Comparison of skin cancer risk between renal transplant recipients and patients with glomerular diseases in rural Queensland.

INTROUDCTION: There is increased risk of skin cancer in patients with gloermular disease or those with renal transplant. OBJECTIVES: To compare the risk of skin cancer between kidney recipients (KTRs) and patients with glomerular disease (GD). DESIGN: The cohort comprised patients with KTRs (n = 61) and GD (n = 51) in Central and Central West Queensland, Australia. A quantitative cohort study was undertaken to study the risk of skin cancer in rural communities between two subgroups of patients with kidney diseases in relationship to immunosuppression. Statistical analyses of the differences in incidence of skin cancers between the two groups were done by chi-square test, Fisher's exact test, independent t-test and McNemar's test. FINDINGS: KTRs with non-melanoma skin carcinoma (NMSC) increased significantly after treatment with immunosuppressants (pre-transplantation, n = 11 [18.0%], post-transplantation, n = 28 [45.9%]; p < 0.001). There were no differences in number of patients with NMSC observed in the GD group (pre-diagnosis, n = 6 [11.8%], post-diagnosis, n = 7 [13.7%]; p = 1.000). Compared to the risks at 1 year post-immunosuppressants, the incidence of NMSC of KTRs increased significantly at 3 years (20.3% vs. 35.4%, p < 0.001) and 5 years (20.3% vs. 62.2%, p < 0.001) post-immunosuppressants, whereas the increased incidence of NMSC was observed only at 5 years (2.1% vs. 11.8%, p = 0.012) in the GD cohort. The mean cumulative number of NMSC in KTRs increased significantly at 3 years (p = 0.011), and 5 years (p = 0.001) post-immunosuppressants, compared to the risks at 1 year post-immunosuppressants, however, no differences were noted in the GD cohort. DISCUSSION: Immunosuppressants increased the risk of NMSC in KTRs. The increased risk is likely dependent on the intensity and duration of immunosuppressants. CONCLUSION: In patients with a high risk of NMSC, reducing skin cancer risk should be considered in conjunction with the optimisation of treatment.

Lipopolysaccharide-binding protein as a biomarker in oral and maxillofacial tumors.

Oral and maxillofacial tumors (OMTs), such as oral squamous cell carcinoma (SCC), pleomorphic adenoma, and ameloblastoma, are common head and neck tumors. Lipopolysaccharide-binding protein (LBP) is a type I acute reactive protein, which participates in body inflammatory response modulation through lipopolysaccharide (LPS)-induced signaling pathway by targeting macrophages (expressing cluster of differentiation 204 [CD204]). Although it is well established that LBP is associated with the development of multiple types of cancer, little is known about the role of LBP in OMTs. This study aims to explore the expression of LBP in OMTs. Here, immunohistochemical (IHC) double staining of LBP and CD204 and enzyme-linked immunosorbent assay (ELISA) were conducted to explore the LBP expression in OMTs. The findings demonstrated that the LBP expression in OMTs was significantly elevated (p < 0.001). In addition, the LBP expression was associated with the clinical stage (p < 0.001), T classification (p < 0.001), and lymph node metastasis (p < 0.001, except ELISA) but independent of histological grade of SCC, gender, and age in patients with SCC. The optional cutoff of the LBP serum level is 0.721 µg/ml. To conclude, LBP contributes to the development of OMTs and could be a biomarker in the screening and predicting metastasis in patients with OMTs.

Analysis of metabolomics and transcriptomics data in head and neck squamous cell carcinoma.

OBJECTIVE: Studies have shown that cancer progression of head and neck squamous cell carcinoma (HNSCC) is related with metabolic alterations. The aim of this study is to identify the clinical roles of metabolic alterations in HNSCC. MATERIALS AND METHODS: Metabolism-related genes associated with HNSCC were searched in public databases. A predictive and efficacious LASSO model was fabricated to optimize the diagnosis that was based on these genes. Meantime, ultra-performance liquid chromatography-quadrupole/orbitrap high resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) was used to compare patients with HNSCC (n = 73) with healthy controls (n = 51) for serum metabolites. Potential biomarkers and alterations in serum metabolites were analysed and evaluated using t test analysis, principal component analysis and orthogonal partial least square-discrimination analysis. RESULTS: Overall, 21 differential metabolites were probed in serum, of which eight metabolites had potential for clinical uses. Transcriptome analysis showed that four genes in the constructed LASSO model were found to be associated with seven differential metabolites. Metabolic pathway analysis by MetaboAnalyst showed that the biomarkers that were related with HNSCC were closely related to four metabolism pathways (p < 0.05). CONCLUSION: To conclude, future research on HNSCC should be directed towards multi-omics to provide treatment, intervention or diagnosis of the disease.

