High Risk Of Developing Cancer Research Articles

CVID-Associated Tumors: Czech Nationwide Study Focused on Epidemiology, Immunology, and Genetic Background in a Cohort of Patients With CVID.

Background: Common variable immunodeficiency disorder (CVID) is one of the most frequent inborn errors of immunity, increased occurrence of malignancies, particularly lymphomas, and gastric cancers, has long been noted among CVID patients. Multifactorial etiology, including immune dysregulation, infections, chronic inflammation, or genetic background, is suggested to contribute to tumor development. Here, we present the results of the first Czech nationwide study focused on epidemiology, immunology and genetic background in a cohort of CVID patients who also developed tumorsMethods: The cohort consisted of 295 CVID patients followed for 3,070 patient/years. Standardized incidence ratio (SIR) was calculated to determine the risk of cancer, and Risk ratio (RR) was established to evaluate the significance of comorbidities. Moreover, immunophenotyping, including immunoglobulin levels and lymphocyte populations, was assessed. Finally, Whole exome sequencing (WES) was performed in all patients with lymphoma to investigate the genetic background.Results: Twenty-five malignancies were diagnosed in 22 patients in a cohort of 295 CVID patients. SIR was more than 6 times greater in comparison to the general population. The most common neoplasias were gastric cancers and lymphomas. History of Immune thrombocytopenic purpura (ITP) was established as a potential risk factor, with over 3 times higher risk of cancer development. The B cell count at diagnosis of lymphoma was reduced in the lymphoma group; moreover, post-treatment B and T cell lymphopenia, associated with poorer outcome, was found in a majority of the patients. Intriguingly, no NK cell depression was observed after the chemotherapy. WES revealed heterogeneous genetic background among CVID patients with tumors, identifying gene variants associated with primary immunodeficiencies (such as CTLA4, PIK3CD, PMS2) and/or increased cancer susceptibility (including BRCA1, RABEP1, EP300, KDM5A).Conclusions: The incidence of malignancy in our CVID cohort was found to be more than 6 times greater compared to the general population. Gastric cancers and lymphomas were the most frequently diagnosed tumors. ITP was identified as a risk factor for malignancy in CVID patients. WES analysis confirmed a wide genetic heterogeneity among CVID patients. The identified causative or modifying gene variants pointed to errors in mechanisms contributing to both immunodeficiency and malignancy.

Increased DNA Damage, Instability and Cytokinesis Defects in Occupationally Exposed Car Painters.

Car painting is considered an occupational exposure job with high risk for cancer development, due to the association with harmful chemicals and mutagens. This study aimed to profile car painters occupationally exposed and determine its association with DNA damage and genomic instability. We collected a questionnaire and buccal cells of 74 individuals (37 car painters and 37 non-exposed workers) paired by age, alcohol and smoking habits. The number of pyknotic cells, karyolitic cells, karyorrhetic cells, condensed chromatin, binucleated cells, basal cells, differentiated cells (DIFF), micronucleated cells and nuclear buds were evaluated using the Buccal Micronucleus Cytome Assay protocol. A statistically significant increase was observed in all parameters (p<0.05) in the exposed group, but DIFF showed a statistically significant decrease (p<0.001), compared to the control group. In association with the poor work environment and lack of personal and collective protective equipment, occupational exposure of car painters leads to high DNA damage, genomic instability and alterations in cellular kinetics.

A review of statistical and machine learning methods for modeling cancer risk using structured clinical data.

Advancements are constantly being made in oncology, improving prevention and treatment of cancers. To help reduce the impact and deadliness of cancers, they must be detected early. Additionally, there is a risk of cancers recurring after potentially curative treatments are performed. Predictive models can be built using historical patient data to model the characteristics of patients that developed cancer or relapsed. These models can then be deployed into clinical settings to determine if new patients are at high risk for cancer development or recurrence. For large-scale predictive models to be built, structured data must be captured for a wide range of diverse patients. This paper explores current methods for building cancer risk models using structured clinical patient data. Trends in statistical and machine learning techniques are explored, and gaps are identified for future research. The field of cancer risk prediction is a high-impact one, and research must continue for these models to be embraced for clinical decision support of both practitioners and patients.

