Disease relevance of Aneuploidy

• The Rpa1 mutation resulted in defects in DNA double-strand break repair and precipitated chromosomal breaks as well as aneuploidy in primary heterozygous mutant mouse embryonic fibroblasts [1].
• Eight of the nine specimens of infiltrating ductal carcinoma that contained high levels of LIP were negative for estrogen receptor and progesterone receptor (ER-/PR-); all nine tumors were aneuploid and poorly differentiated, and eight of nine were highly proliferative [2].
• However, the DNA histograms of cells in hyperbasophilic (intensely toluidine blue-positive) foci were aneuploid (2C-18C) and resembled those of cells in hepatocellular carcinomas (2C-23C) [3].
• BACKGROUND & AIMS: Expression of the mucin-associated carbohydrate antigen sialyl-Tn (STn) and DNA aneuploidy has each been shown to correlate with malignant transformation in patients with sporadic colon cancer and in those with ulcerative colitis (UC) [4].
• Although SMAD4 mutations have been associated with late-stage or metastatic disease, our combined molecular and cytogenetic data best fit a model in which SMAD4 mutations occur before colorectal cancers become aneuploid/polyploid, but after the MSI(+) and MSI(-) pathways diverge [5].

Psychiatry related information on Aneuploidy

• Comparison with previously reported cases of multiple aneuploidy suggests that mosaic variegated aneuploidy with PCD may be a clinically recognizable syndrome with major phenotypes being mental retardation, microcephaly, structural brain anomalies (including Dandy-Walker malformation), and possible cancer predisposition [6].
• Quantitation enables sex chromosome aneuploidy to be determined, and the amelogenin intron sequence can also be co-amplified with several highly polymorphic microsatellite loci, thereby providing a combined gender/identity DNA test [7].

High impact information on Aneuploidy

• Plk4+/- embryonic fibroblasts had increased centrosomal amplification, multipolar spindle formation and aneuploidy compared with wild-type cells [8].
• Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B [9].
• We identified a common genetic variant in STK15 (resulting in the amino acid substitution F31I) that is preferentially amplified and associated with the degree of aneuploidy in human colon tumors [10].
• Meiotic arrest and aneuploidy in MLH3-deficient mice [11].
• We have previously shown in small numbers of patients that disruption of TP53 and CDKN2A typically occurs before aneuploidy and cancer [12].

Chemical compound and disease context of Aneuploidy

• Nonendometrioid carcinomas (NEECs; serous and clear cell forms) are not estrogen related, are frequently aneuploid, and are clinically aggressive [13].
• We have applied the technique to map DNA gains and losses in 33 cases of formalin-fixed, paraffin-embedded primary breast tumors (13 fibroadenomas and 10 diploid and 10 aneuploid carcinomas) [14].
• IO treatment also reduced the steady-state level of aneuploid cells in HPV-16 E7-expressing cell populations [15].
• RESULTS: Taxol and discodermolide interact synergistically over a range of concentrations and molar ratios that cause drug-induced aneuploidy in ovarian carcinoma cells [16].
• All patients with positive 111In-pentetreotide imaging results had elevated urinary catecholamine levels, and the two most 111In-pentetreotide-positive metastases were found in neuroblastomas from children with an aneuploid primary tumor [17].

Biological context of Aneuploidy

• In fact, we calculated the presence of EGF-R positivity overall in 35% of 253 aneuploid tumors vs. in only 15% of 114 diploid tumors (P less than 0.0001) [18].
• A dysfunctional kinetochore represents one possible source for chromosome instability (CIN) and the generation of aneuploidy [19].
• In mitosis, the spindle checkpoint protein Mad2 averts aneuploidy by delaying anaphase onset until chromosomes align [20].
• CONCLUSION: STK15 gene amplification and associated increased expression of the mitotic kinase it encodes are associated with aneuploidy and aggressive clinical behavior in human bladder cancer [21].
• High-level p53 accumulation was associated with high histologic grade (P less than .001), DNA aneuploidy (P less than .05), and high cell proliferation rate as defined by flow cytometric S-phase analysis (P less than .01) or PCNA expression (P less than .01) [22].

