Genomic Rearrangements Associated with -5/del(5q) and -7/del(7q) in Myeloid Leukemias.
Authors: Tennant Thelma R. , Huo Dezheng , Davis Elizabeth M. , Larson Richard A. , Le Beau Michelle M. 
Published: April 2020

An important aspect of leukemia biology is the elucidation of the spectrum of chromosomal abnormalities and molecular mutations that cooperate in the pathways leading to leukemogenesis. To identify those chromosomal abnormalities that are associated with drug resistance and a poor outcome, we analyzed a cohort of 3,438 pts (primary MDS, 1155; AML de novo, 1832; and therapy-related MDS/t-AML, 451) ascertained between 1970–2007 at the University of Chicago. 866 (25%) had either -5/del(5q) (276, 8%), -7/del(7q) (313, 9%), or both (277, 8%). The incidence of loss of 5q, 7q, or both was 19% in primary MDS, 20% in AML de novo, and 61% in t-MDS/t-AML. Of note, 71% of the karyotypic abnormalities in these pts led to loss of chromosomal material. Balanced rearrangements accounted for 10% of the additional abnormalities, and the remaining 19% led to a gain of material. Abnormalities of chr 5 were associated with karyotypic instability. Pts with -5/del(5q) had an average of 7 karyotypic abnormalities, whereas pts with -7/del(7q) had an average of 3 abnormalities. Pts with both -5/del(5q) and -7/del(7q) had an average of 10 abnormalities. Only 13% of pts with an abnormality of chr 5 had -5/del(5q) as their sole karyotypic abnormality, whereas 41% of pts with an abnormality of chr 7 had -7/del(7q) as their sole karyotypic abnormality. In addition to increased complexity of the karyotype, abnormalities of chr 5 were associated with specific recurring abnormalities: -17/loss of 17p, 39%;-3/loss of 3p or 3q, 30%; -18/loss of 18q, 24%; -12/loss of 12p, 24%; +8, 23%; -13/del(13q), 18%; -20/del(20q), 18% (values refer to the percentage of each abnormality among pts with 5q loss). The relative frequency of these abnormalities in pts with -7/del(7q) ranged from 4–8%, and no specific abnormality was observed in more than 10% of cases with loss of 7q. These observations extend previous studies which demonstrated a high incidence of abnormalities of 17p, TP53 mutations, and complex karyotypes in t-MDS/t-AML characterized by abnormalities of chr 5 (Pedersen-Bjergaard J. NEJM152:1491, 2005). Our observations, together with those in the literature, suggest that different molecular pathways are involved in the pathogenesis of primary MDS/AML and t-MDS/t-AML associated with abnormalities of chr 5 or 7. The subgroup of pts with abnormalities of chr 7 without chr 5 abnormalities typically has mutations of the RAS pathway (KRAS1, NRAS, NF1, PTPN11), methylation of the promoter of CDKN2B/p15, and a poor prognosis. In contrast, pts with loss of 5q, with or without abnormalities of chr 7, are characterized by complex karyotypes, TP53 mutations and -3/loss of 3p or 3q, +8, -12/loss of 12p, -13/del(13q), -17/loss of 17p, -18/loss of 18q, and -20/del(20q), and a poor prognosis. Emerging technologies, such as high throughput genomic analysis, may facilitate further delineation of the genetic pathways leading to myeloid diseases.

Recurring Abnormalities in Patients with Abnormalities of Chromosomes 5 and/or 7 Subgroup -3/loss of 3p or 3q +8/+8q -12/loss of 12p -13/del(13q) -17/loss of 17p -18/loss of 18q -20/del(20q) -5/del(5q) (276 pts) 62 (22%) 55 (20%) 30 (11%) 40 (14%) 101 (36%) 59 (21%) 35 (13%) -7/del(7q) (313 pts) 16(5%) 25 (8%) 12 (4%) 11 (3.5%) 15 (5%) 13 (4%) 22 (7%) -5/del(5q) & -7/del(7q) (277 pts) 106 (38%) 71 (26%) 103 (37%) 59 (21%) 116 (42%) 72 (26%) 67 (24%) Total (866 pts) 184 (21%) 151 (17%) 145 (17%) 110 (13%) 232 (27%) 144 (17%) 124 (14%)