TY - JOUR
T1 - Genetic Characterization of Primary Mediastinal B-Cell Lymphoma
T2 - Pathogenesis and Patient Outcomes
AU - Noerenberg, Daniel
AU - Briest, Franziska
AU - Hennch, Cornelius
AU - Yoshida, Kenichi
AU - Hablesreiter, Raphael
AU - Takeuchi, Yasuhide
AU - Ueno, Hiroo
AU - Staiger, Annette M
AU - Ziepert, Marita
AU - Asmar, Fazila
AU - Locher, Benjamin N
AU - Toth, Erika
AU - Weber, Thomas
AU - Amini, Rose-Marie
AU - Klapper, Wolfram
AU - Bouzani, Maria
AU - Poeschel, Viola
AU - Rosenwald, Andreas
AU - Held, Gerhard
AU - Campo, Elías
AU - Ishaque, Naveed
AU - Stamatopoulos, Kostas
AU - Kanellis, George
AU - Anagnostopoulos, Ioannis
AU - Bullinger, Lars
AU - Goldschmidt, Neta
AU - Zinzani, Pier Luigi
AU - Bödör, Csaba
AU - Rosenquist, Richard
AU - Vassilakopoulos, Theodoros P
AU - Ott, German
AU - Ogawa, Seishi
AU - Damm, Frederik
PY - 2024/2/1
Y1 - 2024/2/1
N2 - 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.
AB - 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.
KW - Antibodies, Monoclonal, Murine-Derived/therapeutic use
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Cyclophosphamide/therapeutic use
KW - Doxorubicin/therapeutic use
KW - Female
KW - Guanine Nucleotide Exchange Factors/therapeutic use
KW - Humans
KW - Lymphoma, Large B-Cell, Diffuse/drug therapy
KW - Prednisone/therapeutic use
KW - Rituximab/therapeutic use
KW - Treatment Outcome
KW - Vincristine/therapeutic use
UR - http://www.scopus.com/inward/record.url?scp=85183948838&partnerID=8YFLogxK
U2 - 10.1200/JCO.23.01053
DO - 10.1200/JCO.23.01053
M3 - Journal article
C2 - 38055913
SN - 0732-183X
VL - 42
SP - 452
EP - 466
JO - Journal of clinical oncology : official journal of the American Society of Clinical Oncology
JF - Journal of clinical oncology : official journal of the American Society of Clinical Oncology
IS - 4
ER -