Chromosomal instability in chromosome band 12p13: multiple breaks leading to complex rearrangements including cytogenetically undetectable sub-clones

Abstract

During fluorescence in situ hybridization (FISH) analysis of metaphase cells from 70 patients with lymphoid and myeloid hematologic malignancies and chromosomal rearrangements involving band 12p13, we identified nine patients (four with lymphoid malignancies, four with myeloid malignancies and one with biphenotypic leukemia) who showed more complicated rearrangements than we had expected from conventional cytogenetic study. In six patients, multiple breaks occurred in small segments of 12p with subsequent translocations and insertions of these segments into other chromosomes, sometimes to unexpected regions. In three patients additional chromosome breaks resulted in a sub-clone which was cytogenetically indistinguishable from the main clone in each patient based on the cytogenetic analysis. These subtle molecular events were detected exclusively in a region covering TEL/ETV6 and KIP1/CDKN1B. Seven of nine had a previous history of chemo/radiotherapy; all the patients showed complex karyotypes, even though they were newly diagnosed with leukemia. Survival data were available in five patients, and all survived less than 6 months. These findings suggest that the 12p13 region, especially the above-mentioned region, is genetically unstable and fragile. It is likely that multiple chromosome breaks were induced through mutagens used in chemo/ radiotherapy, and are associated with a sub-group of patients with an extremely bad prognosis. Leukemia (2001) 15, 1193-1202.

Genetic evolution in colon cancer KM12 cells and metastatic derivates

“…Chromosome 12 is also frequently involved in translocations, and the short arm is often deleted. 35 We also observed frequent loss of chromosome 18q, which is in agreement with previous reports in primary colorectal tumors. 11,36 HCT116, DLD-1 and LoVo cell lines are classified as MSI tumors since they show few chromosomal abnormalities and MSI.…”

Molecular cytogenetic characterization of breakpoints in 19 patients with hematologic malignancies and 12p unbalanced translocations

“…Cases with unbalanced 12p translocations appear to be closely associated with complex karyotypes, and in most cases the breakpoints have been reported to be outside ETV6, as was true for all our patients [14,15]. SKY is an important tool to characterize the aberrations in these cases [23].…”

“…These deletions in some cases are different from the region reported in ETV6-CBFA2 positive ALL [12]. Unbalanced translocations involving ETV6 have rarely been described [13,14], and cases with breakpoints outside ETV6 appear to be strongly associated with complex karyotypes [14,15].…”

Disruption of ETV6 in intron 2 results in upregulatory and insertional events in childhood acute lymphoblastic leukaemia

“…Material from 7q was also inserted into the long arm of this der (9). The second copy of chromosome 12 had an interstitial deletion including part of ETV6.…”

“…2 Subsequently it has been shown that ETV6 is involved in a significant number of cases with visible cytogenetic abnormalities of 12p or loss of heterozygosity (LOH) in that region. [3][4][5][6][7][8][9] There is some evidence that the gene is more often involved when the 12p rearrangements are balanced rather than unbalanced, the latter often being associated with a complex karyotype. 10,11 The inherent instability of the ETV6 gene has been demonstrated in several different studies by the use of cosmid probes to its individual exons.…”