Gene Expression Analysis of Immune Regulatory Genes in Circulating Tumour Cells and Peripheral Blood Mononuclear Cells in Patients with Colorectal Carcinoma.

Information regarding genetic alterations of driver cancer genes in circulating tumour cells (CTCs) and their surrounding immune microenvironment nowadays can be employed as a real-time monitoring platform for translational applications such as patient response to therapeutic targets, including immunotherapy. This study aimed to investigate the expression profiling of these genes along with immunotherapeutic target molecules in CTCs and peripheral blood mononuclear cells (PBMCs) in patients with colorectal carcinoma (CRC). Expression of p53, APC, KRAS, c-Myc, and immunotherapeutic target molecules PD-L1, CTLA-4, and CD47 in CTCs and PBMCs were analysed by qPCR. Their expression in high versus low CTC-positive patients with CRC was compared and clinicopathological correlations between these patient groups were analysed. CTCs were detected in 61% (38 of 62) of patients with CRC. The presence of higher numbers of CTCs was significantly correlated with advanced cancer stages (p = 0.045) and the subtypes of adenocarcinoma (conventional vs. mucinous, p = 0.019), while being weakly correlated with tumour size (p = 0.051). Patients with lower numbers of CTCs had higher expression of KRAS. Higher KRAS expression in CTCs was negatively correlated with tumour perforation (p = 0.029), lymph node status (p = 0.037), distant metastasis (p = 0.046) and overall staging (p = 0.004). CTLA-4 was highly expressed in both CTCs and PBMCs. In addition, CTLA-4 expression was positively correlated with KRAS (r = 0.6878, p = 0.002) in the enriched CTC fraction. Dysregulation of KRAS in CTCs might evade the immune system by altering the expression of CTLA-4, providing new insights into the selection of therapeutic targets at the onset of the disease. Monitoring CTCs counts, as well as gene expression profiling of PBMCs, can be helpful in predicting tumour progression, patient outcome and treatment.

Correction: Aktar et al. Gene Expression Analysis of Immune Regulatory Genes in Circulating Tumour Cells and Peripheral Blood Mononuclear Cells in Patients with Colorectal Carcinoma. Int. J. Mol. Sci. 2023, 24, 5051.

Faysal Bin Hamid was not included as an author in the original publication [...].

Comprehensive assessment of actionable genomic alterations in primary colorectal carcinoma using targeted next-generation sequencing.

BACKGROUND: The clinical utility of comprehensive genomic profiling (CGP) for guiding treatment has gradually become the standard-of-care procedure for colorectal carcinoma (CRC). Here, we comprehensively assess emerging targeted therapy biomarkers using CGP in primary CRC. METHODS: A total of 575 primary CRCs were sequenced by ACTOnco® assay for genomic alterations, tumour mutational burden (TMB), and microsatellite instability (MSI). RESULTS: Eighteen percent of patients were detected as MSI-High (MSI-H), and the remaining cases were classified as microsatellite stable (MSS). Driver mutation prevalence in MSS CRCs were APC (74%), TP53 (67%), KRAS (47%), PIK3CA (21%) and BRAF (13%). The median TMBs for MSI-H and MSS patients were 37.8 mutations per mega base (mut/Mb) and 3.9 mut/Mb, respectively. Forty-seven percent of MSI-H CRC harboured at least one loss-of-function mutations in genes that may hamper immune checkpoint blockade. Among MSS RAS/RAF wild-type CRCs, 59% had at least one actionable mutation that may compromise the efficacy of anti-EGFR therapy. For late-stage CRC, 51% of patients are eligible for standard care actionability and the remaining 49% could be enrolled in clinical trials with investigational drugs. CONCLUSIONS: This study highlights the essential role of CGP for identifying rational targeted therapy options in CRC.

An integrated skin cancer education program in renal transplant recipients and patients with glomerular disease.

