B-cell Function Gene Mutations in Diffuse Large B-cell Lymphoma: A Retrospective Cohort Study.
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous subtype of non-Hodgkin lymphoma. In addition to clinical and immunophenotypic characteristics, recurrent gene mutations have recently been identified in patients with DLBCL using next-generation sequencing technologies. The aim of this study is to investigate the clinical relevance of B-cell function gene mutations in DLBCL. Clinical analysis was performed on 680 Chinese DLBCL patients (146 non-CR and 534 CR cases) treated with six cycles of 21-day R-CHOP (Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), alone or followed by two additional doses of rituximab consolidation on patients' own intention. Somatic mutations of B-cell function genes were further screened on 275 (71 non-CR and 204 CR) cases with available tumor samples by targeted sequencing, including genes involved in B-cell receptors (BCRs) pathway (CARD11, LYN, CD79A, and CD79B), Toll-like receptors (TLRs) pathway (MYD88), and tumor necrotic factor receptor (TNFR) pathway (TRAF2 and TNFAIP3). B-cell function gene mutations occurred in 44.0% (121/275) of DLBCL patients. The TLRs and TNFR related gene mutations were more frequently observed in non-CR patients (p=0.019 and p=0.032, respectively). BCRs related gene mutations, as well as revised IPI (R-IPI) and double BCL-2/MYC expression, were independently related to short progression-free survival in DLBCL after CR. The adverse prognostic effect of BCRs related gene mutations could be overcome by two additional doses of rituximab consolidation. These results highlight the molecular heterogeneity of DLBCL and identify a significant role of B-cell function gene mutations on lymphoma progression and response to rituximab in DLBCL.
State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine; 197 Rui Jin Er Road, Shanghai, China.
Peng-Peng
PP
Xu
State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine; 197 Rui Jin Er Road, Shanghai, China.
Hui-Juan
HJ
Zhong
State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine; 197 Rui Jin Er Road, Shanghai, China.
Yao-Hui
YH
Huang
State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine; 197 Rui Jin Er Road, Shanghai, China.
Xiao-Dong
XD
Gao
State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine; 197 Rui Jin Er Road, Shanghai, China; Pôle de Recherches Sino-Français en Science du Vivant et Génomique; Laboratory of Molecular Pathology; Shanghai, China.
Xia
X
Zhao
State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine; 197 Rui Jin Er Road, Shanghai, China.
Yang
Y
Shen
State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine; 197 Rui Jin Er Road, Shanghai, China.
Shu
S
Cheng
State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine; 197 Rui Jin Er Road, Shanghai, China.
Jin-Yan
JY
Huang
State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine; 197 Rui Jin Er Road, Shanghai, China; Pôle de Recherches Sino-Français en Science du Vivant et Génomique; Laboratory of Molecular Pathology; Shanghai, China.
Sai-Juan
SJ
Chen
State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine; 197 Rui Jin Er Road, Shanghai, China; Pôle de Recherches Sino-Français en Science du Vivant et Génomique; Laboratory of Molecular Pathology; Shanghai, China.
Li
L
Wang
State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine; 197 Rui Jin Er Road, Shanghai, China; Pôle de Recherches Sino-Français en Science du Vivant et Génomique; Laboratory of Molecular Pathology; Shanghai, China. Electronic address: zhao.weili@yahoo.com.
Wei-Li
WL
Zhao
D000595:Amino Acid Sequence; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000378:metabolism*; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D011241:Prednisone / Q000008:administration & dosage; D011379:Prognosis; D012074:Remission Induction; D012189:Retrospective Studies; D000069283:Rituximab / Q000008:administration & dosage; D017386:Sequence Homology, Amino Acid; D016896:Treatment Outcome; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000235:genetics; D014750:Vincristine / Q000008:administration & dosage
C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D011241:Prednisone
B-cell function gene mutations; Diffuse large B-cell lymphoma; Prognosis; Rituximab