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Loss of genomic stability in the cell due to defects in the checkpoint of DNA damage, mitotic checkpoint, and telomere maintenance led to increased incidences of base pair alterations. Therefore, that genomic instability plays a critical role in tumor initiation and progression. Tumor progression requires a dynamic tumor/normal exchange in their microenvironment to support tumor growth. The histological alteration seen in the tumor at early stages confirms that the surface between the epithelium and the stroma undergoes progressive disturbance. Tumor progression is also affected by the immune system in which chronic inflammations promote the growth of tumor. Tumor cells experience altered metabolic profiling to support their growth. Cancer cells are characterized by uncontrolled cell division. For that, they utilize glucose as a source of energy to help them grow faster than normal cells. Hence, Glycolysis is a key metabolomics pathway consumed at a high rate during carcinogenesis.

Different types of signalling pathways have been approved to be involved in cancer imitation and progression. These signalling pathways include the JAK-STAT signalling, NF-κB signalling, Wnt, Notch and Hedgehog. STAT (Signal Transducer and Activator of Transcription) transports signals between proteins from the cell membrane into the nucleus to contribute to cancer progression. NF-κB signalling is essential for the survival of the B cell tumor types. The Wnt, Notch, and Hedgehog signalling pathways play a significant role in carcinogenesis by upregulating the genes associated with these pathways. Hence, pharmacological inhibitors of WNT, NOTCH, and HH pathways are required in clinical studies. Such inhibitors have features that make them important during the clinical trial since they offer great potential as novel therapeutics for cancer. They also have an antitumor response which should be taken into consideration. The three signalling pathways are also known to shape cell fate determination and differentiation. In case of depletion of a single molecular component within the three pathways, embryonic lethality will form.

The MCPH1 gene, also known as BRCT-repeat inhibitor of hTERT expression (BRIT1), has three BRCA1 carboxyl-terminal domains which is an important regulator of DNA repair, cell cycle checkpoints and chromosome condensation. MCPH1/BRIT1 is also known as a tumour suppressor in different types of human cancer. The expression level of the MCPH1/BRIT1 gene is decreased at the DNA, RNA or protein level in a number of types of cancers including breast cancer, lung cancer, cervical cancer, prostate cancer and ovarian cancer compared to normal tissue. This review also showed that deregulation of MCPH1/BRIT1 is significantly associated with reduced overall survival in 57% (12/21) and relapsed free survival in 33% (7/21) of cancer types especially in oesophageal squamous cell carcinoma and renal clear cell carcinoma. A common finding of this study is that the loss of MCPH1/BRIT1 gene expression plays a key role in promoting genome instability and mutations supporting its function as a tumour suppressor gene.

Background Oral tongue squamous cell carcinoma (OTSCC) is a highly aggressive malignancy characterized by frequent recurrence, poor survival with relatively few therapeutic options due to the late diagnosis in many cases. Objectives Understanding the molecular pathways underlying OTSCC tumourigenesis and the discovery of diagnostic and/or prognostic biomarkers. Methods We performed high-throughput mutational analysis of 44 OTSCC formalin-fixed paraffin-embedded (FFPE) cases using the Cancer Hotspots Panel (CHP) v2 on the Ion Torrent™platform. We determined the frequency of human papilloma virus (HPV) using PCR and Epstein bar virus (EBV) positivity using immunohistochemistry. As a control for EBV infection we screened matched non-tumourous tissues. Results Sequencing analysis identified missense, nonsense and frameshift mutations in TP53 (66%), PIK3CA (27%), CDKN2A (25%), EGFR (18%), and PTEN (14%). Interestingly, no significant associations were found between damaging mutations and clinicopathological data. A total of 10/44 of the OTSCC samples (23%) tested was positive for HPV18 DNA. OTSCC patients with positive HPV infection had worse overall survival compared to HPV-negative cases as determined by Kaplan-Meier survival (p= 0.023). Furthermore, EBNA1 expression showed a strong tumour-enriched expression pattern in 20 out of 21 samples (95%) in the epithelial compartments of the tissues analysed. Conclusions Taken together, this study highlights that the two most common events in OTSCC are TP53 mutations and EBV positivity. Helping to understand the contribution of TP53 mutations and EBV infection events could serve as useful biomarkers for OTSCC.