Sun-protective strategies focusing on skin cancer awareness are needed in immunosuppressed patients at risk of skin cancers. The study aims to determine the effect of an integrated skin cancer education program on skin cancer awareness and sun-protective behaviours in renal transplant recipients (RTRs) and patients with glomerular disease (GD) treated with long-term immunosuppressants. A pilot prospective cohort study in Central Queensland, Australia was undertaken among adult RTRs and patients with GD, who completed survey questionaries on skin cancer and sun-health knowledge (SCSK), sun-protection practices and skin examination pre- and post-education. Fifty patients (25 RTRs, 25 patients with GD) participated in the study. All of them completed questionnaires at pre-, 3-month post-education and 92%(n = 46) at 6-month post-education. There was a significant increase in SCSK scores from baseline at 3-months (p < 0.001) and 6-months post-intervention (p < 0.01). Improved knowledge was retained for 6 months after education. There were changes in 2 of 8 photoprotective behaviours at 6 months. Interventional education enhanced regular self-skin examination rate (p < 0.001) as well as the frequency of full skin checks by general practitioners (GPs) (p < 0.001). Overall, RTRs had better compliance with sun-protective methods and higher skin examination rates by themselves and/ or GPs before and after the intervention of education compared to patients with GD. To conclude, an integrated skin cancer education program improved knowledge of skin cancer and skin health as well as the frequency of self-skin examination and formal skin assessments. However, improvement in patient compliance did not extend to other sun-protective practices.

FE-learning and the virtual transformation of histopathology teaching during COVID-19: its impact on student learning experience and outcome.

BACKGROUND: Medical and pathology education has gone through an immense transformation from traditional face-to-face teaching mode to virtual mode during the COVID-19 pandemic. This study evaluated the effectiveness of online histopathology teaching in medical education during the 2020 COVID-19 pandemic in Griffith University, Australia. METHODS: Second-year medical students (n = 150) who had previously completed one year of face-to-face histopathology teaching, completed an online questionnaire rating their learning experiences before and during the COVID-19 pandemic after the completion of their histology and pathology practical sessions. The students' histopathology assessment results were then compared to the histopathology results of a prior second-year cohort to determine if the switch to online histopathology teaching had an impact on students' learning outcome. RESULTS: A thematic analysis of the qualitative comments strongly indicated that online histopathology teaching was instrumental, more comfortable to engage in and better structured compared to face-to-face teaching. Compared to the previous year's practical assessment, individual performance was not significantly different (p = 0.30) and compared to the prior cohort completing the same curriculum the mean overall mark was significantly improved from 65.36% ± 13.12% to 75.83% ± 14.84% (p < 0.05) during the COVID-19 impacted online teaching period. CONCLUSIONS: The transformation of teaching methods during the 2020 COVID-19 pandemic improved student engagement without any adverse effects on student learning outcomes in histology and pathology education.

Clinicopathological and Molecular Features of Secondary Cancer (Metastasis) to the Thyroid and Advances in Management.

Secondary tumours to the thyroid gland are uncommon and often incidentally discovered on imaging. Symptomatic patients often present with a neck mass. Collision tumours of secondary tumours and primary thyroid neoplasms do occur. Ultrasound-guided fine-needle aspiration, core-needle biopsy, and surgical resection with histological and immunohistochemical analysis are employed to confirm diagnosis as well as for applying molecular studies to identify candidates for targeted therapy. Biopsy at the metastatic site can identify mutations (such as EGFR, K-Ras, VHL) and translocations (such as EML4-ALK fusion) important in planning target therapies. Patients with advanced-stage primary cancers, widespread dissemination, or unknown primary origin often have a poor prognosis. Those with isolated metastasis to the thyroid have better survival outcomes and are more likely to undergo thyroid resection. Systemic therapies, such as chemotherapy and hormonal therapy, are often used as adjuvant treatment post-operatively or in patients with disseminated disease. New targeted therapies, such as tyrosine kinase inhibitors and immune checkpoint inhibitors, have shown success in reported cases. A tailored treatment plan based on primary tumour features, overall cancer burden, and co-morbidities is imperative. To conclude, secondary cancer to the thyroid is uncommon, and awareness of the updates on diagnosis and management is needed.

Dual role of heme iron in cancer; promotor of carcinogenesis and an inducer of tumour suppression.

