The enigma of monosomy 7

Abstract

Since a report of some 50 years ago describing refractory anemia associated with group C monosomy, monosomy 7 (-7) and interstitial deletions of chromosome 7 (del(7q)) have been established as one of the most frequent chromosomal aberrations found in essentially all types of myeloid tumors regardless of patient age and disease etiology. In the last century, researchers sought recessive myeloid tumor-suppressor genes by attempting to determine commonly deleted regions (CDRs) in del(7q) patients. However, these efforts were not successful. Today, tumor suppressors located in 7q are believed to act in a haploinsufficient fashion, and powerful new technologies such as microarray comparative genomic hybridization and high-throughput sequencing allow comprehensive searches throughout the genes encoded on 7q. Among those proposed as promising candidates, 4 have been validated by gene targeting in mouse models. (sterile α motif domain 9) and (SAMD9-like) encode related endosomal proteins, mutations of which cause hereditary diseases with strong propensity to infantile myelodysplastic syndrome (MDS) harboring monosomy 7. Because MDS develops in -deficient mice over their lifetime,/ are likely responsible for sporadic MDS with -7/del(7q) as the sole anomaly. (enhancer of zeste homolog 2) and (mixed lineage leukemia 3) encode histone-modifying enzymes; loss-of-function mutations of these are detected in some myeloid tumors at high frequencies. In contrast to /, loss of or likely contributes to myeloid tumorigenesis in cooperation with additional specific gene alterations such as of or genes involved in the p53/Ras pathway, respectively. Distinctive roles with different significance of the loss of multiple responsible genes render the complex nature of myeloid tumors carrying -7/del(7q).

Somatic mosaic monosomy 7 and UPD7q in a child with MIRAGE syndrome caused by a novel SAMD9 mutation

“…In some cases, uniparenteral disomy (UPD) as a true genetic reversion in SAMD9/9L genes with reduplication of the wild‐type allele was observed. This mechanism was noted in patients with transient monosomy 7 …”

“…The disease‐associated gene SAMD9 is located on 7q21.2 and encodes a sterile alpha motif domain‐containing protein 9 (SAMD9), which influences the structure and functionality of the endosome system causing growth restriction . Loss of the long arm of chromosome 7 or of the whole chromosome 7 (‐7/7q‐) is associated with myeloid‐lineage hematopoietic malignancies, that is, MDS and myeloid leukemia . The complex dynamic somatic changes in SAMD9 were described to be important for the disease phenotype and survival of patients with MIRAGE syndrome.…”

Puzzling pieces of chromosome 7 loss or deletion

“…Targeted sequencing of candidate myeloid tumor suppressor genes located within a 2.5-Mb 7q22 CDR delineated by Le Beau et al and recent comprehensive genomic analyses of clinical specimens implicate a haploinsufficient role of 7q22 deletions in leukemogenesis. 1,3 Consistent with the proposed mechanism, biallelic inactivation of any 7q gene is rare in MDS patients with 27/del(7q), and haploinsufficiency seems to be the pathogenic mechanism. Given the number of genes involved and also various biallelic or monoallelic mutations, as also reviewed in Inaba et al, the question remains if the pathophysiology is more complex than just haploinsufficiency for 1 or multiple genes.…”

“…This work emphasizes that altered expression of genes involving lipid metabolism are important during late red cell maturation. 1 The mature red cell is unique. Although highly specialized for gas transport, it is much more than an inert receptacle for hemoglobin, with many surprisingly sophisticated properties.…”

“…1 Large hemizygous deletions that may be drivers of cancer are found in various types of tumors. 27 and del(7q) are recurrent cytogenetic abnormalities that are strongly associated with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with adverse outcome (eg, in AML with chromosome 3q26 abnormalities and aberrant EVI1 expression).…”