Prion diseases are a group of rare neurodegenerative disorders that develop as a result of the conformational conversion of normal prion protein (PrPC) to the disease-associated isoform (PrPSc). The mechanism that actually causes disease remains unclear. However, the mechanism underlying the conformational transformation of prion protein is partially understood—in particular, there is strong evidence that copper ions play a significant functional role in prion proteins and in their conformational conversion. Various models of the interaction of copper ions with prion proteins have been proposed for the Cu (II)-binding, cell-surface glycoprotein known as prion protein (PrP). Changes in the concentration of copper ions in the brain have been associated with prion diseases and there is strong evidence that copper plays a significant functional role in the conformational conversion of PrP. Nevertheless, because copper ions have been shown to have both a positive and negative effect on prion disease onset, the role played by Cu (II) ions in these diseases remains a topic of debate. Because of the unique properties of paramagnetic Cu (II) ions in the magnetic field, their interactions with PrP can be tracked even at single atom resolution using nuclear magnetic resonance (NMR) spectroscopy. Various NMR approaches have been utilized to study the kinetic, thermodynamic, and structural properties of Cu (II)-PrP interactions. Here, we highlight the different models of copper interactions with PrP with particular focus on studies that use NMR spectroscopy to investigate the role played by copper ions in prion diseases.

Conformational diseases are caused by the aggregation of misfolded proteins. The risk for such pathologies develops years before clinical symptoms appear, and is higher in people with alpha-1 antitrypsin (AAT) polymorphisms. Thousands of people with alpha-1 antitrypsin deficiency (AATD) are underdiagnosed. Enemy-aggregating proteins may reside in these underdiagnosed AATD patients for many years before a pathology for AATD fully develops. In this perspective review, we hypothesize that the AAT protein could exert a new and previously unconsidered biological effect as an endogenous metal ion chelator that plays a significant role in essential metal ion homeostasis. In this respect, AAT polymorphism may cause an imbalance of metal ions, which could be correlated with the aggregation of amylin, tau, amyloid beta, and alpha synuclein proteins in type 2 diabetes mellitus (T2DM), Alzheimer's and Parkinson's diseases, respectively.

Aims The aim of this study was to explore the correlation of hTERT splice variant expression with MCPH1/BRIT1 and BRCA1 expression in epithelial ovarian cancer (EOC) samples. Background Telomerase activation can contribute to the progression of tumors and the development of cancer. However, the regulation of telomerase activity remains unclear. MCPH1 (also known as BRIT1, BRCT-repeat inhibitor of hTERT expression) and BRCA1 are tumor suppressor genes that have been linked to telomerase expression. Methods qPCR was used to investigate telomerase splice variants, MCPH1/BRIT1 and BRCA1 expression in EOC tissue and primary cultures. Results The wild type α+/β+ hTERT variant was the most common splice variant in the EOC samples, followed by α+/β− hTERT, a dominant negative regulator of telomerase activity. EOC samples expressing high total hTERT demonstrated significantly lower MCPH1/BRIT1 expression in both tissue (p = 0.05) and primary cultures (p = 0.03). We identified a negative correlation between MCPH1/BRIT1 and α+/β+ hTERT (p = 0.04), and a strong positive association between MCPH1/BRIT1 and both α−/β+ hTERT and α−/β− hTERT (both p = 0.02). A positive association was observed between BRCA1 and α−/β+ hTERT and α−/β− hTERT expression (p = 0.003 and p = 0.04, respectively). Conclusions These findings support a regulatory effect of MCPH1/BRIT1 and BRCA1 on telomerase activity, particularly the negative association between MCPH1/BRIT1 and the functional form of hTERT (α+/β+).

Hypermethylation in the CpG island promoter regions of tumor suppressors is known to play a significant role in the development of HNSCC and the detection of which can aid the classification and prognosis of HNSCC. This study aims to profile the methylation patterns in a panel of key genes including CDKN2A, CDKN2B, KLOTHO (KL), RASSF1A, RARB, SLIT2, and SFRP1, in a group of HNSCC samples from Saudi Arabia. The extent of methylation in these genes is determined using the MethyLight assay and correlated with known clinicopathological parameters in our samples of 156 formalin-fixed and paraffin-embedded HNSCC tissues. SLIT2 methylation had the highest frequency (64.6%), followed by RASSF1A (41.3%), RARB (40.7%), SFRP1 (34.9), KL (30.7%), CKDN2B (29.6%), and CKDN2A (29.1%). KL and SFRP1 methylation were more predominant in nasopharyngeal tumors (P = 0.001 and P = 0.031 respectively). Kaplan Meier analysis showed that patients with moderately differentiated tumors who display SFRP1 methylation have significantly worse overall survival in comparison with other samples. In contrast, better clinical outcomes were seen in patients with KL methylation. In conclusion, our findings suggest that the detection of frequent methylation in SFRP1 and KL genes' promoters could serve as prognostic biomarkers for HNSCC.