Anatomical context of Aneuploidy

• Bone marrow cells isolated from Zmpste24-/- mice show increased aneuploidy and the mice are more sensitive to DNA-damaging agents [23].
• FINDINGS: Of 40 fetuses with mild increase in bowel sonodensity (grade 1), none had CF or aneuploidy [24].
• Whereas EBV-transformed lymphoblasts from an established cell line revealed these phenomena at frequencies equal to those in PHA-stimulated lymphocytes and cultured skin fibroblasts, aneuploid cells from a metastatic melanoma displayed them at 50% lower frequency [25].
• Thus, we report that estrogen is causally linked via estrogen receptor alpha to Aur-A overexpression, centrosome amplification, CIN, and aneuploidy leading to BC in susceptible mammary gland cells [26].
• Individuals with defects in meiotic recombination typically produce high levels of aneuploid gametes and exhibit low fertility or are sterile [27].

Associations of Aneuploidy with chemical compounds

• Relating the level of cathepsin D to other prognostic factors in the patients with node-negative disease, we found an association with aneuploidy but none with estrogen or progesterone receptors, tumor size, or the age of the patient [28].
• (i) Random aneuploidy was detected before transformation in up to 90% of CH embryo cells treated with the carcinogen nitrosomethylurea (NMU) [29].
• Avicins, a family of triterpenoid saponins from Acacia victoriae (Bentham), suppress H-ras mutations and aneuploidy in a murine skin carcinogenesis model [30].
• Sperm nuclei from eight normal, healthy donors were hybridized in situ with the biotin-labeled Y-specific pHY2.1 DNA probe to evaluate the X:Y ratio, the location of the Y chromosome, and the frequency of Y aneuploidy in human sperm [31].
• Expression of BubR1Delta579Delta610 augmented the mitotic delay induced by spindle disruption in transfected cells as well as in clones engineered to inducibly express the mutant protein upon exposure to doxycycline and ultimately led to increased aneuploidy [32].

Gene context of Aneuploidy

• Furthermore, although BubR1 hypomorphic mice have less aneuploidy than Bub3/Rae1 haploinsufficient mice, they age much faster [33].
• Thus, both increased and decreased NDC1 dosage can lead to aneuploidy [34].
• The mitotic spindle checkpoint protein Bub1 has been found to be mutated at low frequency in certain human cancers characterized by aneuploidy [35].
• The MPC, detected on the basis of bright CD38 expression (CD38+2), demonstrated DNA aneuploidy in 65% of cases (DNA index range of 0.9 to 1.3) [36].
• These experiments reveal an important new functional assay regulated by the BRCA1-dependent ubiquitin ligase, and the results suggest that the loss of this BRCA1 activity could cause the centrosome hypertrophy and subsequent aneuploidy typically found in breast cancers [37].

Analytical, diagnostic and therapeutic context of Aneuploidy

• Determination of Y chromosome aneuploidy in human sperm nuclei by nonradioactive in situ hybridization [31].
• NOVP chemotherapy for Hodgkin's disease transiently induces sperm aneuploidies associated with the major clinical aneuploidy syndromes involving chromosomes X, Y, 18, and 21 [38].
• We investigated 15 cytological fine-needle biopsies of aneuploid HCC and 5 touch prints of cadaver livers without cancer [39].
• We examined the effects of simultaneous antisense- or immunosuppression of EGFR and c-erbB-2 expression on the invasive phenotype, aneuploidy, and genotype of cultured human ovarian carcinoma cells (NIH:OVCAR-8) [40].
• Flow cytometry and karyotypic analyses revealed increased polyploidy and aneuploidy in F5E6 cells only at passages > 16, although these cells displayed defective mitotic spindle checkpoint function associated with inactivation of p53 at passages 5 and 16 [41].

References