Routes of Clonal Evolution Into Complex Karyotypes in Myelodysplastic Syndrome Patients with Del(5q)

A complex karyotype, detected in approximately 10%-15% of patients with myelodysplastic syndromes (MDS), is associated with a very short median survival and a high risk of transformation into AML. The most frequent chromosome aberration in complex karyotypes is a deletion of 5q (del(5q)). It is still unclear, how complex karyotypes develop. One possibility is via stepwise accumulation of chromosome aberrations according to the so-called Vogelstein model (Fearon ER, Vogelstein B, Cell 1990; 61:759–67). Another possibility is a one-step catastrophic event called chromothripsis that seems to be associated with TP53 inactivation (Rausch T et al., Cell 2012;148:59–71). We recently described that leukemic progression in low-grade MDS with isolated del(5q) is associated with clonal evolution (Tehranchi R et al., N Engl J Med 2010;363:1025–37, Göhring G et al., Ann Hematol 2010; 89:365–74) and identified TP53 mutations and excessive telomere shortening as driving forces for clonal evolution and leukemic progression in MDS with del(5q) (Jädersten M et al., J Clin Oncol 2011; 29:1971–9, Göhring G et al., Leukemia 2012; 26:356–8). Yet, the modes of clonal evolution and the mechanisms responsible for the induction of chromosomal instability in MDS with isolated del(5q) remain largely unclear.

Among 1645 patients with MDS and del(5q) investigated cytogenetically in our institution, 157 patients (9.5%) acquired additional aberrations and thus underwent clonal evolution. We reviewed the cytogenetic follow-up data of the 157 patients and carefully evaluated all additional aberrations, particularly those of complex karyotypes, which are defined as at least 3 aberrations, i.e. del(5q) and two additional chromosome abnormalities. Moreover, we investigated the clonal heterogeneity and the presence of independent clones, defined as clones that do not contain a del(5q).

During follow-up, 76 of 157 patients (48%) acquired two or more aberrations, thus evolving into a complex karyotype. Eighty-nine of 157 patients (57%) underwent a stepwise accumulation of additional aberrations (range 1–8, median: 1), while 38 patients (24%) developed highly complex clones (no of aberrations: 3–35, median: 7.5) at one time point during follow-up. This “catastrophic” route led to the development of a complex karyotype significantly more frequently than the stepwise accumulation of chromosome aberrations (38 of 38 cases compared to 38 of 89 patients; p<0.00001). In 12 cases, the complex clones were preceded by a clone containing one additional aberration, e.g. −7, del(12p) or del(17p). Independent clones that did not contain a del(5q) were detected in 43 of 157 patients (27%). A few aberrations were seen significantly more frequently in complex karyotypes than as single additional aberrations, e.g. −7/del(7q) (p=0.0001), del(9p) (p=0.01), +11/add(11q) (p=0.0003), −11/del(11q) (p=0.03), −16/del(16q) (p=0.0006), −17/del(17p) (p=0.00001), and +22/add(22q) (p=0.006). Trisomy 8 (p=0.008) and trisomy 21 (p=0.00001) occurred mostly in del(5q) clones with one additional aberration. Trisomy 8 was the most frequent aberration in independent clones.

Although MDS with del(5q) is assumed to be a genetically stable hematologic neoplasm, clonal evolution, even into complex karyotypes, occurs in a significant proportion of patients. There are two routes of clonal evolution. One route of stepwise acquisition of additional aberrations resulted in clonal selection of clones that had accumulated mostly only one or two additional aberrations. In contrast, the other route led to an immediate development of highly complex clones. In some of these cases, this catastrophic event was preceded by the acquisition of one aberration, repeatedly by loss of 12p or loss of 17p harboring the ETV6/TEL and TP53 genes, respectively. These data provide further evidence that the inactivation of TP53 seems to play an important role in clonal evolution and leukemic progression.

No relevant conflicts of interest to declare.