This work was funded and supported by King Abdullah University of Science and Technology (KAUST). The authors thank Ali I. Al-Naimi Petroleum Engineering Research Center (ANPERC) at KAUST for the assistance with the CT scanner imaging. The authors thank Mr. Tariq Ali Alghamdi (KAIMRC) and Samer Yahya Zakari (KAIMRC) for their help in tissue sectioning and staining. The authors thank Dr. Shahida Shafi and Dr. Abdelhamid Saoudi for their support.

Mutations in the MCPH1 (Microcephalin) and ASPM (abnormal spindle-like microcephaly associated) genes cause primary microcephaly. Both are centrosomal associated proteins involved in mitosis. Microcephalin plays an important role in DNA damage response and ASPM is required for correct division of proliferative neuro-epithelial cells of the developing brain. Reduced MCPH1 mRNA expression and ASPM mRNA over-expression have been implicated in the development of human carcinomas. Epithelial ovarian cancer (EOC) is characterised by highly aneuploid tumours. Previously we have reported low Microcephalin and high ASPM protein levels and associations with clinico-pathological parameters in malignant cells from ascitic fluids. To confirm these previous findings on a larger scale Microcephalin and ASPM expression levels and localisations were evaluated by immunohistochemistry in two cohorts; a training set of 25 samples and a validation set of 322 EOC tissue samples. Results were correlated to the associated histopathological data. In normal ovarian tissues the Microcephalin nuclear staining pattern was consistently strong. In the cancer tissues, we identified low nuclear Microcephalin expression in high grade and advanced stage tumours (p

Highly aneuploid tumours are common in epithelial ovarian cancers (EOC). We investigated whether NuMA expression was associated with this phenomenon. NuMA protein levels in normal and tumour tissues, ovarian cell lines and primary cultures of malignant cells derived from ovarian ascitic fluids were analysed by Affymetrix microarray analysis, immunoblotting, immunohistochemistry (IHC) and immunofluorescence (IF), with results correlated to associated clinical data. Aneuploidy status in primary cultures was determined by FACS analysis. Affymetrix microarray data indicated that NuMA was overexpressed in tumour tissue, primary cultures and cell lines compared to normal ovarian tissue. IHC revealed low to weak NuMA expression in normal tissues. Expression was upregulated in tumours, with a significant association with disease stage in mucinous EOC subtypes (p = 0.009), lymph node involvement (p = 0.03) and patient age (p = 0.04). Additional discontinuous data analysis revealed that high NuMA levels in tumours decreased with grade (p = 0.02) but increased with disease stage (p = 0.04) in serous EOC. NuMA expression decreased in late disease stage 4 endometrioid EOCs. High NuMA levels decreased with increased tumour invasion in all subtypes (p = 0.03). IF of primary cultures revealed that high NuMA levels at mitotic spindle poles were significantly associated with a decreased proportion of cells in cytokinesis (p = 0.05), increased binucleation (p = 0.021) and multinucleation (p = 0.007), and aneuploidy (p = 0.008). NuMA is highly expressed in EOC tumours and high NuMA levels correlate with increases in mitotic defects and aneuploidy in primary cultures.

Background: The clinico-pathological and molecular heterogeneity of epithelial ovarian cancer (EOC) complicates its early diagnosis and successful treatment. Highly aneuploid tumours and the presence of ascitic fluids are hallmarks of EOC. Two microcephaly-associated proteins, abnormal spindle-like microcephaly-associated protein (ASPM) and microcephalin, are involved in mitosis and DNA damage repair. Their expression is deregulated at the RNA level in EOC. Here, ASPM and microcephalin protein expression in primary cultures established from the ascites of patients with EOC was determined and correlated with clinical data to assess their suitability as biomarkers. Methods: Five established ovarian cancer cell lines, cells derived from two benign ovarian ascites samples and 40 primary cultures of EOC derived from ovarian ascites samples were analysed by protein slot blotting and/or immunofluorescence to determine ASPM and microcephalin protein levels and their cellular localisation. Results were correlated with clinico-pathological data. Results: A statistically significant correlation was identified for ASPM localisation and tumour grade, with high levels of cytoplasmic ASPM correlating with grade 1 tumours. Conversely, cytoplasmic microcephalin was only identified in high-grade tumours. Furthermore, low levels of nuclear microcephalin correlated with reduced patient survival. Conclusion: Our results suggest that ASPM and microcephalin have the potential to be biomarkers in ovarian cancer.