The Role of Centromere Defects in Cancer

Beh, Thian Thian; Kalitsis, Paul

doi:10.1007/978-3-319-58592-5_22

Cited by 9 publications

(5 citation statements)

References 61 publications

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“…Indeed it has been demonstrated that as many as 90% of solid organ and 50% of haemopoietic cancers are aneuploid which directly implicates epigenomic centromeric/kinetochore processes in tumourigensis [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

“…One of the most intriguing things about the pattern of CCA disease to be discussed is the cellular mechanisms which might be responsible. Whilst various disruptions of normal chromosomal physiology were described several decades ago as noted above [ 16 , 27 , 66 , 67 ], major advances in our understanding of the machinery of mitosis and meiosis have occurred in the decades since that time [ 68 , 69 , 70 , 71 , 72 , 73 ] and it would seem obvious from the pairing of trisomic chromosomal disorders with the monosomy of Turners syndrome [ 2 , 8 ] that chromosomal mis-segregation must be involved by some mechanism. However, as explored in some detail in the Discussion section, the exact mechanism of this is not understood in molecular terms.…”

Section: Introductionmentioning

confidence: 99%

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Cannabis- and Substance-Related Epidemiological Patterns of Chromosomal Congenital Anomalies in Europe: Geospatiotemporal and Causal Inferential Study

Reece

Hulse

2022

IJERPH

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Introduction: Laboratory data link cannabinoid exposure to chromosomal mis-segregation errors. Recent epidemiological reports confirm this link and raise concern that elevated chromosomal congenital anomaly rates (CCAR) may be occurring in Europe which is experiencing increased cannabis use, daily intensity of use and cannabinoid potency. Methods: CCAR data from Eurocat. Drug use data from the European Monitoring Centre for Drugs and Drug Addiction. Income from World Bank. Bivariate, multivariate, panel and geotemporospatial regressions analyzed. Inverse probability weighting of panel models and E-values used as major quantitative causal inferential methodologies. Results: In countries where daily cannabis use was rising the trend for CCA’s was upwards whereas in those where daily use was declining it was usually downwards (p = 0.0002). In inverse probability weighted panel models terms for cannabis metrics were significant for chromosomal disorders, trisomies 21 and 13 and Klinefelters syndrome from p < 2.2 × 10−16. In spatiotemporal models cannabis terms were positive and significant for chromosomal disorders, genetic disorders, trisomies 21, 18 and 13, Turners and Klinefelters syndromes from 4.28 × 10−6, 5.79 × 10−12, 1.26 × 10−11, 1.12 × 10−7, 7.52 × 10−9, 7.19 × 10−7 and 7.27 × 10−7. 83.7% of E-value estimates and 74.4% of minimum E-values (mEV) > 9 including four values each at infinity. Considering E-values: the sensitivity of the individual disorders was trisomy 13 > trisomy 21 > Klinefelters > chromosomal disorders > Turners > genetic syndromes > trisomy 18 with mEV’s 1.91 × 1025 to 59.31; and daily cannabis use was the most powerful covariate (median mEV = 1.91 × 1025). Conclusion: Data indicate that, consistent with reports from Hawaii, Canada, Colorado, Australia and USA, CCARs are causally and spatiotemporally related to metrics and intensity of cannabis exposure, directly impact 645 MB (21.5%) of the human genome and may implicate epigenomic-centrosomal mechanisms.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cannabis- and Substance-Related Epidemiological Patterns of Chromosomal Congenital Anomalies in Europe: Geospatiotemporal and Causal Inferential Study

Reece

Hulse

2022

IJERPH

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“…Defects in centromere-and kinetochore-associated proteins have been proposed to contribute to aneuploidy and chromosomal instability, which are associated with cancer progression in several types of human tumor (24,25). The presence of aneuploid cells is detected in ~90% of solid tumors and ~50% of hematopoietic cancers (26). Chromosomal instability is believed to be the driver of cancer predisposition, progression and intratumoral heterogeneity, whereas aneuploidy and chromosomal instability have been attributed to poor patient prognosis, metastasis and chemotherapeutic resistance (27).…”

