17p Deletion Associated with Poor Survival regardless of p53 Status

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AuthorZenz, Thorsten , Ulm, University of Ulm Germany

Co-author(s) Häbe, Sonja , Ulm, University of Ulm

Kröber, A. , Ulm, University of Ulm

Benner, A , Heidelberg, German Cancer Research Center

Kienle, D. , Ulm, University of Ulm

Bühler, A. , Ulm, University of Ulm

Denzel, T. , Ulm, University of Ulm

Winkler, D. , Ulm, University of Ulm

Döhner, H. , Ulm, University of Ulm

Stilgenbauer, Stephan , Ulm, University of Ulm

Topic26. Chronic lymphocytic leukemia and related disorders -

biology

KeywordsChronic lymphocytic leukemia,Mutation,p53,

Background: CLL patients with 17p deletion have a dismal prognosis.

The exact prognostic role of TP53 mutations in the absence of 17p

deletion and any differential impact of the mutation in cases with

17p deletion (vs. sole deletion) is currently unclear.

Aim: To assess the incidence and prognostic impact of TP53 mutations

as assessed by direct sequencing and DHPLC in a well characterized

patient population.

Methods: We studied 126 CLL patients from a single institution. The

population is well characterized clinically and detailed genetic

characteristics are available (FISH, VH-Status, CD38 expression). We

used direct sequencing (n=126) and DHPLC (n=80) to detect TP53

mutations in the coding exons (2-11). The mutation analysis was

performed on samples taken a median of 0.6 months after diagnosis.

Results: We found an overall incidence of TP53 mutations of 13.5%

(17/126 patients). The mutations were mainly located in the DNA

binding domain (Exons 4-9).

All mutations detected by direct sequencing were also detected by

DHPLC. DHPLC was also informative in determining the allele status

in the presence of heterozygous polymorphisms.

Twelve of 15 patients with 17p deletions also had a TP53 mutation

(80%). We also found TP53 mutations in the absence of 17p deletions

in 4.5% (5/111). In the subgroup of patients with trisomy 12q we did

not find TP53 mutations as opposed to 17/ 103 (16.5%) in all other

subgroups combined (p= 0.04).

To study the impact on overall survival we confined the analysis to

patients who were studied within 24 months of diagnosis to avoid

bias. In this subgroup (n=108) we found a significant impact of the

presence of the TP53 mutation (median survival 65 months vs. 15

months, P<0.0001).

When separating the groups according to presence or absence of TP53

mutation and / or 17p deletion we found a highly significant

influence of the presence of the TP53 mutation and / or 17p deletion

on survival from the date of study (Fig.1)( P<0.0001). Overall

survival (from the time of study) was similar in the groups with

deletion 17p and mutation (7.9 months), sole TP53 mutation (5.1

months) and 17p deletion without TP53 mutation (4.4 months) (vs.

66.7 months)(Fig. 1). In 8 / 17 patients the mutation was found

within 1 year of diagnosis. 4 of 6 patients with TP53 mutations and

availability of serial samples, showed acquisition of mutations over

time.

Conclusion: TP53 mutations are associated with poor survival in CLL.

TP53 mutations occur at a low incidence without 17p deletion and

appear to be associated with poor survival once they occur. While

the majority of cases with 17p deletion also have TP53 mutations,

the prognosis appears to be equally poor for patients 17p deletion

in the absence of TP53 mutations.

These findings need to be confirmed in prospective trials. The

mechanisms underlying the poor prognosis of patients with 17p

deletion without TP53 mutation are under investigation.