Female-specific association among I, J and K mitochondrial genetic haplogroups and cancer: A longitudinal cohort study

Recent studies highlighted the role of mitochondrial dysregulation in cancer, suggesting that the different mitochondrial haplogroups might play a role in tumorigenesis and risk of cancer development. Our aim is to investigate whether any mitochondrial haplogroups carried a significant higher risk of cancer development in a large prospective cohort of North American people. The haplogroup assignment was performed by a combination of sequencing and PCR-RFLP techniques. Our specific outcome of interest was the incidence of any cancer during follow-up period. Overall, 3222 participants were included in the analysis. Women having I, J, K haplogroup reported a significant higher incidence of cancer compared to people with other haplogroups (p < 0.0001), whilst in men non association was found. In the multivariate analysis, women having I, J, K mitochondrial haplogroup reported a 50% increased risk of cancer (HR = 1.50; 95%CI: 1.04–2.16; p = 0.03). This gender-linked association may be partly explained by the role of mitochondrial function in female-specific (e.g. BRCA-driven) oncogenesis, but further studies are needed to better understand this potential correlation. Our findings may have important implications for cancer epidemiology and prevention.

Scoping review on formaldehyde toxicity in occupationally exposed workers

The presence of formaldehyde at workplace remains significant. Exposure to it results in local irritation of the eye, nose and upper respiratory tract mucous membranes, and it has been chronically related to a higher risk of cancer development at the paranasal sinuses, naso-oropharynx and lungs. The aim of our work has been the updating of the bibliography and the categorization of the most up to date scientific evidence of formaldehyde effects on human body. Bibliographic search on the electronic database Medline / PubMed, restricted to the last 10 years through a combination of free and controlled language.Review of 185 scientific articles, finally including 54 due to duplicity, language, and inclusion criteria. We find among the main results a major evidence regarding genotoxicity; limited, inconsistent, and contradictory evidence regarding various neoplastic pathologies; and lack of evidence regarding bronchial asthma. Further studies have to be carried out, especially longitudinal studies and greater epidemiological power, to generate new knowledge about the behavior of this toxic.

Synergism between BRCA1 Mutation and Impaired Estrogen Signaling in Oxidative Stress Modulation Makes Estrogen Responsive Tissues (Breast) More Susceptible to Develop Cancer

Specific inherited mutations in BRCA1 increases the risk of female breast and ovarian cancers. BRCA1 critically maintains genome stability and cell cycle progression. BRCA1 is a well-known tumor suppressor gene; germline mutations in this gene confer increased susceptibility to developing breast and ovarian cancer. Though breast cancer associated with BRCA1 mutations were considered sporadic for mostly being Erα(-). Significant numbers of Erα(+) BRCA1 mutated breast cancer patients were also discovered. There are two questions prevailing with BRCA1 breast cancers. Why BRCA1 related patients have higher risk for cancer development mainly in estrogen responsive tissues such as breast and ovary. And the second is, the therapeutic approach for Erα(+) BRCA1 breast cancers may not be same as Erα(-) BRCA1 cancers. Recently BRCA1 in context with oxidative stress is been widely studied. The association of BRCA1 and cancers in estrogen responsive tissues may be explained by BRCA1, estrogen and ER cooperation mediated by oxidative stress.