PURPOSE: Heme is a crucial compound for cell survival but is also equipped with the potential to be toxic and carcinogenic to cells. However, with the recent advancement of knowledge regarding ferroptosis, the iron mediated cell death, heme can be postulated to induce tumour suppression through ferroptosis. This review summarizes the literature on the carcinogenic and anticarcinogenic properties of heme with specific emphasis on the alterations observed on heme synthesis, metabolism and transport in tumour cells. METHODS: Literature search was performed in PubMed data base using the MeSH terms 'heme iron or heme', 'cancer or carcinogenesis' and 'tumour suppression' or 'anticarcinogenic properties. Out of 189 results, 166 were relevant to the current review. RESULTS: Heme supports carcinogenesis via modulation of immune cell function, promoting inflammation and gut dysbiosis, impeding tumour suppressive potential of P53 gene, promoting cellular cytotoxicity and reactive oxygen species generation and modulating Nfr2 /HO-1 axis. The carcinogenic and anticarcinogenic properties of heme are both dose and oxygen concentration dependant. At low doses, heme is harmless and even helpful in maintaining the much-needed redox balance within the cell. However, when heme exceeds physiological concentrations, it could initiate and propagate carcinogenesis, due to its ability to produce reactive oxygen species (ROS). The same phenomenon of heme mediated ROS generation could be manipulated to initiate tumour suppression via ferroptosis, but the therapeutic doses are yet to be determined. CONCLUSION: Heme iron possesses powerful carcinogenic and anticarcinogenic properties which are dosage and oxygen availability dependant.

Anaplastic Thyroid Carcinoma: Current Issues in Genomics and Therapeutics.

PURPOSE OF REVIEW: Anaplastic thyroid carcinoma is a type of thyroid carcinoma with the most aggressive biological behaviour amongst thyroid cancer. Here, we review the current genomic and the impacts of advances in therapies to improve the management of patients with the cancer. RECENT FINDINGS: Common mutations being identified in anaplastic thyroid carcinoma are p53 and TERT promoter mutations. Other common mutated genes included BRAF, RAS, EIF1AX, PIK3CA, PTEN and AKT1, SWI/SNF, ALK and CDKN2A. Changes in expression of different microRNAs are also involved in the pathogenesis of anaplastic thyroid carcinoma. Curative resection combined with radiotherapy and combination chemotherapies (such as anthracyclines, platins and taxanes) has been shown to have effects in the treatment of some patients with anaplastic thyroid carcinoma. Newer molecular targeted therapies in clinical trials target mostly the cell membrane kinase and downstream proteins. These include targeting the EGFR, FGFR, VEGFR, c-kit, PDGFR and RET on the cell membrane as well as VEGF itself and the downstream targets such as BRAF, MEK and mTOR. Immunotherapy is also being tested in the cancer. Updated knowledge of genomic as well as clinical trials on novel therapies is needed to improve the management of the patients with this aggressive cancer.

Polycyclic Aromatic Hydrocarbons Detected in Processed Meats Cause Genetic Changes in Colorectal Cancers.

Polycyclic aromatic hydrocarbons (PAHs) are commonly ingested via meat and are produced from high-temperature cooking of meat. Some of these PAHs have potential roles in carcinogenesis of colorectal cancer (CRC). We aimed to investigate PAH concentrations in eight types of commonly consumed ready-to-eat meat samples and their potential effects on gene expressions related to CRC. Extraction and clean-up of meat samples were performed using QuEChERS method, and PAHs were detected using GC-MS. Nine different PAHs were found in meat samples. Interestingly, roast turkey contained the highest total PAH content, followed by salami meat. Hams of varying levels of smokedness showed a proportional increase of phenanthrene (PHEN), anthracene (ANTH), and fluorene (FLU). Triple-smoked ham samples showed significantly higher levels of these PAHs compared to single-smoked ham. These three PAHs plus benzo[a]pyrene (B[a]P), being detected in three meat samples, were chosen as treatments to investigate in vitro gene expression changes in human colon cells. After PAH treatment, total RNA was extracted and rtPCR was performed, investigating gene expression related to CRC. B[a]P decreased mRNA expression of TP53. In addition, at high concentrations, B[a]P significantly increased KRAS expression. Treatments with 1 µM PHEN, 25 µM, and 10 µM FLU significantly increased KRAS mRNA expression in vitro, implying the potential basis for PAH-induced colorectal carcinogenesis. Opposingly, the ANTH treatment led to increased TP53 and APC expression and decreased KRAS expression, suggesting an anti-carcinogenic effect. To conclude, PAHs are common in ready-to-eat meat samples and are capable of significantly modifying the expression of key genes related to CRC.

