Disease relevance of Chromosomal Instability

• Ataxia-telangiectasia (A-T) is a recessive multi-system disorder caused by mutations in the ATM gene at 11q22-q23 (ref. 3). The risk of cancer, especially lymphoid neoplasias, is substantially elevated in A-T patients and has long been associated with chromosomal instability [1].
• Mutations in the gene defective in Fanconi anemia complementation group C, FAC, are responsible for a subset of Fanconi anemia, a group of autosomal recessive disorders characterized by chromosomal instability, hypersensitivity to cross-linking agents, and cancer susceptibility [2].
• To date, LIG4 mutations have only been described in a radiosensitive leukemia patient and in 4 patients with a designated LIG4 syndrome, which is associated with chromosomal instability, pancytopenia, and developmental and growth delay [3].
• Fanconi anemia (FA) is an autosomal recessive chromosomal instability syndrome with at least seven different complementation groups [4].
• Patients with an inherited syndrome characterized by immunodeficiency, microcephaly, and chromosomal instability: genetic relationship to ataxia telangiectasia [5].

Psychiatry related information on Chromosomal Instability

• Seckel syndrome (SCKL) is a rare, genetically heterogeneous disorder, with dysmorphic facial appearance, growth retardation, microcephaly, mental retardation, variable chromosomal instability, and hematological disorders [6].

High impact information on Chromosomal Instability

• Mutation in Rpa1 results in defective DNA double-strand break repair, chromosomal instability and cancer in mice [7].
• Collectively, our data suggest that Chfr is a tumor suppressor and ensures chromosomal stability by controlling the expression levels of key mitotic proteins such as Aurora A [8].
• These results suggest that reduced expression of CDX2 is important in colon tumorigenesis through mTOR-mediated chromosomal instability [9].
• Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Delta716 Cdx2+/- compound mutant mice [9].
• Securin is required for chromosomal stability in human cells [10].

Chemical compound and disease context of Chromosomal Instability

• DEGA/AMIGO-2, a leucine-rich repeat family member, differentially expressed in human gastric adenocarcinoma: effects on ploidy, chromosomal stability, cell adhesion/migration and tumorigenicity [11].
• To investigate whether the fragile X syndrome is associated with a generalised chromosomal instability, we compared the frequency and distribution of chromosomal breakage in lymphocytes grown in low folate medium from normal subjects and from patients with the syndrome [12].
• Chromosomal aberrations were investigated in 16 women from each area in 72 hour lymphocyte cultures treated with gentian violet to enhance any chromosomal instability induced by the pollution [13].
• The objective of this study was to address the need for early diagnosis of Fanconi anemia (FA), an autosomal recessive chromosomal instability syndrome characterized by a unique cellular hypersensitivity to DNA cross-linking agents, such as diepoxybutane, and by a high risk of malignancies [14].
• Increased bleomycin-induced chromosome damage in lymphocytes of patients with common variable immunodeficiency indicates an involvement of chromosomal instability in their cancer predisposition [15].

Biological context of Chromosomal Instability

• Suv39h-deficient mice display severely impaired viability and chromosomal instabilities that are associated with an increased tumor risk and perturbed chromosome interactions during male meiosis [16].
• FA cells are hypersensitive to DNA cross-linking agents that cause chromosomal instability and cell death [17].
• As truncations of the Adenomatous Polyposis Coli (APC) gene are found in most colorectal tumours, we thought that mutations in APC might be responsible for chromosomal instability [18].
• KLF6 mutations were present in tumors with either microsatellite or chromosomal instability and were more common, particularly in the IBD-related cancers, in the presence of wild-type APC [19].
• Telomere length dynamics and chromosomal instability in cells derived from telomerase null mice [20].

Anatomical context of Chromosomal Instability

• Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death [21].
• Our data are consistent with a role for APC in kinetochore-microtubule attachment and suggest that truncations in APC that eliminate microtubule binding may contribute to chromosomal instability in cancer cells [22].
• Deficiency for the p53 cell cycle checkpoint protein has little effect on spontaneous levels of chromosomal instability in Lig4-deficient fibroblasts [23].
• Proper centrosome duplication and spindle formation are crucial for prevention of chromosomal instability, and BRCA1 plays a role in this process [24].
• The human genetic disorder, Nijmegen breakage syndrome, is characterized by radiosensitivity, immunodeficiency, chromosomal instability and an increased risk for cancer of the lymphatic system [25].

Associations of Chromosomal Instability with chemical compounds

• FA cells exhibit chromosomal instability and hyper-responsiveness to the clastogenic and cytotoxic effects of bifunctional alkylating (cross-linking) agents, such as diepoxybutane (DEB) and mitomycin C (MMC) [26].
• Moreover, these cells exhibited chromosomal instability as demonstrated by higher frequencies of both spontaneous and MNNG-induced sister chromatid exchanges [27].
• Recently, human T-T hybrids have been described; however, their use has been hampered by slow growth and chromosomal instability due at least in part to the presence of thymidine in the traditional hypoxanthine/aminopterin/thymidine (HAT) selection medium [28].
• We found that cells resistant to the bulky-adduct-forming agent 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) exhibited a chromosomal instability (CIN), whereas cells resistant to the methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) exhibited a microsatellite instability (MIN) associated with mismatch repair defects [29].
• Replenishment of intracellular glutathione (GSH) with GSH monoethylester abolished ERK activation and reduced the chromosomal instability induced by FAA by 80% [30].

Gene context of Chromosomal Instability

• There are strong parallels between the pattern of radiosensitivity, chromosomal instability and cancer predisposition in A-T patients and that in patients with Nijmegen breakage syndrome (NBS) [31].
• Mre11 deficiency in Arabidopsis is associated with chromosomal instability in somatic cells and Spo11-dependent genome fragmentation during meiosis [32].
• Since then, SIR2 and its homologs have been suggested to play additional roles in suppression of recombination, chromosomal stability, metabolic regulation, meiosis, and aging [33].
• Telomerase maintains cell viability and chromosomal stability through the addition of telomere repeats to chromosome ends [34].
• The BRCA1 tumor suppressor has been implicated in the maintenance of chromosomal stability through homology-directed repair of DNA double-strand breaks [35].

Analytical, diagnostic and therapeutic context of Chromosomal Instability

• We found that, compared with controls, there is greater chromosomal instability, particularly at fragile sites, in SCKL1-affected patient cells after treatment with aphidicolin, an inhibitor of DNA polymerase alpha and other polymerases [6].
• To evaluate the potential role of a defective mitotic spindle checkpoint as a cause of this chromosomal instability, we used flow cytometry to monitor the response of cells to nocodazole-induced mitotic spindle damage [36].
• For chromosomal instability analysis, Ki-ras mutations were determined by single-strand polymerase chain reaction, and p53 protein staining was studied by immunohistochemistry [37].
• To further evaluate the effect of Ink4a/Arf-deficiency on chromosomal stability in vitro, we isolated Ink4a/Arf deficient primary murine embryonic fibroblasts (MEFs), serially passaged them, and analyzed their chromosomal stability by spectral karyotyping (a 24-color chromosome paint-FISH technique) [38].
• Although this now enables molecular diagnosis in the majority of patients, because of the considerable molecular heterogeneity, the diepoxybutane/mitomycin-C stress test based on the increased chromosomal instability seen in FA cells, compared to normal controls, remains the front-line diagnostic test [39].

References