Myelodysplastic neoplasms with unbalanced whole-arm translocation der(5;19)(p10;q10): association with double-hit TP53 mutations.

Abstract

Unbalanced whole-arm translocation der(5;19)(p10;q10) is a rare but recurrent cytogenetic aberration noted in patients with myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). Eight cases of MDS/AML with der(5;19)(p10;q10) have been previously reported. Here, we describe three additional cases of MDS with der(5;19)(p10;q10) at our institution, in which we identified myeloid malignancy-associated mutations using next-generation sequencing. All patients had two TP53 mutations, each with >10% variant allele frequency, suggesting double-hit TP53 mutations. Double-hit TP53 mutations are only found in approximately 2% of patients with MDS, and may be involved in the development of the cytogenetic abnormalities der(5;19)(p10;q10), +19, and complex karyotype, often associated with exposure to alkylating agents. We propose der(5;19)(p10;q10) as a potential cytogenetic indicator of biallelic TP53 inactivation through double-hit mutations. These data suggest that MDS with der(5;19)(p10;q10) is clinically characterized by aberrant CD7 expression in blasts, a tendency for leukemic transformation, resistance to anti-leukemia therapies, and poor survival outcomes. We also noted that cases of der(5;19)(p10;q10) MDS/AML have been reported exclusively by Japanese institutions. Geographical and ethnic factors may contribute to oncogenesis, which can be triggered by exposure to alkylating agents.