Unbalanced Translocation t(5;17) Resulting In a TP53 Loss As Recurrent Aberration In Myelodysplastic Syndrome With Complex Karyotype

A complex karyotype, detected in approximately 10%-15% of patients with myelodysplastic syndrome (MDS), is associated with a very short median survival and a high risk of transformation into AML. The most frequent chromosome aberrations in complex karyotypes are deletion of 5q (del(5q)) and deletion of 17p (del(17p)) harboring the tumor suppressor gene TP53. It is still unclear, how complex karyotypes develop.

We have identified an unbalanced translocation der(5)t(5;17)(q11∼q13;q11∼q13) in 199 patients with MDS or secondary AML after MDS. The cohort consists of 111 male (56 %) and 88 (44 %) female patients between 4 and 91 years of age (median age 68 years).

In order to better understand the underlying pathomechanism of this aberration, we have investigated these cases in greater detail. For all patients, we performed cytogenetic banding analysis, fluorescence in-situ hybridization (FISH) and, in about one third, multicolor-FISH.

In all patients, a complex aberrant karyotype with a median of 7 aberrations was observed, indicating high chromosomal instability. In 30 patients, clonal evolution was identified. To identify the breakpoints in 5q and 17q more precisely, array-CGH was performed in 7 patients. The breakpoints on 5q and 17p were located between the centromere of chromosome 5 and 5p15 and between the centromere of chromosome 17 and 17q22, respectively. The breakpoints were in gene-poor regions, suggesting that no fusion genes would result from these rearrangements. Notably, the breakpoints were all very close to the centromeric region and heterochromatin. It is known that an altered methylation of heterochromatic regions plays an important role in tumor development. Therefore, alterations of DNA methylation or histone modifications may be involved in the generation of the unbalanced translocation t(5;17).

Using whole exome sequencing, we sought to define the mutational spectrum of complex karyotypes with t(5;17). In one patient we were able to analyse bone marrow cells from different time points: complex karyotype at diagnosis, complete remission and relapse with complex karyotype again. As possible candidate genes for driver mutations we identified mutations in the genes NF1, ETV6 (TEL) and KMT2C (MLL3). Of note, in this patient the allele frequencies of mutations affecting NF1 and KMT2C (MLL3) increased during the course of the disease, whereas the ETV6 (TEL) mutation found at diagnosis was lost at relapse indicating clonal evolution. Especially the identification of a mutation in NF1, a negative regulator of the RAS pathway, is of great significance. NF1 is encoded on 17q11.2. A possible underlying mechanism could be a downregulation of NF1 by a mutation of one allele and by a deletion evolved from the unbalanced translocation t(5;17) of the second allele. These data provide further evidence that the inactivation of NF1 seems to play an important role in clonal evolution and leukemic progression.