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Aneuploidy in Human Oocytes and Preimplantation Embryos
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
The causes of chromosome instability and embryonic arrest are currently not clear. A genome-wide association study suggested that common variants of PLK4 may contribute to mitotic instability in early preimplantation embryos (55), but functional assessment and mechanistic studies are yet to be conducted on how specific PLK4 alleles would alter the cell divisions. DNA damage during the embryonic divisions may also contribute towards the high arrest rate of cleavage-stage embryos (48,49,56). This is consistent with the transcriptional upregulation of cell cycle and DNA damage response genes in mature oocytes (57), which drive the first 2–3 mitotic divisions until the embryonic genome activation (EGA; Figure 8.5) (58).
Genetics of Uterine Leiomyomata
Published in John C. Petrozza, Uterine Fibroids, 2020
C. Scott Gallagher, Cynthia C. Morton
Chromosomal rearrangement is hypothesized to alter gene activity by recombining regions of the genome (Figure 5.1). Breakage and repair may be nonviable in many cases, but, at a low frequency, they can create gene fusions encoding novel chimeric proteins and dysregulate gene expression by introducing foreign regulatory elements or removing native ones. Resolution of chromosomal damage can generate cells with survival or growth advantages and result in benign transformation of a myometrial cell [7,57]. Alternatively, chromosomal instability may mostly be inert, with dysregulated growth resulting from primary mutations elsewhere in the genome [6].
Oncogenes and Cancer
Published in Pimentel Enrique, Oncogenes, 2020
Increased chromosome fragility (chromosome instability) is found in several clinical syndromes associated with increased cancer risk.348 A similar fragility has been found in patients with multiple endocrine neoplasia,349 as well as in patients with sporadic unilaterial retinoblastoma.350 A possible relationship between chromosome fragility and neoplastic diseases may be anticipated if this fragility results in loss or alteration of genome segments involved in the transcriptional control of oncogenes or in deletion of tumor-suppressing genes. In general, it is interesting to look for a possible association of familial chromosome fragility at specific sites, especially those corresponding to proto-oncogene loci, and increased incidence of specific types of cancer segregating with the fragile site(s) in the same families.351
The role of urine and serum biomarkers in the early detection of ovarian epithelial tumours
Published in Journal of Obstetrics and Gynaecology, 2022
Qurat ul Ain, Shan Muhammad, Yang Hai, Li Peiling
In the near future, innovative technologies based on very small samples are projected to alter medical practice radically. However, liquid biopsy tests that are now available are not yet ready for clinical usage. In addition, there is still much work to be done to develop effective assays for early OC diagnosis. The underlying genetic instability of OC is one of the problems for future management. Gene mutations that can be targeted are scarce in high-grade serous OC (HGSC) (Nguyen et al. 2013). Except for TP53 mutations and BRCA1/2 abnormalities, all additional genetic changes are found in less than 10% of HGSC. Instead, in HGSC, chromosome instability is typical: it causes widespread gains and losses in DNA-activating oncogenes and inactivates tumour suppressors, resulting in tumour growth and resistance to chemotherapy (Cancer Genome Atlas Research Network 2011, Birrer et al. 2015, Mirza et al. 2016). Characterising and validating potential druggable targets in big amplicons remains a significant problem in turning molecular discoveries from multiple comprehensive genomic research into clinically valuable treatments (Ciriello et al. 2013). Thorough biology and laboratory-based research will be required to discover the tumour’s driving factors and how they evolve throughout the disease’s natural history.
Novel and emerging targets for cholangiocarcinoma progression: therapeutic implications
Published in Expert Opinion on Therapeutic Targets, 2022
Lionel A. Kankeu Fonkoua, Pedro Luiz Serrano Uson Junior, Kabir Mody, Amit Mahipal, Mitesh J. Borad, Lewis R. Roberts
Molecular markers such as fluorescence in situ hybridization (FISH) and digital image analysis (DIA) have been shown to be particularly helpful in the nonsurgical distinction of benign from malignant biliary strictures in setting of negative routine cytology. [47] They allow for assessment of aneuploidy and chromosomal instability by detecting nuclear DNA and quantifying loss or gain of chromosomes, respectively[48]. In an evaluation of trisomy 7 as a marker of benign disease in PSC vs non-PSC patients, Levy et al. showed that FISH provided the greatest sensitivity (45%), while the sensitivity of DIA was comparable to routine cytology for patients with PSC and higher than routine cytology for patients without PSC. Composite DIA/FISH assessment provided a one- to fivefold increase over routine cytology. These results were consistent with another large study by Fritcher et al which demonstrated superior sensitivity of FISH over routine cytology for detecting biliary tract cancers[49]. In this study, FISH was able to detect 49/227 (22%) of biliary tract cancers initially interpreted as nonmalignant by routine cytology, without compromising specificity. Kipp et al further investigated and compared cytology and FISH to KRAS mutational analysis, given the incidence of KRAS gene alterations in 20–100% of patients with CCA [45,50]. This study revealed a sensitivity of 30% for KRAS mutation testing which improved to 54% when combined with FISH, again without compromising a specificity of 96% with both modalities[50].
Prognostic and clinicopathological value of BUB1B expression in patients with lung adenocarcinoma: a meta-analysis
Published in Expert Review of Anticancer Therapy, 2021
Jie Chen, Yi Liao, Xianming Fan
Many studies, to date, have found that chromosome instability plays an important role in tumorigenesis and progression [34,35]. Abnormal expression of BUB1B will lead to spindle failure, and defective cells will continue to divide to produce characteristic aberrant chromatin, eventually leading to malignant transformation [36]. A decrease or increase in the expression level of BUB1B can cause chromosomal instability. In colorectal cancer, Burum-Auensen et al. [37] found that decreased protein levels of BUB1B are related to the development of DNA aneuploidy. However, it has been reported that BUB1B is overexpressed in renal cell carcinoma [38], breast cancer [39], gastric cancer [40] and other tumors. Yang et al. [41] found that the expression of BUB1B promotes tumor cell proliferation and correlates highly with the expression of CDC20, CCNB1 and CCNB2 in multiple myeloma. Lee et al. [42] studied glioblastoma multiforme (GBM) and divided GBM patients into BUB1B sensitive (BUB1BS) and BUB1BR resistant (BUB1BR) groups. They found that the classification of BUB1BS/R can predict clinical course and sensitivity to drug therapy and that the prognosis of patients with BUB1BS is much worse, regardless of tumor subtype [42]. These studies show that BUB1B plays an important role in the occurrence and development of tumors. It is imperative to clarify the molecular mechanism of spindle formation-related genes and their clinical significance.