Value in Clinical Outcomes.

ABSTRACT: Background: We analyzed telomere maintenance mechanisms (TMMs) in lymph node samples from HL patients treated with standard therapy. The TMMs correlated with clinical outcomes of patients. Materials and Methods: Lymph node biopsies obtained from 38 HL patients and 24 patients with lymphadenitis were included in this study. Seven HL cell lines were used as in vitro models. Telomerase activity (TA) was assessed by TRAP assay and verified through hTERT immunofluorescence expression; alternative telomere lengthening (ALT) was also assessed, along with EBV status. Results: Both TA and ALT mechanisms were present in HL lymph nodes. Our findings were reproduced in HL cell lines. The highest levels of TA were expressed in CD30-/CD15- cells. Small cells were identified with ALT and TA. Hodgkin and Reed Sternberg cells contained high levels of PML bodies, but had very low hTERT expression. There was a significant correlation between overall survival (p < 10-3), event-free survival (p < 10-4), and freedom from progression (p < 10-3) and the presence of an ALT profile in lymph nodes of EBV+ patients. Conclusion: The presence of both types of TMMs in HL lymph nodes and in HL cell lines has not previously been reported. TMMs correlate with the treatment outcome of EBV+ HL patients.

SUBMITTER: M'kacher R

PROVIDER: S-EPMC6025489 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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The Transition between Telomerase and ALT Mechanisms in Hodgkin Lymphoma and Its Predictive Value in Clinical Outcomes.

M'kacher Radhia R Cuceu Corina C Al Jawhari Mustafa M Morat Luc L Frenzel Monika M Shim Grace G Lenain Aude A Hempel William M WM Junker Steffen S Girinsky Theodore T Colicchio Bruno B Dieterlen Alain A Heidingsfelder Leonhard L Borie Claire C Oudrhiri Noufissa N Bennaceur-Griscelli Annelise A Moralès Olivier O Renaud Sarah S Van de Wyngaert Zoé Z Jeandidier Eric E Delhem Nadira N Carde Patrice P

Cancers 20180530 6

<i>Background</i>: We analyzed telomere maintenance mechanisms (TMMs) in lymph node samples from HL patients treated with standard therapy. The TMMs correlated with clinical outcomes of patients. <i>Materials and Methods</i>: Lymph node biopsies obtained from 38 HL patients and 24 patients with lymphadenitis were included in this study. Seven HL cell lines were used as in vitro models. Telomerase activity (TA) was assessed by TRAP assay and verified through hTERT immunofluorescence expression; a ...[more]

PMID: 29848986

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Project description:Despite decades of intensive research, NHL (non-Hodgkin lymphoma) still remains poorly understood and is largely incurable. Recent molecular studies suggest that genomic variants measured with SNPs (single nucleotide polymorphisms) in genes may have additional predictive power for NHL prognosis beyond clinical risk factors. We analyzed a genetic association study. The prognostic cohort consisted of 346 patients, among whom 138 had DLBCL (diffuse large B-cell lymphoma) and 101 had FL ( follicular lymphoma). For DLBCL, we analyzed 1229 SNPs which represented 122 KEGG pathways. For FL, we analyzed 1228 SNPs which represented 122 KEGG pathways. Unlike in existing studies, we targeted at identifying pathways with significant additional predictive power beyond clinical factors. In addition, we accounted for the joint effects of multiple SNPs within pathways, whereas some existing studies drew pathway-level conclusions based on separate analysis of individual SNPs. For DLBCL, we identified four pathways, which, combined with the clinical factors, had medians of the prediction logrank statistics as 2.535, 2.220, 2.094, 2.453, and 2.512, respectively. As a comparison, the clinical factors had a median of the prediction logrank statistics around 0.552. For FL, we identified two pathways, which, combined with the clinical factors, had medians of the prediction logrank statistics as 4.320 and 3.532, respectively. As a comparison, the clinical factors had a median of the prediction logrank statistics around 1.212. For NHL overall, we identified three pathways, which, combined with the clinical factors, had medians of the prediction logrank statistics as 5.722, 5.314, and 5.441, respective. As a comparison, the clinical factors had a median of the prediction logrank statistics around 4.411. The identified pathways have sound biological bases. In addition, they are different from those identified using existing approaches. They may provide further insights into the biological mechanisms underlying the prognosis of NHL.

Project description:ImportanceThe management of lymphoma diagnosed during pregnancy is controversial and has been guided largely by findings from case reports and small series.ObjectiveTo determine maternal and fetal outcomes of women diagnosed with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) during pregnancy.Design, setting, and participantsThis retrospective analysis studied a cohort of 39 pregnant women diagnosed with HL and NHL (31 HL and 8 NHL) at a single specialized cancer institution between January 1991 and December 2014.Main outcomes and measuresWe examined data on disease and treatment characteristics, as well as maternal and fetal complications and outcomes. The Kaplan-Meier method was used to compare progression free survival (PFS) and overall survival (OS) according to receipt of antenatal therapy and other clinical factors. Univariate and multivariate analyses were performed by using Cox proportional hazard regression models to identify potential associations between clinical and treatment factors and survival.ResultsThe median (range) age of the 39 women in the patient cohort was 28 (19-38) years; 32 women (82%) had stage I or II disease at diagnosis, and 13 had bulky disease. Three women electively terminated the pregnancy to allow immediate systemic therapy; of the remaining 36 women, 24 received antenatal therapy (doxorubicin based combination chemotherapy in 20 of 24 patients), and 12 deferred therapy until after delivery. Four women experienced miscarriage, all of whom had received antenatal systemic therapy and 2 during the first trimester. Delivery occurred at a median (range) of 37 (32-42) weeks and was no different based on receipt of antenatal (median [range], 37 [33-42] weeks) vs postnatal (median [range], 37 [32-42] weeks) therapy (P = .21). No gross fetal malformations or anomalies were detected. At a median (range) follow-up time of 67.9 (8.8-277.5) months since the diagnosis of lymphoma, 5-year rates of PFS and OS were 74.7% and 82.4%, respectively; these rates did not differ according to timing of therapy. On univariate analysis, bulky disease (>10 cm), extranodal nonbone marrow involvement, and poor performance status (Eastern Cooperative Oncology Group score, ≥2) predicted increased risk of disease progression. On multivariate analysis, extranodal nonbone marrow disease and performance status remained significant for both PFS and OS.Conclusions and relevanceSystemic therapy given for lymphoma after the first trimester of pregnancy is likely safe and results in acceptable maternal and fetal outcomes.

Dataset Information

The Transition between Telomerase and ALT Mechanisms in Hodgkin Lymphoma and Its Predictive Value in Clinical Outcomes.

Publications

The Transition between Telomerase and ALT Mechanisms in Hodgkin Lymphoma and Its Predictive Value in Clinical Outcomes.

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