Genetic Heterogeneity of Single Circulating Tumour Cells in Colorectal Carcinoma.

The aim of the present study was to isolate and investigate the genetic heterogeneities in single circulating tumour cells (CTCs) from patients with colorectal carcinoma (CRC). Twenty-eight single CTCs were collected from eight patients with CRC using a negative immunomagnetic enrichment method. After validation with glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene expression in 3 colon cancer cell lines, a panel of 19 genes were used to analyse the single CTCs (n = 28), primary colorectal carcinoma tissues (n = 8) and colon carcinoma cells (n = 6) using real-time qPCR. Genetic heterogeneities were assessed by comparing gene expression profiles of single CTCs from the different patients and in the same patient, respectively. Genetic profiling of the single CTCs showed extensive heterogeneities of the selected genes among the CTCs. Hierarchical clustering analyses exhibited two clusters of CTCs with differentially expressed genes, which highlighted different modifications from the primary carcinomas. Further, the genetic heterogeneities were observed between different patients or in the same patient. Finally, AKT1 expression was significantly (p = 0.0129) higher in single CTCs from CRC of advanced pathological stages (III or IV) CRC than in CTCs from CRC of early stages (I or II). Our findings suggest that single-cell genetic analysis can monitor the genetic heterogeneities and guide the personalised therapeutic targets in clinical sectors.

Hereditary breast cancer; Genetic penetrance and current status with BRCA.

The most important cause of developing hereditary breast cancer is germline mutations occurring in breast cancer (BCs) susceptibility genes, for example, BRCA1, BRCA2, TP53, CHEK2, PTEN, ATM, and PPM1D. Many BC susceptibility genes can be grouped into two classes, high- and low-penetrance genes, each of which interact with multiple genes and environmental factors. However, the penetrance of genes can also be represented by a spectrum, which ranges between high and low. Two of the most common susceptibility genes are BRCA1 and BRCA2, which perform vital cellular functions for repair of homologous DNA. Loss of heterozygosity accompanied by hereditary mutations in BRCA1 or BRCA2 increases chromosomal instability and the likelihood of cancer, as well as playing a key role in stimulating malignant transformation. With regard to pathological features, familial breast cancers caused by BRCA1 mutations usually differ from those caused by BRCA2 mutations and nonfamilial BCs. It is essential to acquire an understanding of these pathological features along with the genetic history of the patient to offer an individualized treatment. Germline mutations in BRCA1 and BRCA2 genes are the main genetic and inherited factors for breast and ovarian cancer. In fact, these mutations are very important in developing early onset and increasing the risk of familial breast and ovarian cancer and responsible for 90% of hereditary BC cases. Therefore, according to the conducted studies, screening of BRCA1 and BRCA2 genes is recommended as an important marker for early detection of all patients with breast or ovarian cancer risk with family history of the disease. In this review, we summarize the role of hereditary genes, mainly BRCA1 and BRCA2, in BC.

GAEC1 drives colon cancer progression.

Gene amplified in esophageal cancer 1 (GAEC1) expression and copy number changes are frequently associated with the pathogenesis of colorectal carcinomas. The current study aimed to identify the pathway and its transcriptional factors with which GAEC1 interacts within colorectal cancer, to gain a better understanding of the mechanics by which this gene exercises its effect on colorectal cancer. Two colonic adenocarcinoma cell lines (SW48 and SW480) and a nonneoplastic colon epithelial cell line (FHC) were transfected with GAEC1 to assess the oncogenic potential of GAEC1 overexpression. Multiple in vitro assays, including cell proliferation, wound healing, clonogenic, apoptosis, cell cycle, and extracellular flux, were performed. Western blot analysis was performed to identify potential gene-interaction partners of GAEC1 in vitro. Results showed that the overexpression of GAEC1 significantly increased cell proliferation, migration, and clonogenic potential ( P < 0.05) of colonic adenocarcinoma. Furthermore, GAEC1 portrayed its ability to influence mitochondrial respiration changes. The observations were in tandem with a significant increase in the expression of phosphorylated protein kinase B, forkhead box O3, and matrix metallopeptidase 9. Thus, GAEC1 has a role in regulating gene pathways, potentially in the Akt pathway. This could help in developing targeted therapies in the future.

Tumour suppressor properties of miR-15a and its regulatory effects on BCL2 and SOX2 proteins in colorectal carcinomas.

