Type of TP53 Mutations Affects Subclonal Configuration and Selection Pressure for Acquisition of Additional Hits in Contralateral Alleles

Somatic TP53 mutations are found in 10% of adult patients with MDS and de novo AML and in up to 20% of patients with therapy-related myeloid neoplasms. TP53 status is associated with complex karyotype (CK), aberrations of chromosome 5 and poor survival. Moreover, mutated TP53 (TP53MT) may be an indication for hematopoietic cell transplantation, but also predictive of relapse following the procedure, making this particular category of myeloid neoplasms (MN) a conundrum of clinical management. Unlike other tumor suppressor genes, missense (ms) mutations within the DNA-binding domain (DBD) are the most common genetic alterations in TP53 gene representing up to 80% of somatic hits, with involvement of canonical hotspots (R175H, Y220C, M237I, R248Q, R273H, R282W) in around 30% of cases. A loss-of-function (LOF) dominant-negative effect (DN) may explain the ability of TP53MT to interfere with wild type (WT) functions. Moreover, TP53 germ line (GL) mutations are responsible for Li-Fraumeni syndrome, and GL contamination may also exist in adult MN. Here we comprehensively characterize TP53MT MNs to better dissect the role of specific mutational configurations and identify the selective forces affecting outcomes in this poor prognostic MN category. A total of 764 TP53 mutations were found in 632 MN patients. Ms mutations were the most common (75%) followed by frameshift (11%), splice site (7%), nonsense (5%) and insertion/deletions (2%), with 20% of patients harboring more than 1 lesion. Topographical annotation revealed that ms mutations typically (98%) occurred within the DBD (residues 102-292) and only 2% occurred outside this region (vs. 28% in case of truncating mutations, p