Emerging evidence for CHFR as a cancer biomarker : from tumor biology to precision medicine

Novel insights in the biology of cancer have switched the paradigm of a "one-size-fits-all" cancer treatment to an individualized biology-driven treatment approach. In recent years, a diversity of biomarkers and targeted therapies has been discovered. Although these examples accentuate the promise of personalized cancer treatment, for most cancers and cancer subgroups no biomarkers and effective targeted therapy are available. The great majority of patients still receive unselected standard therapies with no use of their individual molecular characteristics. Better knowledge about the underlying tumor biology will lead the way toward personalized cancer treatment. In this review, we summarize the evidence for a promising cancer biomarker: checkpoint with forkhead and ring finger domains (CHFR). CHFR is a mitotic checkpoint and tumor suppressor gene, which is inactivated in a diverse group of solid malignancies, mostly by promoter CpG island methylation. CHFR inactivation has shown to be an indicator of poor prognosis and sensitivity to taxane-based chemotherapy. Here we summarize the current knowledge of altered CHFR expression in cancer, the impact on tumor biology and implications for personalized cancer treatment

Ovarian Cancer Genetics: Subtypes and Risk Factors

The genetics of ovarian cancer are a complex, ever evolving concept that presents hurdles in classification, diagnosis, and treatment in the clinic. Instead of common driver mutations, genomic instability is one of the hallmarks of ovarian cancer. While ovarian cancer is stratified into different clinical subtypes, there still exists extensive genetic and progressive diversity within each subtype. In high-grade serous ovarian cancer, the most common subtype, TP53 is mutated in over 90% of all patients while the next most common mutation is less than 20%. However, next-generation sequencing and biological statistics have shown that mutations within DNA repair pathways, including BRCA1 and BRCA2, are common in about 50% of all high-grade serous patients leading to the development of a breakthrough therapy of poly ADP ribose polymerase (PARP) inhibitors. This is just one example of how a better understanding of the complex genetic background of ovarian cancer can improve clinical treatment. A thorough review of ovarian cancer genetics and the effect it has on disease development, diagnosis, progression, and treatment will enhance the understanding of how to better research and treat ovarian cancer

Molecular Research of Endometrial Pathophysiology

The endometrium has been the subject of intense research in a variety of clinical settings, because of its importance in the reproductive process and its role in women’s health. In the past 15 years, significant efforts have been invested in defining the molecular phenotype of the receptive phase endometrium as well as of various endometrial pathologies. Although this has generated a wealth of information on the molecular landscape of human endometrium, there is a need to complement this information in light of the novel methodologies and innovative technical approaches. The focus of this International Journal of Molecular Sciences Special Issue is on molecular and cellular mechanisms of endometrium and endometrium-related disorders. The progress made in the molecular actions of steroids, in the metabolism of steroids and intracrinology, in endometrial intracellular pathways, in stem cells biology, as well as in the molecular alterations underlying endometrium-related pathologies has been the focus of the reviews and papers included

Molecular analysis and application of tissue microarray technology to the histopathological and immunohistochemical analysis of cervical adenocarcinoma

Cervical cancer is the second most common cancer among women worldwide. Cervical adenocarcinoma accounts for 15-25% of all cervical cancers and the incidence appears to be increasing. Although some of this increase may be due to better recognition by pathologists, there is evidence that the incidence of both endocervical adenocarcinoma and its preinvasive precursor lesion cervical glandular intraepithelial neoplasia is actually increasing in real terms. In this study, tissue microarray technology was used to study the morphological features of cervical adenocarcinoma archival donor blocks, to evaluate the immunoprofile of a large set of cervical adenocarcinomas with an extended panel of antibodies to compare the profile of AIS with invasive subtypes of cervical adenocarcinomas. The prevalence of HPV 16&18 in cervical adenocarcinoma cases was assessed to evaluate its relation to cervical adenocarcinoma. Using haematoxylin and eosin staining method 273 samples (blocks) were obtained from 177 biopsies composed of 16 normal cervical biopsies, 139 different patients with endocervical adenocarcinomas, and 22 patients with second biopsies. Pathology reports and cervical smear history reports were reviewed. Morphological and histopathological features of 139 patients with cervical adenocarcinomas revealed that there were 20 patients with adenocarcinoma-in-situ and 119 with invasive adenocarcinoma. Sixteen of 119 patients with invasive adenocarcinoma had early invasive adenocarcinoma which met criteria for FIGO stage IAi carcinoma of the cervix. The tissue microarray technique has been demonstrated to be efficient and applicable to various tumour types, but methodological evaluations are few. A tissue microarray was constructed using paraffin-embedded, formalin-fixed tissues from 273 samples (blocks). Two paired 0.6-mm cores were obtained from selected regions of archival donor blocks and subsequently were arrayed into a recipient paraffin array blocks. More than 2 areas were taken from some tumours. The novel array blocks and some whole sections were used for immunohistochemical analysis and H&E staining. Results revealed that the tissue microarray method yields staining of good quality and is feasible for histopathological and immunohistochemical studies in cervical adenocarcinoma. In general, the average staining pattern agreed with the whole section in each. Analysis of two TMA cores achieved 100% representation for histopathological type and greater than 97% representation for immunohistochemical studies. Tissue array sections were immunostained with 8 antibodies, carcinoembryonic antigen (CEA), Cytokeratin7 (CK7), Cytokeratin20 (CK20), estrogen receptor (ER), progesterone receptor (PgR), phosphatase and tensin homolog deleted on chromosome ten (PTEN), MIB-1 proliferation marker, and p53 suppressor gene utilizing the "Power Vision" technique for ER only and "Envision" technique for all other antibodies. Our findings support that all of these 8 antibodies are of potential biomarkers of a panel of antibodies for diagnosis of cervical adenocarcinomas. HPV DNA was extracted from paraffin-embedded, formalin-fixed tissues of 161 specimens of 139 patients excluding 22 patients with second samples and 16 normal cervical tissues. HPV DNA was detected by PCR test using type specific primers from the E6 gene and E7 gene of HPV type 16 and HPV type 18. Out of a total of 257 cervical biopsies from 139 women with various cervical adenocarcinomas lesions, HPV DNA was identified in 87 cases (62.6%) in which, HPV16 was positive for 65 (47%) patients and HPV 18 was positive for 41 (29%) patients. Genotyping by RFLP and PCR revealed that HPV type 16 was the most frequent type of infection comprising 46 cases (33%), followed by HPV type 18 in 22 cases (16%), and both HPV typel6 and HPV type 18 in 19 cases (14%). HPV typing in all cases of 16 normal cervical biopsies was negative with both HPV typel6 and HPV type 18. The findings support that HPV 16, along with HPV 18, may play a possible role in the pathogenesis of adenocarcinoma of the uterine cervix

