dic(5;17): A recurring abnormality in malignant myeloid disorders associated with mutations ofTP53

Abstract

We have identified three unbalanced translocations involving chromosomes 5 and 17, der(5)t(5;17), der(17)t(5;17), and dic(5;17), in the malignant cells from 17 patients with myeloid neoplasms. Six patients had a primary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) de novo; ten patients had therapy‐related MDS and/or AML (t‐MDS/t‐AML), and one patient had chronic myelogenous leukemia in myeloid blast phase. Two of the six patients with MDS or AML de novo had extensive exposure to industrial solvents, and one patient had Seckel syndrome. The primary diagnoses for the ten patients with t‐MDS/t‐AML were breast carcinoma and Hodgkin's disease in two patients each, and non‐Hodgkin's lymphoma, multiple myeloma, chronic lymphocytic leukemia, ovarian carcinoma, thyroid carcinoma, and rhabdomyosarcoma in one patient each. Four patients had received both prior chemotherapy and radiotherapy, four others received prior chemotherapy only, and the remaining two patients only prior radiotherapy. Fluorescence in situ hybridization of centromere‐specific probes for chromosomes 5 and 17 revealed that a dicentric rearrangement was the most common (13/16 patients examined). The genetic consequences of these chromosomal rearrangements are partial monosomy for 5q and 17p. Two of six patients examined had point mutations in TP53, suggesting that loss of function of TP53 in addition to loss of a tumor suppressor gene on 5q may be involved in the pathogenesis of the malignant disease in some of these patients. Genes Chromosomes Cancer 20:282–291, 1997. © 1997 Wiley‐Liss, Inc.

Increased frequency of dicentric chromosomes in therapy-related MDS and AML compared to de novo disease is significantly related to previous treatment with alkylating agents and suggests a specific susceptibility to chromosome breakage at the centromere

“…16 In this model deletions or loss of the short arm of chromosome 17 or loss of a whole chromosome 17 were secondary cytogenetic events. A dic(5p;17q) has previously been closely related to mutations of the p53 gene located at 17p13, and to a complex karyotype, 8 and our results support the latter association.…”

“…In previous studies of t-MDS and t-AML dicentric chromosomes have often been observed, and specific dicentric chromosomes such as the dic(1;7), 6,7 the dic(5;17), 8 and the dic(7;12) 9 have been discussed in separate reports. However, the occurrence of dicentric chromosomes has not been studied in general in a large series of patients with t-MDS and t-AML.…”

The Role of Dicentric Chromosome Formation and Secondary Centromere Deletion in the Evolution of Myeloid Malignancy

“…Dicentric chromosomes which have been identified in hematological malignancies include the recurrent dic(17;20) [36, 37] and dic(5;17) [38] in MDS and AML and the dic(9;20) in acute lymphoblastic leukemia [39], as well as a range of other abnormalities [3, 39–41]. These are usually interpreted as unbalanced reciprocal translocations (see Figure 1), with breakpoints often described at or near the centromere [40, 42, 43].…”

Alterations of DNA damage-response genes ATM and ATR in pyothorax-associated lymphoma

“…19,20 Hematological malignancies may occur in patients with Seckel syndrome, in whom not only aberrant spliced transcript but also wild-type transcript of ATR are expressed, indicating that mutations of this gene may be involved in the pathogenesis of hematological malignancies in a dominant negative fashion. 23,35 Previous studies have also demonstrated that mice with heterozygous defects in ATR exhibit increased incidence of lymphoma. 19 In the present study, heterozygous frameshift and point mutations affecting the PI3K domain of ATR, 33 thus indicative of the loss-offunction mutation, were detected in two PAL lines.…”