Section: Discussionmentioning

confidence: 99%

shRNA‑mediated knockdown of KNTC1 suppresses cell viability and induces apoptosis in esophageal squamous cell carcinoma

et al. 2019

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Kinetochore-associated proteins are critical components of mitotic checkpoints, which are essential for faithful chromosomal segregation and spindle assembly during cell division. Recent advances have demonstrated that kinetochore-associated proteins are upregulated and serve significant roles in the carcinogenesis of numerous types of cancer. However, the effects of kinetochore-associated protein 1 (KNTC1) on human cancer, particularly on esophageal squamous cell carcinoma (ESCC), remain unclear. The present study revealed that KNTC1 was highly expressed in ESCC cell lines. Subsequently, lentivirus-mediated short hairpin RNAs were used to knockdown KNTC1 expression in human ESCC cell lines. Cell growth and viability were measured using multiparametric high-content screening and the MTT assay, respectively. Cell apoptosis was assessed by staining cells with Annexin V-allophycocyanin and was detected using FACScan flow cytometry. The results demonstrated that knockdown of KNTC1 effectively inhibited cell viability and increased apoptosis. In addition, a gene set enrichment analysis of online ESCC datasets indicated that KNTC1 overexpression was associated with increases in the mitotic spindle and hypoxia pathways, and decreases in the DNA repair and mismatch repair pathways. The findings of the present study suggested that KNTC1 may have an essential role in mediating cell viability and apoptosis in human ESCC cells and may serve as a novel therapeutic target for ESCC.

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“…Chromosomes are bound to the growing plus ends of the half spindle rays. The chromosomes separate at anaphase due to the pulling forces exerted by dynein-dynactin molecular motors, which retract the chromosomes toward the minus ends of the microtubules and the new pronuclear poles [108][109][110][111][112][113].…”

Section: Epigenomic Control Of Chromosomal Centromeric Functionmentioning

confidence: 99%

Epidemiology of Δ8THC-Related Carcinogenesis in USA: A Panel Regression and Causal Inferential Study

Reece

Hulse

2022

IJERPH

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The use of Δ8THC is increasing at present across the USA in association with widespread cannabis legalization and the common notion that it is “legal weed”. As genotoxic actions have been described for many cannabinoids, we studied the cancer epidemiology of Δ8THC. Data on 34 cancer types was from the Centers for Disease Control Atlanta Georgia, substance abuse data from the Substance Abuse and Mental Health Services Administration, ethnicity and income data from the U.S. Census Bureau, and cannabinoid concentration data from the Drug Enforcement Agency, were combined and processed in R. Eight cancers (corpus uteri, liver, gastric cardia, breast and post-menopausal breast, anorectum, pancreas, and thyroid) were related to Δ8THC exposure on bivariate testing, and 18 (additionally, stomach, Hodgkins, and Non-Hodgkins lymphomas, ovary, cervix uteri, gall bladder, oropharynx, bladder, lung, esophagus, colorectal cancer, and all cancers (excluding non-melanoma skin cancer)) demonstrated positive average marginal effects on fully adjusted inverse probability weighted interactive panel regression. Many minimum E-Values (mEVs) were infinite. p-values rose from 8.04 × 10−78. Marginal effect calculations revealed that 18 Δ8THC-related cancers are predicted to lead to a further 8.58 cases/100,000 compared to 7.93 for alcoholism and −8.48 for tobacco. Results indicate that between 8 and 20/34 cancer types were associated with Δ8THC exposure, with very high effect sizes (mEVs) and marginal effects after adjustment exceeding tobacco and alcohol, fulfilling the epidemiological criteria of causality and suggesting a cannabinoid class effect. The inclusion of pediatric leukemias and testicular cancer herein demonstrates heritable malignant teratogenesis.

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The Role of Centromere Defects in Cancer

Cited by 9 publications

References 61 publications

Cannabis- and Substance-Related Epidemiological Patterns of Chromosomal Congenital Anomalies in Europe: Geospatiotemporal and Causal Inferential Study

Cannabis- and Substance-Related Epidemiological Patterns of Chromosomal Congenital Anomalies in Europe: Geospatiotemporal and Causal Inferential Study

shRNA‑mediated knockdown of KNTC1 suppresses cell viability and induces apoptosis in esophageal squamous cell carcinoma

Epidemiology of Δ8THC-Related Carcinogenesis in USA: A Panel Regression and Causal Inferential Study

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