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.
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
Ken H
KH
Young
Karen
K
Leroy
Michael B
MB
Møller
Gisele W B
GW
Colleoni
Margarita
M
Sánchez-Beato
Fábio R
FR
Kerbauy
Corinne
C
Haioun
Jens C
JC
Eickhoff
Allen H
AH
Young
Philippe
P
Gaulard
Miguel A
MA
Piris
Terry D
TD
Oberley
William M
WM
Rehrauer
Brad S
BS
Kahl
James S
JS
Malter
Elias
E
Campo
Jan
J
Delabie
Randy D
RD
Gascoyne
Andreas
A
Rosenwald
Lisa
L
Rimsza
James
J
Huang
Rita M
RM
Braziel
Elaine S
ES
Jaffe
Wyndham H
WH
Wilson
Louis M
LM
Staudt
Julie M
JM
Vose
Wing C
WC
Chan
Dennis D
DD
Weisenburger
Timothy C
TC
Greiner
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