Monosomy 7 Of Bone Marrow

A number sign (#) is used with this entry because loss of chromosome 7 or deletion of genes on chromosome 7q are associated with development of myelodysplastic syndrome and acute myelogenous leukemia (AML). One putative candidate gene in this region is EZH2 (601573).

Description

Monosomy 7 or partial deletion of the long arm of chromosome 7 (7q-) is a frequent cytogenetic finding in the bone marrow of patients with myelodysplasia (MDS) and acute myelogenous leukemia (AML). Furthermore, monosomy 7 or 7q- is the most frequent abnormality of karyotype in cases of AML that occur after cytotoxic cancer therapy or occupational exposure to mutagens. The age distribution of de novo cases shows peaks in the first and fifth decades. Monosomy 7 is found in about 5% of de novo and 40% of secondary cases of AML. These findings suggest that loss of certain genes at this region is an important event in the development of myelodysplasia (summary by Shannon et al., 1989).

Clinical Features

Childhood bone marrow monosomy 7 has been observed in 2 or more sibs at least 7 times, according to Shannon et al. (1989). The segment that is deleted in common in these cases is 7q22-q34. Shannon et al. (1989) studied 3 families, each with 2 cases with bone marrow monosomy 7. The first family was ascertained through a 6-year-old girl with AML and bone marrow monosomy 7. Her 5-year-old brother, who shared HLA antigens, was found during evaluation for donation of bone marrow to have mild thrombocytopenia, erythrocyte macrocytosis, and a minor subpopulation of bone marrow cells with monosomy 7. He went on to develop AML. The second family had 2 sisters, aged 16 and 17 years, with myelodysplasia and monosomy 7. The third family, like the first, was ascertained through a child with AML and monosomy 7 whose brother was found to have bone marrow monosomy 7 when he was evaluated as a possible transplant donor.

Gilchrist et al. (1990) described 2 brothers, aged 3 and 5 years, with myelodysplasia and leukemia syndrome associated with monosomy 7. Since bone marrow transplantation is the only effective treatment of MLSM7, the familial occurrence should be kept in mind when searching for a donor.

Kwong et al. (2000) described a family with 3 sibs affected by AML in whom monosomy 7 was demonstrated. The family showed several unusual features, including the late onset of AML (34 and 37 years of age in 2 of the sibs) and the presence of an antecedent myelodysplastic phase before leukemia developed. By fluorescence in situ hybridization, the monosomy 7 clone was shown to be capable of partial maturation, which was consistent with the biologic behavior of myelodysplasia. They pointed to the earlier report of Mitelman and Heim (1992), and the reports of familial cases by Larsen and Schimke (1976), Chitambar et al. (1983), Carroll et al. (1985), and Paul et al. (1987), among others.

Minelli et al. (2001) described 2 sisters with a myelodysplastic syndrome associated with partial monosomy 7. Trisomy 8 was also present in 1 of the sisters, who later developed acute myeloid leukemia of the M0 FAB-type and died, whereas the other sister died with no evolution into AML. The authors found that the parental origin of the deleted chromosome 7 was different in the 2 sisters, thus confirming that familial monosomy 7 is not explained by a germline mutation of a possible tumor suppressor gene. Similar results were obtained in 2 other families of the 12 reported in the literature. Noteworthy was the association with a mendelian disorder in 3 of the 12 monosomy 7 families, which suggested that a mutator gene, capable of inducing both karyotype instability and a mendelian disorder, may act to induce chromosome 7 anomalies in the marrow.

Mapping

Reasoning along the lines of the Knudson model of oncogenesis, Shannon et al. (1989) used probes that mapped to chromosome 7q22-q34 to investigate 3 families with monosomy 7. It was demonstrated that different parental chromosomes 7 were retained in the leukemic bone marrows of the sibs of these families; thus, a familial predisposition to myelodysplasia could not be located within the consistently deleted segment. In the first family studied, markers on proximal 7q showed that the leukemic chromosome 7 came from the mother in both sibs, but in 1 sib a somatic recombination had occurred, resulting in paternal derivation of the distal part of 7q in leukemic cells. In further studies of 3 pairs of sibs, Shannon et al. (1992) found no overlapping region where all 3 pairs retained DNA derived from the same paternal or maternal chromosome, suggesting that there may not be a familial disposition to the disorder resulting from germline events. However, the findings suggested that there may be multiple somatic events involving 7q in the pathogenesis of myelodysplasia.

Molecular Genetics

Using microarray-based comparative genomic hybridization (CGH) analysis, Asou et al. (2009) identified a common microdeletion involving chromosome 7q21.2-q21.3 in 8 of 21 JMML patients with normal karyotype. The microdeletion was verified by quantitative PCR analysis and involved 3 contiguous genes, SAMD9 (610456), SAMD9L (611170), and HEPACAM2 (614133). These 3 genes were heterozygously deleted at high frequency in both adult and childhood myeloid leukemia and were commonly lost with larger deletions of chromosome 7 in 15 of 61 adult MDS/AML patients.

Nikoloski et al. (2010) identified heterozygous acquired (somatic) deletions and at chromosome 7q36.1 encompassing the EZH2 (601573) and CUL1 (603134) genes in bone marrow cells derived from 13 of 102 individuals with myelodysplastic syndromes, including refractory anemia (RA). Two additional affected individuals had uniparental disomy (UPD) of this region. Genomic analysis of the remaining allele in 1 patient showed no aberrations in CUL1, but a truncating mutation in EZH2. Further sequencing of the EZH2 gene identified somatic mutations in 8 (26%) of 126 individuals, including the original 102 individuals. Three individuals had biallelic mutations. Collectively, 23% of affected individuals had deletions and/or point mutations in the EZH2 gene, and 40% of these individuals also had defects in the TET2 gene (612839). Individuals with defects at chromosome 7q showed significantly worse survival compared to those without these defects. The findings suggested that EZH2 may act as a tumor suppressor gene in some cases, and likely influences epigenetic modifications that may lead to cancer, since EZH2 functions as a histone methyltransferase.

Ernst et al. (2010) found that 9 of 12 individuals with myelodysplastic/myeloproliferative neoplasms and acquired UPD encompassing chromosome 7q36 also had a homozygous EZH2 mutation. Further sequencing of 614 individuals with myeloid disorders revealed 49 monoallelic or biallelic EZH2 mutations in 42 individuals; the mutations were found most commonly in those with myelodysplastic/myeloproliferative neoplasms (27 of 219, 12%) and in those with myelofibrosis (4 of 30, 13%). Several patients had refractory anemia, suggesting that somatic acquisition of these abnormalities may be an early event in the disease process. The mutations identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that EZH2 can act as a tumor suppressor for myeloid malignancies.

Makishima et al. (2010) analyzed the EZH2 gene in 344 patients with myeloid malignancies, of whom 15 had UDP7q, 30 had del(7q), and 299 had no loss of heterozygosity of chromosome 7. They found 4 different EZH2 mutations in 3 (20%) of 15 patients with UDP7q and in 2 (7%) of 30 patients with del(7q); in 1 patient without LOH7q, a heterozygous frameshift mutation was identified. All were somatic mutations located in exon 18 or 19, coding for the SET domain of the EZH2 gene.

History

The occurrence of mosaicism for trisomy 7 in normal tissues (kidney, liver, brain), as found by Mittelman (1989), is noteworthy, as is the occurrence of uniparental disomy involving chromosome 7 and leading to cystic fibrosis (see 219700).