Karyotypic and ras gene mutational analysis in idiopathic myelofibrosis

Abstract

Karyotypic analysis was performed in a total of 69 patients with well-characterized idiopathic myelofibrosis. Karyotypic abnormalities were detected in 46% of cases examined during the chronic phase (29/63); with three abnormalities, del(13q), del(20q) and partial trisomy 1q, accounting for 75% of all abnormalities at diagnosis. The absence of del(5q), trisomy 8 and 21, as well as the rarity of monosomy 7, contrasts with pooled published data and may reflect our exclusion of closely related disorders, in particular MDS with fibrosis. Chromosomal aberrations increased to approximately 90% (8/9) in patients analysed during acute transformation. Mutational activation of codons 12, 13 and 61 of N-, Ha- and Ki-ras genes were assessed by polymerase chain reaction and hybridization with synthetic non-radioactive digoxigenin-labelled probes. Three mutations were detected in samples of peripheral blood DNA taken from 50 patients during the chronic phase of their disease: one N12 Asp (GGT-->GAT) and two N12 Ser (GGT-->AGT) mutations. The results from this study indicate that karyotypic abnormalities are present in at least 29% of cases at diagnosis and that del(13q), del(20q) and partial trisomy 1q are the most frequent findings. Ras mutations were relatively infrequent (6%) and appeared restricted to the N-ras gene. Karyotypic analysis at diagnosis was found to be of prognostic significance.

Pathogenetic insight and prognostic information from standard and molecular cytogenetic studies in the BCR-ABL-negative myeloproliferative neoplasms (MPNs)

“…21,22 PMF has the highest aberration rate of the Philadelphianegative MPNs, with a third having an abnormal karyotype at diagnosis. 23,24 It has been suggested, however, that many of these changes may represent secondary subclones resultant upon the genetic instability of the original clone. 25 Over the last 15 years the publication of three large studies, involving a total of 256 well characterized patients, has helped to clarify the cytogenetic profile of PMF cases.…”

Cytogenetic abnormalities and their prognostic significance in idiopathic myelofibrosis: a study of 106 cases

“…The disease is recognized as a clonal haemopoietic stem cell disorder in which the fibroblast proliferation is a secondary, or reactive, phenomenon (for review see Reilly, 1994). Cytogenetic data in idiopathic myelofibrosis is both sparse and inconclusive when compared to other chronic myeloproliferative disorders, with fewer than 170 abnormal cases having been reported (Mertens et al, 1991;Reilly et al, 1994;Dupriez et al, 1996). The proportion of cases with abnormal karyotypes, for example, varies from 30% to 75% (Besa et al, 1982;Borgström et al, 1984;Demory et al, 1988;Miller et al, 1985;Reilly et al, 1994;Smadja et al, 1987;Whang-Peng et al, 1978;Dupriez et al, 1996), with widely differing frequencies of specific abnormalities.…”

“…Reports of the prognostic significance of karyotype in idiopathic myelofibrosis are conflicting. A shorter survival has been associated with chromosomal abnormalities by some groups (Demory et al, 1988;Reilly et al, 1994;Dupriez et al, 1996), but not by others (Miller et al, 1985;Whang-Peng et al, 1978). Silverstein (1983), and Dupriez et al (1996) identified hepatomegaly as a significant adverse prognostic factor, in contrast to Rupoli et al (1994) and Varki et al (1983), whereas the importance of age (Iványi et al, 1994;Demory et al, 1988), sex (Dupriez et al, 1996;Visani et al, 1990), leucocyte (Visani et al, 1990;Varki et al, 1983) and platelet counts (Visani et al, 1990;Iványi et al, 1994;Dupriez et al, 1996) remain unclear.…”

Long-term follow-up of a patient with idiopathic myelofibrosis associated with chromosome 11 and 13 abnormalities

“…One third of cases of IMF have abnormal karyotypes at diagnosis [6][7][8][9], cytogenetic abnormalities, typically complex changes, increase to approximately 90% following acute transformation [6]. Herein we report a case of long-lasting IMF with myeloid metaplasia (MMM) associated with deletion of the long arms of chromosomes 11 and 13 that was terminated in acute micromegakaryocytic leukemia associated with a deletion in the long arm of chromosome 11.…”