Genetic characterization of primary mediastinal B-cell lymphoma: pathogenesis and patient outcomes

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Item Type:	Article
Title:	Genetic characterization of primary mediastinal B-cell lymphoma: pathogenesis and patient outcomes
Creators Name:	Noerenberg, D., Briest, F., Hennch, C., Yoshida, K., Hablesreiter, R., Takeuchi, Y., Ueno, H., Staiger, A.M., Ziepert, M., Asmar, F., Locher, B.N., Toth, E., Weber, T., Amini, R.M., Klapper, W., Bouzani, M., Poeschel, V., Rosenwald, A., Held, G., Campo, E., Ishaque, N., Stamatopoulos, K., Kanellis, G., Anagnostopoulos, I., Bullinger, L., Goldschmidt, N., Zinzani, P.L., Bödör, C., Rosenquist, R., Vassilakopoulos, T.P., Ott, G., Ogawa, S. and Damm, F.
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.
Keywords:	Antineoplastic Combined Chemotherapy Protocols, Cyclophosphamide, Diffuse Large B-Cell Lymphoma, Doxorubicin, Guanine Nucleotide Exchange Factors, Murine-Derived Monoclonal Antibodies, Prednisone, Rituximab, Treatment Outcome, Vincristine
Source:	Journal of Clinical Oncology
ISSN:	0732-183X
Publisher:	Lippincott Williams & Wilkins
Volume:	42
Number:	4
Page Range:	452-466
Date:	1 February 2024
Official Publication:	https://doi.org/10.1200/jco.23.01053
PubMed:	View item in PubMed

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