Comparison of TP53 mutations in myelodysplasia and acute leukemia suggests divergent roles in initiation and progression

Abstract

TP53 mutation predicts adverse prognosis in many cancers, including myeloid neoplasms, but the mechanisms by which specific mutations affect disease biology, and whether they differ between disease categories, remain unknown. We analyzed TP53 mutations in 4 myeloid neoplasm subtypes (myelodysplastic syndrome [MDS], acute myeloid leukemia [AML], AML with myelodysplasia-related changes [AML-MRC], and therapy-related AML), and identified differences in mutation types, spectrum, and hot spots between disease categories and in comparison to solid tumors. Missense mutations in the DNA-binding domain were most common across all categories, whereas inactivating mutations and mutations outside the DNA binding domain were more common in AML-MRC than in MDS. TP53 mutations in MDS were more likely to retain transcriptional activity, and comutation profiles were distinct between disease categories and mutation types. Our findings suggest that mutated TP53 contributes to initiation and progression of neoplasia via distinct mechanisms, and support the utility of specific identification of TP53 mutations in myeloid malignancies.