Missense Mutations Located in Structural p53 DNA-Binding Motifs

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BlankAmerican Society of Clinical Oncology

Missense Mutations Located in Structural p53 DNA-Binding Motifs Are Associated

With Extremely Poor Survival in Chronic Lymphocytic Leukemia

1.. Trbusek?,

2.. Jana Smardova,

3.. Jitka Malcikova,

4.. Ludmila Sebejova,

5.. Petr Dobes,

6.. Miluse Svitakova,

7.. Vladimira Vranova,

8.. Marek Mraz,

9.. Hana Skuhrova Francova,

10.. Doubek,

11.. Yvona Brychtova,

12.. Petr Kuglik,

13.. Sarka Pospisilova and

14.. Jiri Mayer

+ Author Affiliations

1.. All authors: University Hospital Brno; Central European Institute of

Technology, Masaryk University, Brno, Czech Republic.

1.. Corresponding author: Trbusek, PhD, University Hospital Brno,

Department of Internal Medicine–Hematooncology, Jihlavska 20, 625 00 Brno, Czech

Republic; e-mail: mtrbusek@....

Abstract

Purpose There is a distinct connection between TP53 defects and poor prognosis

in chronic lymphocytic leukemia (CLL). It remains unclear whether patients

harboring TP53 mutations represent a homogenous prognostic group.

Patients and Methods We evaluated the survival of patients with CLL and p53

defects identified at our institution by p53 yeast functional assay and

complementary interphase fluorescence in situ hybridization analysis detecting

del(17p) from 2003 to 2010.

Results A defect of the TP53 gene was identified in 100 of 550 patients. p53

mutations were strongly associated with the deletion of 17p and the unmutated

IgVH locus (both P < .001). Survival assessed from the time of abnormality

detection was significantly reduced in patients with both missense (P < .001)

and nonmissense p53 mutations (P = .004). In addition, patients harboring

missense mutation located in p53 DNA-binding motifs (DBMs), structurally

well-defined parts of the DNA-binding domain, manifested a clearly shorter

median survival (12 months) compared with patients having missense mutations

outside DBMs (41 months; P = .002) or nonmissense alterations (36 months; P =

..005). The difference in survival was similar in the analysis limited to

patients harboring mutation accompanied by del(17p) and was also confirmed in a

subgroup harboring TP53 defect at diagnosis. The patients with p53 DBMs mutation

(at diagnosis) also manifested a short median time to first therapy (TTFT; 1

month).

Conclusion The substantially worse survival and the short TTFT suggest a strong

mutated p53 gain-of-function phenotype in patients with CLL with DBMs mutations.

The impact of p53 DBMs mutations on prognosis and response to therapy should be

analyzed in investigative clinical trials.