Does TP53 guard ALL genomes?

The genomic landscape of ALL is characterized by primary chromosomal abnormalities and a wide range of secondary deletions and mutations, which target key pathways implicated in leukemogenesis. There is a strong correlation between specific primary chromosomal abnormalities and the spectrum of cooperating mutations (see figure). Despite this extensive genetic heterogeneity, TP53 mutations have not previously been reported to occur at a high frequency. This is in contrast to other cancers, especially solid tumors, where TP53 is widely reported as the most frequently altered gene. Using next-generation sequencing, researchers at the Munich Leukemia Laboratory screened a large cohort of ALL patients for evidence of TP53 mutations. Overall, they observed TP53 mutations in 16% of patients; a frequency much higher than expected. The use of amplicon deepsequencing enabled the detection of low level clones, which may explain the difference because the mutational load in one-third of patients was,30%. The architecture of TP53 disruption in ALL appears to be similar to other cancers. The vast majority of mutations detected occurred in known mutational hotspots, and there was a strong correlation with deletion of the second allele to generate a so-called double hit. Although Stengel et al screened 625 patients, the cohort was not typical of ALL as a whole. Children were significantly underrepresented, and the cohort included patients with mature B-cell ALL (Burkitt leukemia), which represents a distinct clinical entity. Examination of the data revealed that TP53 mutations were not distributed evenly across ALL subtypes but associated with certain primary abnormalities (see figure). In particular, 3 genetic subtypes had a high frequency of TP53 mutations: low hypodiploidy (92%), MYC translocations (63%), and complex karyotype (23%). Moreover, two-thirds of all TP53 mutations occurred within these 3 genetic subtypes. The association between low hypodiploidy (30-39 chromosomes) and TP53 mutations has been described before, but because low hypodiploidy is rare, confirmation of this finding was important. Chromosome 17 is usually one of the chromosomes lost in low hypodiploidy; therefore, the vast majority of these patients would have a TP53 double hit. Some children with low hypodiploidy were found to harbor germ-line rather than somatic TP53 mutations. However, studies of low hypodiploidy in adults, where it is more prevalent, have not revealed a similar association. Nonetheless, this intriguing observation coupled with the finding, in this study, that low hypodiploid cases have a high TP53 mutational load does question the order with which these abnormalities are acquired. Evidence from relapsed childhoodALL clearly indicates that TP53 mutations and deletions can represent secondary abnormalities that are acquired at relapse. However, can they also represent primary events that are capable of inducing low hypodiploidy? The high frequency of TP53 mutations among patients with a MYC translocation (65%) is a novel observation. TP53 mutations are known to occur in 30% to 40% of patients with Burkitt lymphoma, which is broadly consistent with the frequency of TP53 mutations in other lymphoid malignancies. Functional studies have demonstrated that p53 represses c-myc transcription. Therefore, loss of p53 function could act to accelerate the oncogenic effect of MYC overexpression. Complex karyotype is not well defined or widely used in ALL classification but does occur in 5% of adult ALL. Loss of chromosome arm 17p has been reported in 15% cases with a complex karyotype. Therefore, the observation that 23% of complex karyotypes harbor a TP53 mutation provides the first good evidence of a recurrent lesion within this subtype of ALL. The frequencies of all 3 TP53-enriched subtypes are known to increase with age. Therefore, the higher frequency of TP53 mutations in this cohort, compared with previous studies, is partly explained by the fact that older patients are over-represented. TP53 mutations were much less frequent among Overview of key cooperating mutations in relation to distinct genetic subtypes of B-cell precursor ALL.