OBJECTIVES: In this study, we aimed to investigate the expression pattern, clinicopathological significance and tumour suppressive properties of miR-15a in patients with colorectal carcinomas. METHODS: Tissue samples from 87 patients with primary colorectal carcinomas, 50 matched metastatic lymph node and 37 non-neoplastic colon (control) were prospectively recruited. The expression level of miR-15a was measured by quantitative real-time polymerase chain reaction. Restoration/overexpression of the miR-15a was achieved by exogenous transfection. Four colon cancer cell lines (SW480, CaCO2, SW48 and HCT116) and a non-cancer colon cell line (FHC) were also used for examining the miR-15a induced tumour suppression properties using various in-vitro and immunological assays. RESULTS: Downregulation of miR-15a was noted in ~ 62% of the colorectal carcinoma tissues and it was positively correlated with the presence of cancer recurrence in patients with colorectal carcinomas (p = 0.05). Also, these patients with low miR-15a expression showed relatively shorter survival time when compared to those with miR-15a overexpression. Following miR-15a exogenous overexpression, colon cancer cells showed reduced cell proliferation, low colony formation, less cell invasion properties and mitochondrial respiration when compared to control cells. In addition, BCL2 and SOX2 proteins showed a significant downregulation following miR-15a overexpression suggesting its regulatory role in cancer growth, apoptosis and stemness. CONCLUSION: This study has confirmed the tumour suppressor properties of miR-15a in colorectal cancers. Therefore, its modulation has potential implications in controlling various biological and pathogenic processes in colon carcinogenesis via targeting its downstream proteins such as BCL2 and SOX2.

Promoter hypermethylation inactivate tumor suppressor FAM134B and is associated with poor prognosis in colorectal cancer.

The present study aims to examine promoter methylation status of FAM134B in a large cohort of patients with colorectal adenocarcinomas. The clinical significances and correlations of FAM134B promoter methylation with its expression are also analysed. Methylation-specific high-resolution melt-curve analysis followed by sequencing was used to identify FAM134B promoter methylation in colorectal adenomas (N = 32), colorectal adenocarcinomas (N = 164), matched adjacent non-neoplastic colorectal mucosae (N = 83) and colon cancer cell lines (N = 4). FAM134B expression was studied by real-time quantitative polymerase chain reaction, immunohistochemistry, and Western blots. FAM134B promoter methylation was more frequent in adenocarcinomas (52%; 85/164) when compared to that of adenomas (28%; 9/32) and non-neoplastic mucosae (35%; 29/83). Cancer cells exhibited higher methylation when compared to non-neoplastic cells. FAM134B promoter methylation was inversely correlated with low FAM134B copy number and mRNA/protein expressions, whereas in-vitro demethylation has restored FAM134B expression in colon cancer cells. FAM134B promoter methylation was associated with high histological grade (P = .025), presence of peri-neural infiltration (P = .012), lymphovascular invasion (P = .021), lymph node metastasis (P = .0001), distant metastasis (P = .0001) and advanced pathological stages (P = .0001). In addition, FAM134B promoter methylation correlated with cancer recurrence and poor survival rates of patients with colorectal adenocarcinomas. To conclude, FAM134B promoter methylation plays a key role in regulating FAM134B expression in vitro and in vivo, which in turn contributes to the prediction of the biological aggressiveness of colorectal adenocarcinomas. Furthermore, FAM134B methylation might act as a marker in predicting clinical prognosis in patients with colorectal adenocarcinomas.

RETREG1 (FAM134B): A new player in human diseases: 15 years after the discovery in cancer.