Inflammatory bowel disease and gastrointestinal malignancies – risks, incidence and management

Summary: Inflammatory bowel disease (IBD) can be characterized as immunomediated chronic inflammation conditions in either form of a Crohn's disease (CD) or ulcerative colitis (UC). Although the exact cause of IBD is not entirely clear it is based on a widely accepted hypothesis of abnormal reaction of immune system towards physiological microbiota in colon and small bowel as pathogens. IBD has long been associated with increased risk of malignancies. The main risk is represented by IBD-associated colorectal cancer due to the chronic inflammation followed by other cancers (including extraintestinal) that may develop as a result of both, inflammation and the subsequent treatment by immunosuppressors/ biologics. The recent advancement in immunosuppressive therapies has significantly improved prognosis as well as quality of life of IBD patients. The longer survival, naturally, means a prolonged exposure to chronic inflammation as well as to immunosupression (biologics), which translates into higher risk of cancer development. Therefore in addition to the anti-inflammatory therapies, current strategies for management of IBD patients also include cancer prevention and treatment by surgery, systemic therapy, radiotherapy or hormonal therapy. The current paper is directed at major risk factors of malignancy in IBD patients, an overview of the most commonly occurring IBD-associated gastrointestinal cancers and their management.

간암 국가암검진사업에 참여한 만성B형간염 환자에서 간암 발생률 조사

Background/Aims: To optimize efficacy of National Liver Cancer Screening Program (NLCSP) for subjects with chronic hepatitis B (CHB), it is needed to know the incidence of liver cancer and its predisposing factors in the program. MethodsFrom January 2010 to December 2014, all the hepatitis B surface antigen (HBsAg) positive participants who received at least two or more abdominal ultrasonography under NLCSP were retrospectively enrolled in a single tertiary hospital. Annual incidence of primary liver cancer was calculated and related clinical factors were investigated. ResultsDuring 5 years, 541 subjects were enrolled. Mean age was 53 years old and 292 subjects (54%) were receiving antiviral agents. Liver cirrhosis (LC) was diagnosed in 212 (39.2%). Mean follow-up time was 2.36 years and 15 hepatocellular carcinoma and 1 intrahepatic cholangiocarcinoma were diagnosed. Annual incidence of primary liver cancer was 9.8 per 1,000 patient year. Cumulative incidence at 1, 3, and 5 year was 0.6%, 2.6%, and 6.4%, respectively. In multivariate analyses, LC (hazard ratio [HR] 8.74, 95% confidence interval [CI] 1.97–38.71, P=0.024), age (HR 1.08, 95% CI 1.01–1.15, P=0.024) were significantly associated with cancer development. ConclusionsDespite of high rate of oral antiviral therapy, incidence of primary liver cancer is not low in CHB patients in Korea. Old age and presence of LC are independently associated with higher risk of cancer development during surveillance. This study could be used as baseline data for quality control of NLCSP.

Malignancy in the Lung Transplant Population

The risk for developing a variety of malignancies is significantly elevated in the setting of lung transplantation. Malignancy remains among the three major causes of death in post-transplant recipients, and the relatively high risk of cancer development as well as metastatic aggression pose special threats to this population due to the need for continued immunosuppression. A variety of risks such as tobacco use and inflammatory lung diseases that led to the lung pathology prompting lung transplantation, in addition to immunosuppression and unique post-transplantat viral infections, introduce particularly high risks for carcinomas of the lung and head-and-neck, skin, endothelium (Kaposi sarcoma), colon and anogenital tracts, liver and kidneys. A uniquely high risk of developing non-hodgkins lymphoma or post-transplant lymphoproliferative disorder remains particularly challenging in this population. In this review, we discuss mechanisms leading to risk, details on malignancy presentation and characteristics, and special points on management and prevention in respective sections. In addition to highlighting key features, a major goal is to stimulate future advancements in the prevention and management of malignancy in this unique clinical setting.

Presence of histopathological premalignant lesions and infection caused by high-risk genotypes of human papillomavirus in patients with suspicious cytological and colposcopy results: A prospective study.

