The Incidence of TP53 Mutations Is Low in Leukemia Overall but High in the Subgroups with Complex Aberrant Karyotypes: A Study on 309 Cases.
Authors: Dicker Frank , Herholz Hannes , Kern Wolfgang , Haferlach Torsten , Schnittger Susanne , Schoch Claudia 
Published: April 2020

TP53 is the key tumor suppressor that regulates the response of the cell to DNA damage and various types of cellular stress. As a result TP53 activates signaling pathways for the induction of cell cycle arrest or apoptosis, thereby preventing the transmission of chromosomal aberrations and mutations to daughter cells. The incidence of TP53 aberrations in solid tumors like colorectal cancer is often high with 50% of patients being affected. At the same time a complex pattern of cytogenetic abnormalities is observed. However, the incidence of TP53 mutations is overall low in leukemia amounting to about 10% of patients. Oftentimes, these cases are associated with poor overall survival. To characterize TP53 aberrations in different leukemia entities, i.e. AML and CLL, in more detail, we analyzed unselected patient populations with a combination of chromosomal banding analysis and mutation screening of the TP53 gene (exons 3–9, amino acids 26-331) by denaturating high performance liquid chromatography (DHPLC) in conjunction with direct sequencing. In both disease entities, AML (n = 149) and CLL (n = 160), a comparable fraction of patients with TP53 mutations was detected with 13.4% (n = 20) and 9% (n = 14), respectively. A highly significant correlation of TP53 mutations and complex aberrant karyotypes was found in comparison to other cytogenetic subclasses in both leukemia entities (p &lt; 0.001). Complex aberrant karyotypes were defined by the presence of 3 and more clonal abnormalities indicating an underlying mechanism for genetic instability. Of the 20 complex aberrant karyotypes in AML 17 (85%) were TP53-mutated while 10 of 22 complex aberrant CLL cases (46%) were affected. In CLL with complex aberrant karyotype there was a trend towards a significant association of a higher median age with TP53 mutations (74 y vs 69 y, p = 0.077, t-test). Comparable to other tumor types like colon cancer we find a prevalence of missense over nonsense/frameshift mutations of TP53 in AML (80%) and in CLL (86%) comprising a higher frequency of GC to AT transitions with 70% and 64%, respectively. Most TP53 mutations are selected for impaired DNA-binding and, therefore, impaired transactivation of target genes. Consistent with this in our cohort of AML samples 15/16 missense mutations were located in the DNA-binding domain of TP53 (amino acids 101–292) and all 13 missense mutations in CLL were located in this region. The location of the mutation in the different exons of TP53 was not significantly different between AML and CLL. However, there was trend towards a clustering of TP53 mutations in exon 8 (between amino acids 273 and 290) in CLL samples with 50% of mutations (n = 7) located in this region compared to only 30% (n = 6) of AML TP53 mutations in exon 8. In conclusion, we find 1.) a low overall incidence of TP53 mutations in CLL and AML but 2.) a high incidence in cases with complex aberrant karyotypes and 3.) a high incidence of TP53 missense mutations (&gt; 80%), which are almost exclusively located in the DNA-binding domain of TP53. We hypothesize that TP53 mutations allow for genetic instability and therefore for the accumulation of mutations in leukemic cells resulting in the high incidence of these mutations in complex aberrant karyotypes. In this scenario mutant TP53 might not only play a dominant negative role, but might even act as an oncogene with different mutations conferring different phenotypes to the tumor cells.