Genetic Characterization of Primary Mediastinal B-Cell Lymphoma: Pathogenesis and Patient Outcomes

Daniel Noerenberg, Franziska Briest, Cornelius Hennch, Kenichi Yoshida, Raphael Hablesreiter, Yasuhide Takeuchi, Hiroo Ueno, Annette M Staiger, Marita Ziepert, Fazila Asmar, Benjamin N Locher, Erika Toth, Thomas Weber, Rose-Marie Amini, Wolfram Klapper, Maria Bouzani, Viola Poeschel, Andreas Rosenwald, Gerhard Held, Elías CampoNaveed Ishaque, Kostas Stamatopoulos, George Kanellis, Ioannis Anagnostopoulos, Lars Bullinger, Neta Goldschmidt, Pier Luigi Zinzani, Csaba Bödör, Richard Rosenquist, Theodoros P Vassilakopoulos, German Ott, Seishi Ogawa, Frederik Damm*

*Corresponding author af dette arbejde

Abstract

PURPOSE: Primary mediastinal large B-cell lymphoma (PMBCL) is a rare aggressive lymphoma predominantly affecting young female patients. Large-scale genomic investigations and genetic markers for risk stratification are lacking.

PATIENTS AND METHODS: To elucidate the full spectrum of genomic alterations, samples from 340 patients with previously untreated PMBCL were investigated by whole-genome (n = 20), whole-exome (n = 78), and targeted (n = 308) sequencing. Statistically significant prognostic variables were identified using a multivariable Cox regression model and confirmed by L1/L2 regularized regressions.

RESULTS: Whole-genome sequencing revealed a commonly disrupted p53 pathway with nonredundant somatic structural variations (SVs) in TP53-related genes (TP63, TP73, and WWOX) and identified novel SVs facilitating immune evasion (DOCK8 and CD83). Integration of mutation and copy-number data expanded the repertoire of known PMBCL alterations (eg, ARID1A, P2RY8, and PLXNC1) with a previously unrecognized role for epigenetic/chromatin modifiers. Multivariable analysis identified six genetic lesions with significant prognostic impact. CD58 mutations (31%) showed the strongest association with worse PFS (hazard ratio [HR], 2.52 [95% CI, 1.50 to 4.21]; P < .001) and overall survival (HR, 2.33 [95% CI, 1.14 to 4.76]; P = .02). IPI high-risk patients with mutated CD58 demonstrated a particularly poor prognosis, with 5-year PFS and OS rates of 41% and 58%, respectively. The adverse prognostic significance of the CD58 mutation status was predominantly observed in patients treated with nonintensified regimens, indicating that dose intensification may, to some extent, mitigate the impact of this high-risk marker. By contrast, DUSP2-mutated patients (24%) displayed durable responses (PFS: HR, 0.2 [95% CI, 0.07 to 0.55]; P = .002) and prolonged OS (HR, 0.11 [95% CI, 0.01 to 0.78]; P = .028). Upon CHOP-like treatment, these patients had very favorable outcome, with 5-year PFS and OS rates of 93% and 98%, respectively.

CONCLUSION: This large-scale genomic characterization of PMBCL identified novel treatment targets and genetic lesions for refined risk stratification. DUSP2 and CD58 mutation analyses may guide treatment decisions between rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab.

OriginalsprogEngelsk
TidsskriftJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Vol/bind42
Udgave nummer4
Sider (fra-til)452-466
Antal sider15
ISSN0732-183X
DOI
StatusUdgivet - 1 feb. 2024

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