In patients with premalignant cervical lesions, human papillomavirus (HPV) infection, at any moment, may be spontaneously eliminated, or may persist or transform cervical epithelium from a lower to a higher degree. Due to that, it is necessary to wisely select the patients who are at high risk of cancer development. The aim of the study was to establish the interdependence between a suspicious Papanicolaou (Pap) test and colposcopy with the infection caused by high-risk genotypes of human papillomavirus and the presence of premalignant cervical lesions. This prospective study used cytological, colposcopy, real-time polymerase chain reaction (PCR) of high-risk genotypes of human papillomavirus and histopathological analysis of cervical biopsy specimen. Out of 2,578 female patients sent to cytological analyses in Clinical Center of Montenegro, during 2012, 2013 and 2014, the study included 80 women who had to submit their biopsy specimens due to a suspicious Pap test and atypical colposcopy results. In the group of 80 (3.1%; n = 80/2,578) of the selected female patients with suspicious Pap test and colposcopy, 2/3 or 56 (70%) of them had cervicitis, and 1/3 or 24 (30%) had cervical intraepithelial neoplasia. The most common type in cervical intraepithelial neoplasia was HPV16 in 8 female patients, ie 61.53% out of the number of infected, or 33.33% out of the total number of premalignant lesions Patients with suspicious Papanicolaou test, colposcopy results and infection which is caused by high-risk HPV infection (HPV 16 in particular) often have premalignant cervical lesions. In these cases, histopathological confirmation of lesions is mandatory, since it serves as a definitive diagnostic procedure.

Altered Hematological and Biochemical Parameters in Schoolchildren Living in an Agricultural Community of Merida State, Venezuela

Epidemiological studies have found that children living in a pesticide treated farmland have higher risk of developing cancer or other serious health problems. Their exposure to pesticides could be limited by periodic health assessments; however, there are few biomarkers for pesticide exposure. The aim of this work was to examine the effects of chronic exposure to pesticides on hematological and biochemical parameters in farm-resident children compared to urban-resident control children. A cross-sectional study was conducted in 72 farm schoolchildren and 41 controls; a follow-up study was done two years later on 20 participants. The children underwent a clinical examination, nutritional assessment, and blood sampling for complete hemogram and biochemical analysis of liver and renal functions, lipid and glucose metabolism, plasma cholinesterase, thyroid hormones and total antioxidant capacity. A prevalence of malnutrition and undernutrition were found in both exposed and control children. The most important hematological results were thrombocytosis in 48% of farm children, increased mean lymphocyte and monocyte counts, and decreased mean neutrophil counts compared to control. Butyrylcholinesterase activity was diminished in 35% of farm children. Alterations in biochemical parameters were observed between exposed and control groups, however, most of the results were within normal limits, except for the significant decrease in total antioxidant capacity. Follow-up study 2 years later showed normalized platelet and lymphocyte counts, however, decreased neutrophil counts was still observed. This study demonstrates that children living in an agricultural community are exposed to the health hazards of pesticides. Undernutrition and improper dental hygiene affect children’s overall health status and are likely to increase their vulnerability to toxic effects of pesticides.

Subcellular differential expression of Ep-ICD in oral dysplasia and cancer is associated with disease progression and prognosis

BackgroundIdentification of patients with oral dysplasia at high risk of cancer development and oral squamous cell carcinoma (OSCC) at increased risk of disease recurrence will enable rigorous personalized treatment. Regulated intramembranous proteolysis of Epithelial cell adhesion molecule (EpCAM) resulting in release of its intracellular domain Ep-ICD into cytoplasm and nucleus triggers oncogenic signaling. We analyzed the expression of Ep-ICD in oral dysplasia and cancer and determined its clinical significance in disease progression and prognosis.MethodsIn a retrospective study, immunohistochemical analysis of nuclear and cytoplasmic Ep-ICD and EpEx (extracellular domain of EpCAM), was carried out in 115 OSCC, 97 oral dysplasia and 105 normal oral tissues, correlated with clinicopathological parameters and disease outcome over 60 months for oral dysplasia and OSCC patients. Disease-free survival (DFS) was determined by Kaplan-Meier method and multivariate Cox regression analysis.ResultsIn comparison with normal oral tissues, significant increase in nuclear Ep-ICD and membrane EpEx was observed in dysplasia, and OSCC (p = 0.013 and < 0.001 respectively). Oral dysplasia patients with increased overall Ep-ICD developed cancer in short time period (mean = 47 months; p = 0.044). OSCC patients with increased nuclear Ep-ICD and membrane EpEx had significantly reduced mean DFS of 33.7 months (p = 0.018).ConclusionsOur study provided clinical evidence for Ep-ICD as a predictor of cancer development in patients with oral dysplasia and recurrence in OSCC patients, suggesting its potential utility in enhanced management of those patients detected to have increased risk of progression to cancer and recurrence in OSCC patients.

