TP53 Mutations Are Present In 15.7% Of ALL, Are Especially Frequent In ALL With MYC-Rearrangement and In ALL With Low Hypodiploid Chromosome Status and Are Associated With Poor Prognosis

TP53 is the most frequently mutated gene in cancer. The prognostic impact of TP53 mutations has been demonstrated in CLL, AML, and MDS. However, data on the frequency and prognostic impact of TP53 mutations in ALL is scarce.

We aimed at determining the TP53 mutation frequency, the association with cytogenetic subgroups and age, as well as the impact on survival.

In total, a large cohort of 625 patients with ALL was analyzed for TP53 mutations by deep-sequencing allowing to simultaneously quantify the mutation load. In all patients chromosome banding analyses have been performed. In addition, in 341 patients the copy number state of TP53 was determined by FISH.

The cohort comprised 353 male and 272 female patients, median age was 49.5 years (range: 0.1-91.4 years). The cohort included the following groups: normal karyotype (n=101; 16.2%), t(9;22)(q34;q11) (n=162; 25.9%), MLL-translocations (n=37; 5.9%), MYC-translocations (n=40; 6.4%), t(12;21)(p13;q22) (n=15; 2.4%), low hypodiploidy (<40 chromosomes) (n=24; 3.8%), high hyperdiploidy (51-68 chromosomes) (n=38; 6.1%), complex karyotype (n=69; 11.0%), other cytogenetic abnormalities (n=139; 22.2%). Detailed data on immunophenotyping was available for 408 patients (T-lineage: n=105; B-lineage: n=267, Burkitt: n=36). In the total cohort, the frequency of TP53 mutations was 15.7% (98/625). TP53 mutations were most frequent in ALL with low hypodiploidy (22/24; 91.7%) and MYC-translocated ALL (25/40; 62.5%) and also quite frequent in ALL with complex karyotype (16/69; 23.2%), ALL with normal karyotype (13/101; 17.4%), and in MLL-translocated ALL (6/37; 16.2%). TP53 mutations were rare in t(9;22)(q34;q11) (7/162; 4.3%), high hyperdiploidy (3/38; 6.1%), and other cytogenetic abnormalities (6/139; 4.3%) and absent in ALL with t(12;21)(p13;q22) (0/15; 0%). Furthermore, TP53 mutations were less frequent in T-lineage ALL (8/105; 7.6%) as compared to B-lineage and Burkitt ALL (41/267; 15.4% and 21/36; 58.3%). TP53 mutation frequency increased with age (TP53mut <60 years vs ≥ 60 years 10.8% (45/417) vs 25.5% (53/208), p<0.0001). 25/64 (39.1%) TP53 mutated patients with available TP53 deletion status showed a deletion of the second allele, while in 17/319 (5.3%) TP53wt patients with available TP53 deletion status a TP53 deletion was detected (p<0.001). 11/98 (11.2%) TP53 mutated patients showed two TP53 mutations. Median overall survival (OS) was significantly shorter in TP53mut vs TP53wt patients (18.8 months vs 75.5 months, p<0.0001). OS at 4 years in patients <60 years was 80.1% in TP53wt compared to 56.8% in TP53mut (p=0.012) and 59.3% vs 22.6% in patients ≥ 60 years (p<0.0001). Also within the cytogenetic categories MYC-translocated and complex karyotype TP53 mutations had a significant adverse impact on overall survival. Further, patients with either two TP53 mutations or one TP53 mutation and an accompanying TP53 deletion had a significantly shorter OS as compared to patients with only one altered TP53 allele (median OS 11.5 vs 63.1 months, p=0.009). In contrast, OS in patients with a TP53 deletion without a TP53 mutation did not differ from patients without TP53 alterations. In addition, the TP53 mutation load was investigated by next-generation sequencing and varied between 2% and 98% (median: 41%). Within the subset of patients with TP53 mutation, patients with a mutation load >20% showed a significantly shorter OS as compared to patients with a lower mutation load (median OS 11.5 months vs not reached, p=0.003). Interestingly, OS in patients with a TP53 mutation load ≤ 20% did not differ from TP53wt patients. In multivariate Cox regression analysis including parameters significantly associated with shorter OS in univariate analysis the following factors retained an independent adverse impact on OS: age (<60 years vs ≥ 60 years, HR=2.2; p=0.01), MLL-translocation (HR=2.8; p=0.03), and TP53mut >20% (HR: 3.1, p=0.01).

1. TP53 is mutated in 15.7% of ALL with the highest frequency in ALL with low hypodiploidy (91.7%) and MYC-translocated ALL (62.5%). 2. The TP53 mutation frequency increases with age. 3. TP53 mutations are associated with short survival independent of age and specific cytogenetic alterations. 4. TP53 mutations had a significant impact on OS only if the mutation load was >20%.

Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Weissmann:MLL Munich Leukemia Laboratory: Employment. Kuznia:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.