Genetic Pathways in t-MDS and t-AML, a Revised Model.

Jens Pedersen-Bjergaard, Debes H. Christiansen, Mette K. Andersen. Dept. Clinical Genetics, University Hospital Rigshospitalet, Copenhagen, Denmark. 140 unselected patients with t-MDS (n=90) or overt t-AML (n=50) were studied for chromosome aberrations, for mutations of 6 different genes and 69 patients were examined for methylation of the p15 promotor. Cytogenetically, 5q−/ −5: n=34; 7q−/ −7 but normal chromosomes 5: n=39; balanced translocations: n=23; normal karyotype: n=24; other abnormalities: n=20. Mutations of p53: n=34; AML1: n=22; FLT3: n=11; c-KIT: n=2; K- or N-RAS: n=14; BRAF: n=2; methylation of the p15 promotor: 55/69 cases.

Abnormalities of chromosomes 5 and 7 were significantly associated with t-MDS (p=0.001), whereas balanced translocations and a normal karyotype were significantly associated with overt t-AML, (p=0.0001 and p=0.006 respectively).

Mutations of p53 were significantly associated with 5q−/ −5 (p=0.001), with 17p−/−17 (p=0.0004), with a complex karyotype (p=0.001), and with MLL and AML1 amplifications. Mutations of AML1 were significantly associated with 7q−/−7 )(p=0.001) and with t-MDS progressing to t-AML (p=0.0001). Mutations of FLT3 were significantly associated with presentation as overt t-AML (p=0.0002), with a normal karyotype (p=0.004) and with previously radiotherapy only (p=0.03). RAS mutations were significantly associated with t-MDS progressing to overt t-AML (p=0.008) and borderline with a normal karyotype (p=0.07). Methylation of p15 was significantly associated with 7q−/−7 (p=0.0006).

Mutations of FLT3, RAS and c-KIT were mutually exclusive, and a synergism between AML1 and RAS mutations (22/5/14, p=0.046) and between p53 and AML1 mutations in patients with 7q−/−7 is suggested.

Based on these findings a revised model of the genetic pathways of t-MDS and t-AML (