A Zebrafish Model of 5q-Syndrome Using CRISPR/Cas9 Targeting RPS14 Reveals a p53-Independent and p53-Dependent Mechanism of Erythroid Failure

5q-syndrome is a distinct form of myelodysplastic syndrome (MDS) where a deletion on chromosome 5 is the underlying cause. MDS is characterized by bone marrow failures, including macrocytic anemia. Genetic mapping and studies using various models support the notion that ribosomal protein S14 (RPS14) is the candidate gene for the erythroid failure. Targeted disruption of RPS14 causes an increase in p53 activity and p53-mediated apoptosis, similar to what is observed with other ribosomal proteins. However, due to the higher risk for cancer development in patients with ribosome deficiency, targeting the p53 pathway is not a viable treatment option. To better understand the pathology of RPS14 deficiency in 5q-deletion, we generated a zebrafish model harboring a mutation in the RPS14 gene. This model mirrors the anemic phenotype seen in 5q-syndrome. Moreover, the anemia is due to a late-stage erythropoietic defect, where the erythropoietic defect is initially p53-independent and then becomes p53-dependent. Finally, we demonstrate the versatility of this model to test various pharmacological agents, such as RAP-011, L-leucine, and dexamethasone in order to identify molecules that can reverse the anemic phenotype.

Cancer Prevention? Fundamental Genomic Alterations Are Present in Preneoplasia, Including Function of High Frequency Selected Mutations (HFSMs)

In a series of publications a special, tetraploid diplochromosomal division system to only two types of progeny cells (4n/4C/G1 and 2n/4C para-diploid) has been suggested to initiate preneoplasia that can lead to a cancerous pathway. Colorectal and other preneoplasia are known with the pathogenic, histological phases of hyperplasia to arrested adenoma/nevi that can give rise to dysplasia with high risk for cancer development. The present theme is to find solutions to tumorigenic unsolved, biological problems (queries), explainable from the tetraploid 4n-system, which would support its operation in the cancerous pathway. Presently admitted, the mutational sequencing of the cancer genome (cancer chemistry) cannot discover so-called “dark matter”, which herein is considered to be the queries. The solutions from the 4n-system were largely supported by mutated APC-induced same type of tetraploidy from the mitotic slippage process. But importantly, these behaviors and consequences could be linked to the beginning of hyperplastic lesions and their development to the arrest-phase of preneoplasia (polyps/nevi). Function of HFSMs is mostly unknown, but for Barrett’s esophagus, HFSMs (p53, p16ink4a) caused inactivation of the Rb gene, leading to dysplasia with 4n, aneuploid, abnormal cell cycles. In vitro models of the 4n-system from normal human cells recapitulated preneoplasia-like histopathological changes. It was speculated that the “cancer-crucial” step to dysplasia could be therapy-vulnerable to CRISPR-caspase editing, and perhaps antibody treatment. Additionally, the 4n-system with spontaneous cell-behaviors together with preneoplasia molecular data promises construction of a more truthful cancer-paradigm than from sequencing data alone.

Research progress of Lgr4 in gastrointestinal carcinomas

Gastrointestinal carcinomas, whose incidence increases in recent years, are among the malignancies with highest morbidity and mortality. Many patients are always advanced stages when having diagnosis. So far, there are no any reliable tumor biomarkers which are able to screen people with high risk of developing cancer. Studies have shown that the expression level of Lgr4 is high in gastrointestinal carcinomas and Lgr4 is useful in diagnosis, differential diagnosis and prognosis judgment of these carcinomas. Lgr4 belongs to the G-protein-coupled receptors family. Its function is to potentiate Wnt signaling and plays an important role in the development of multiple organs. Recent studies find that Lgr4 has close relationship with the development of many gastrointestinal carcinomas, such as gastric cancer and colorectal cancer(CRC). In this article we review recent progress in understanding the relationship between Lgr4 and gastrointestinal carcinomas.

Genotoxic Effect in Autoimmune Diseases Evaluated by the Micronucleus Test Assay: Our Experience and Literature Review

Autoimmune diseases (AD) are classified into organ-specific, systemic, and mixed; all forms of AD share a high risk for cancer development. In AD a destructive immune response induced by autoreactive lymphocytes is started and continues with the production of autoantibodies against different targets; furthermore apoptosis failure and loss of balance in oxidative stress as a consequence of local or systemic inflammation are common features seen in AD as well. Micronucleus (MN) assay can be performed in order to evaluate loss of genetic material in a clear, accurate, fast, simple, and minimally invasive test. The MN formation in the cytoplasm of cells that have undergone proliferation is a consequence of DNA fragmentation during mitosis and the appearance of small additional nuclei during interphase. The MN test, widely accepted for in vitro and in vivo genotoxicity research, provides a sensitive marker of genomic damage associated to diverse conditions. In here, we present a review of our work and other published papers concerning genotoxic effect in AD, identified by means of the MN assay, with the aim of proposing this tool as a possible early biomarker for genotoxic damage, which is a consequence of disease progression. Additionally this biomarker could be used for follow-up, to asses genome damage associated to therapies.

Reliability and validity of the alcohol use disorders identification test - consumption in screening for adults with alcohol use disorders and risky drinking in Japan.

Alcohol is well established as a risk factor for cancer development in many organ sites. To assess the reliability and validity of the Alcohol Use Disorders Identification Test - Consumption (AUDIT-C) for detecting alcohol use disorders or risky drinking in Japanese adults the present study was conducted. A test-retest method was applied with a 2-week interval with 113 health care employees. The κ coefficient, Cronbach's coefficient alpha, Spearman's correlation coefficient, and intraclass correlation coefficient (ICC) were determined and the validity of the AUDIT-C was analyzed using the data from a nationwide survey on adult alcohol use conducted in 2008 (n=4,123). The reliability of the AUDIT-C score was high (??coefficient=0.63, Cronbach's alpha=0.98, correlation coefficient=0.95, and ICC=0.95). According to the likelihood ratio and Youden index, appropriate cutoffs for the AUDIT-C were ≥ 5points in men and ≥4 points in women. The sensitivity and specificity of these cutoffs for identifying ≥8 points on the AUDIT were 0.88 and 0.80, respectively, for men (positive likelihood ratio [LR+]=4.5) and 0.96 and 0.87, respectively, for women (LR+=7.7). The sensitivity and specificity of the cutoffs for identifying ≥ 12 points on the AUDIT were 0.90 and 0.84, respectively, for men (LR+=5.8) and 0.93 and 0.94, respectively, for women (LR+=15.8). The sensitivity and specificity of the cutoffs for identifying ≥ 16 points on the AUDIT were 0.93 and 0.80, respectively, for men (LR+=4.7) and 0.92 and 0.98, respectively, for women (LR+=55.6). With higher scores on the AUDIT, the specificity decreased and false-positives increased. The appropriate cutoffs for identifying risky drinking were the same for both genders. The reliability and validity of the AUDIT-C are high, indicating that it is useful for identifying alcohol use disorders or risky drinking among the general population in Japan, a group at high risk of cancer development.

Bile acid dysregulation, gut dysbiosis, and gastrointestinal cancer.

Because of increasingly widespread sedentary lifestyles and diets high in fat and sugar, the global diabetes and obesity epidemic continues to grow unabated. A substantial body of evidence has been accumulated which associates diabetes and obesity to dramatically higher risk of cancer development, particularly in the liver and gastrointestinal tract. Additionally, diabetic and obese individuals have been shown to suffer from dysregulation of bile acid (BA) homeostasis and dysbiosis of the intestinal microbiome. Abnormally elevated levels of cytotoxic secondary BAs and a pro-inflammatory shift in gut microbial profile have individually been linked to numerous enterohepatic diseases including cancer. However, recent findings have implicated a detrimental interplay between BA dysregulation and intestinal dysbiosis that promotes carcinogenesis along the gut-liver axis. This review seeks to examine the currently investigated interactions between the regulation of BA metabolism and activity of the intestinal microbiota and how these interactions can drive cancer formation in the context of diabesity. The precarcinogenic effects of BA dysregulation and gut dysbiosis including excessive inflammation, heightened oxidative DNA damage, and increased cell proliferation are discussed. Furthermore, by focusing on the mediatory roles of BA nuclear receptor farnesoid x receptor, ileal transporter apical sodium dependent BA transporter, and G-coupled protein receptor TGR5, this review attempts to connect BA dysregulation, gut dysbiosis, and enterohepatic carcinogenesis at a mechanistic level. A better understanding of the intricate interplay between BA homeostasis and gut microbiome can yield novel avenues to combat the impending rise in diabesity-related cancers.

BRCA1 and estrogen/estrogen receptor in breast cancer: where they interact?

BRCA1 mainly acts as a tumor suppressor and BRCA1 mutation correlates with increased cancer risk. Although it is well recognized that BRCA1 related tumorigenesis is mainly caused by the increased DNA damage and decreased genome stability, it is not clear that why BRCA1 related patients have higher risk for cancer development mainly in estrogen responsive tissues such as breast and ovary. Recent studies suggested that BRCA1 and E-ER (estrogen and estrogen receptor) signaling synergistically regulate the mammary epithelial cell proliferation and differentiation. In this current presentation, we reviewed the correlation between mammary gland epithelial cell transformation and the status of BRCA1 and ER. Then the mechanisms of BRCA1 and E-ER interaction at both gene transcription level and protein-protein interaction level are discussed. Furthermore, the tumorigenic mechanisms are discussed by focusing on the synergistic effect of BRCA1 and E-ER on cell metabolism, ROS management, and antioxidant activity in mammary gland epithelial cells. Also, the possibility of cell de-differentiation promoted by coordinated effect between BRCA1 mutation and E-ER signal is explored. Together, the currently available evidences suggest that BRCA1 mutation and E-ER signal together, contribute to breast tumorigenesis by providing the metabolic support for cancer cell growth and even may directly be involved in promoting the de-differentiation of cancer-prone epithelial cells.

S100A7 overexpression is a predictive marker for high risk of malignant transformation in oral dysplasia

Early detection of oral lesions (OLs) at high risk of cancer development is of utmost importance for intervention. There is an urgent unmet clinical need for biomarkers that allow identification of high-risk OLs. Recently, we identified and verified a panel of five candidate protein biomarkers namely S100A7, prothymosin alpha, 14-3-3ζ, 14-3-3σ and heterogeneous nuclear ribonucleoprotein K using proteomics to distinguish OLs with dysplasia and oral cancers from normal oral tissues. The objective of our study was to evaluate the potential of these candidate protein biomarkers for identification of oral dysplastic lesions at high risk of cancer development. Using immunohistochemistry, we analyzed expressions of these five candidate protein biomarkers in 110 patients with biopsy-proven oral dysplasia and known clinical outcome and determined their correlations with p16 expression and HPV 16/18 status. Kaplan-Meier survival analysis showed reduced oral cancer-free survival (OCFS) of 68.6 months (p = 0.007) in patients showing cytoplasmic S100A7 overexpression when compared to patients with weak or no S100A7 immunostaining in cytoplasm (mean OCFS = 122.8 months). Multivariate Cox regression analysis revealed cytoplasmic S100A7 overexpression as the most significant candidate marker associated with cancer development in dysplastic lesions (p = 0.041, hazard ratio = 2.36). In conclusion, our study suggested the potential of S100A7 overexpression in identifying OLs with dysplasia at high risk of cancer development.