FAM134B (family with sequence similarity 134, member B)/RETREG1 and its functional roles are relatively new in human diseases. This review aimed to summarize various functions of FAM134B since our first discovery of the gene in 2001. The protein encoded by FAM134B is a reticulophagy receptor that regulates turnover of the endoplasmic reticulum (ER) by selective phagocytosis. Absence or non-functional expression of FAM134B protein impairs ER-turnover and thereby is involved in the pathogenesis of some human diseases. FAM134B inhibition contributes to impair proteostasis in the ER due to the accumulation of misfolded or aggregated proteins, which in turn leads to compromised neuronal survival and progressive neuronal degenerative diseases. Mutations in FAM134B associated with hereditary sensory and autonomic neuropathy type IIB (HSAN IIB). Selective cleavage of FAM134B by Dengue, Zika, and West Nile virus encoded protease NS2B3 leads to the increased production of infection units, whereas upregulation of FAM134B inhibits viral replication. In cancer, FAM134B acts as a tumor suppressor and inhibit cancer growth both in-vitro and in-vivo. Pharmacological upregulation of FAM134B resulted in reduced cancer cell growth and proliferation. In addition, FAM134B mutations are common in patients with colorectal adenocarcinoma, and oesophageal squamous cell carcinoma. These mutations and expression changes of FAM134B were associated with the biological aggressiveness of these cancers. FAM134B also plays a role in allergic rhinitis, vascular dementia, and identification of stem cells. Taken together, information available in the literature suggests that FAM134B plays critical roles in human diseases, by interacting with different biological and chemical mediators, which are primarily regulated by ER turnover.

Expression of GAEC1 mRNA and protein and its association with clinical and pathological parameters of patients with colorectal adenocarcinoma.

AIM: GAEC1 (Gene amplified in esophageal cancer 1) is an oncogene with key regulatory roles in the pathogenesis of oesophageal and colorectal carcinomas. The aim of this study was to investigate expression profiles and clinicopathological significance of GAEC1 mRNA and protein in patients with colorectal carcinomas. METHOD: Matched cancer and non-cancer fresh frozen tissues were prospectively collected from 80 patients diagnosed with colorectal adenocarcinoma (39 men and 41 women). The tissues were sectioned for RNA extraction and cDNA conversion and quantified by a real-time polymerase chain reaction. GAEC1 protein expression was analysed by immunohistochemistry using a custom made GAEC1 antibody. RESULT: GAEC1 mRNA was upregulated in majority (52%, n=42/80) of the colorectal carcinomas when compared to the matched non-neoplastic tissues. High expression of GAEC1 mRNA as correlated with patients of younger age (p=0.008), with lower grade carcinoma (p=0.028), presence of synchronous adenocarcinomas (p=0.034) and without any associated adenomas (p=0.047). In addition, patients with high GAEC1 mRNA overexpression had a shorter survival time. Furthermore, high GAEC1 protein expression was noted among patients having perforated colorectal carcinoma (p=0.04). CONCLUSION: The high expression of GAEC1 mRNA/protein as well as its correlation with multiple clinicopathological characteristics in patients with colorectal carcinoma strongly suggests that GAEC1 is a key regulator in the initiation of colorectal carcinogenesis.

Whole-exome sequencing reveals critical genes underlying metastasis in oesophageal squamous cell carcinoma.

Oesophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers, owing to a high frequency of metastasis. However, little is known about the genomic landscape of metastatic ESCC. To identify the genetic alterations that underlie ESCC metastasis, whole-exome sequencing was performed for 41 primary tumours and 15 lymph nodes (LNs) with metastatic ESCCs. Eleven cases included matched primary tumours, synchronous LN metastases, and non-neoplastic mucosa. Approximately 50-76% of the mutations identified in primary tumours appeared in the synchronous LN metastases. Metastatic ESCCs harbour frequent mutations of TP53, KMT2D, ZNF750, and IRF5. Importantly, ZNF750 was recurrently mutated in metastatic ESCC. Combined analysis from current and previous genomic ESCC studies indicated more frequent ZNF750 mutation in diagnosed cases with LN metastasis than in those without metastasis (14% versus 3.4%, n = 629, P = 1.78 × 10-5 ). The Cancer Genome Atlas data further showed that ZNF750 genetic alterations were associated with early disease relapse. Previous ESCC studies have demonstrated that ZNF750 knockdown strongly promotes proliferation, migration, and invasion. Collectively, these results suggest a role for ZNF750 as a metastasis suppressor. TP53 is highly mutated in ESCC, and missense mutations are associated with poor overall survival, independently of pathological stage, suggesting that these missense mutations have important functional impacts on tumour progression, and are thus likely to be gain-of-function (GOF) mutations. Additionally, mutations of epigenetic regulators, including KMT2D, TET2, and KAT2A, and chromosomal 6p22 and 11q23 deletions of histone variants, which are important for nucleosome assembly, were detected in 80% of LN metastases. Our study highlights the important role of critical genetic events including ZNF750 mutations, TP53 putative GOF mutations and nucleosome disorganization caused by genetic lesions seen with ESCC metastasis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.