Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study.
The purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53 mutations was significantly worse than those with wild-type TP53 (P < .001). However, subsets of TP53 mutations were found to have different effects on OS. Mutations in the TP53 DNA-binding domains were the strongest predictors of poor OS (P < .001). Mutations in the Loop-Sheet-Helix and Loop-L3 were associated with significantly decreased OS (P = .002), but OS was not significantly affected by mutations in Loop-L2. A subset of missense mutations (His158, His175, Ser245, Gln248, His273, Arg280, and Arg282) in the DNA-binding domains had the worst prognosis. Multivariate analysis confirmed that the International Prognostic Index and mutations in the DNA-binding domains were independent predictors of OS. TP53 mutations also stratified patients with germinal center B cell-like DLBCL, but not nongerminal center B cell-like DLBCL, into molecularly distinct subsets with different survivals. This study shows the prognostic importance of mutations in the TP53 DNA-binding domains in patients with DLBCL.
Young
Ken H
KH
Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, University of of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, USA. khyoung@wisc.edu
Leroy
Karen
K
Møller
Michael B
MB
Colleoni
Gisele W B
GW
Sánchez-Beato
Margarita
M
Kerbauy
Fábio R
FR
Haioun
Corinne
C
Eickhoff
Jens C
JC
Young
Allen H
AH
Gaulard
Philippe
P
Piris
Miguel A
MA
Oberley
Terry D
TD
Rehrauer
William M
WM
Kahl
Brad S
BS
Malter
James S
JS
Campo
Elias
E
Delabie
Jan
J
Gascoyne
Randy D
RD
Rosenwald
Andreas
A
Rimsza
Lisa
L
Huang
James
J
Braziel
Rita M
RM
Jaffe
Elaine S
ES
Wilson
Wyndham H
WH
Staudt
Louis M
LM
Vose
Julie M
JM
Chan
Wing C
WC
Weisenburger
Dennis D
DD
Greiner
Timothy C
TC
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000008:administration & dosage; D004252:DNA Mutational Analysis; D004317:Doxorubicin / Q000008:administration & dosage; D005091:Exons; D005260:Female; D006801:Humans; D007391:International Cooperation; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011239:Prednisolone / Q000008:administration & dosage; D011379:Prognosis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014750:Vincristine / Q000008:administration & dosage
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone