title: Mutations of CREBBP and SOCS1 are independent prognostic factors in diffuse large B cell lymphoma: mutational analysis of the SAKK 38/07 prospective clinical trial cohort.
abstract: Recently, the mutational background of diffuse large B cell lymphoma (DLBCL) has been revealed, identifying specific genetic events that drive lymphomagenesis. However, the prognostic value of these mutations remains to be determined. Prognostic biomarkers in DLBCL are urgently needed, since the current clinical parameter-based factors (e.g., International Prognostic Index (IPI)) are insufficient, particularly in identifying patients with poor prognosis who might benefit from alternative treatments.
  
  
  
  We investigated the prognostic value of somatic mutations in DLBCL in a clinical trial (NCT00544219) patient cohort homogenously treated with six cycles of rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP), followed by two cycles of R (R-CHOP-14). The primary endpoint was event-free survival (EFS) at 2 years. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Targeted high-throughput sequencing (HTS) of tumor genomic DNA was performed on all exons or hotspots of 68 genes frequently mutated in B cell lymphomas. Mutational data was correlated with the endpoints to identify prognostic associations.
  
  
  
  Targeted HTS detected somatic mutations in 71/76 (93%) of investigated cases. The most frequently mutated genes were KMT2D, SOCS1, GNA13, and B2M. Survival analysis revealed that CREBBP- and EP300-mutated cases had significantly worse OS, PFS, and EFS. In addition, ATM mutations predicted worse outcomes for all three clinical endpoints in germinal center B cell-like DLBCL. In contrast, SOCS1 mutations were associated with better PFS. On multivariable analysis taken into account IPI and failure to achieve complete remission, CREBBP and EP300 mutations remained significant to predict worse OS, PFS, and EFS.
  
  
  
  Targeted mutation analysis of a uniformly treated prospective clinical trial DLBCL cohort identifies tumor-based genetic prognostic markers that could be useful in the clinical management of such patients.
  
  
  
  ClinicalTrials.gov NCT00544219.
authors.affiliation: Institute of Pathology, University of Basel and University Hospital Basel, Schoenbeinstrasse 40, CH-4031, Basel, Switzerland.
authors.forename: Darius
authors.initials: D
authors.lastname: Juskevicius
authors.affiliation: Institute of Pathology, University of Basel and University Hospital Basel, Schoenbeinstrasse 40, CH-4031, Basel, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Jucker
authors.affiliation: Swiss Group for Clinical Cancer Research (SAKK), Effingerstrasse 40, CH-3008, Bern, Switzerland.
authors.forename: Dirk
authors.initials: D
authors.lastname: Klingbiel
authors.affiliation: Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, CH-4031, Basel, Switzerland.|Center of Oncology, Hematology and Transfusion Medicine, Cantonal Hospital Aarau, Tellstrasse 25, CH-5000, Aarau, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Mamot
authors.affiliation: Institute of Pathology, University of Basel and University Hospital Basel, Schoenbeinstrasse 40, CH-4031, Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Dirnhofer
authors.affiliation: Institute of Pathology, University of Basel and University Hospital Basel, Schoenbeinstrasse 40, CH-4031, Basel, Switzerland. alexandar.tzankov@usb.ch.
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D050882:CREB-Binding Protein / Q000235:genetics*; D003520:Cyclophosphamide / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000627:therapeutic use; D050881:E1A-Associated p300 Protein / Q000235:genetics; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011241:Prednisone / Q000627:therapeutic use; D011379:Prognosis; D000069283:Rituximab; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000235:genetics*; D015996:Survival Rate; D014750:Vincristine / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D011241:Prednisone
keywords: CREBBP; DLBCL; EP300; Lymphoma; NGS; Prognostic markers; SOCS1; Targeted high-throughput sequencing