Cyclin B1 mediates the effect of UCHL1 in promoting cell cycle progression in uterine papillary serous carcinoma

Uterine papillary serous carcinoma (UPSC) is an aggressive form of endometrial cancer with poor survival rates and a high risk of recurrence. The rarity of UPSC poses challenges to the discovery of novel targeted therapies. Therefore, the purpose of this dissertation was to identify novel therapeutic targets that could aid in the management of UPSC. To do so, we began with the relatively large cohort of UPSC cases in the TCGA data set, which was used to identify differentially expressed genes between UPSC and low-grade endometrioid endometrial carcinoma (EEC) and normal tissue. We identified Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) to be a gene of interest, as it was significantly upregulated in UPSC and correlated with poorer overall survival. These findings were validated through immunohistochemical analysis of an independent cohort of tumor samples. Due to its role as a deubiquitinating enzyme, we hypothesized that UCHL1 contributes to UPSC tumor progression by modulating the protein stability of target genes. To test this hypothesis, we first examined the functional role of UCHL1 in UPSC progression. Subsequently, we found that UCHL1 silencing reduced cell proliferation in vitro and in vivo. The treatment of UPSC-bearing mice with the UCHL1-specific inhibitor LDN-57444 via intraperitoneal injection also reduced tumor growth and increased overall survival times. Next, we found that the effect of UCHL1 on increased cell proliferation was due to its ability to stabilize cyclin B1 protein, an essential protein in mitotic progression. Specifically, we demonstrated that UCHL1 and cyclin B1 interact with each other in both the cytoplasm and nuclear space prior to mitosis. UCHL1 silencing increased the deubiquitination of cyclin B1, suggesting that UCHL1 counteracts the ubiquitination of cyclin B1 by the anaphase-promoting complex. Accordingly, UCHL1 silencing slowed the progression of cells into mitosis. Taken together, our findings indicate that UCHL1 impairs the degradation of cyclin B1, leading to uncontrolled cell cycle progression. In summary, we have identified UCHL1 as a prognostic marker for UPSC and a viable therapeutic target

EPMA position paper in cancer:current overview and future perspectives

At present, a radical shift in cancer treatment is occurring in terms of predictive, preventive, and personalized medicine (PPPM). Individual patients will participate in more aspects of their healthcare. During the development of PPPM, many rapid, specific, and sensitive new methods for earlier detection of cancer will result in more efficient management of the patient and hence a better quality of life. Coordination of the various activities among different healthcare professionals in primary, secondary, and tertiary care requires well-defined competencies, implementation of training and educational programs, sharing of data, and harmonized guidelines. In this position paper, the current knowledge to understand cancer predisposition and risk factors, the cellular biology of cancer, predictive markers and treatment outcome, the improvement in technologies in screening and diagnosis, and provision of better drug development solutions are discussed in the context of a better implementation of personalized medicine. Recognition of the major risk factors for cancer initiation is the key for preventive strategies (EPMA J. 4(1):6, 2013). Of interest, cancer predisposing syndromes in particular the monogenic subtypes that lead to cancer progression are well defined and one should focus on implementation strategies to identify individuals at risk to allow preventive measures and early screening/diagnosis. Implementation of such measures is disturbed by improper use of the data, with breach of data protection as one of the risks to be heavily controlled. Population screening requires in depth cost-benefit analysis to justify healthcare costs, and the parameters screened should provide information that allow an actionable and deliverable solution, for better healthcare provision

MicroRNA and Cancer

MicroRNAs (miRs) are small noncoding RNAs that function as post-transcriptional regulators of gene expression and have important roles in almost all biological pathways. Deregulated miR expression has been detected in numerous cancers, where miRs act as both oncogene and tumor suppressors. Due to their important roles in tumorigenesis, miRs have been investigated as prognostic and diagnostic biomarkers and as useful targets for therapeutic intervention. From a therapeutic point of view, two modalities can serve to rectify gene networks in cancer cells. For oncomiRs, a rational means is downregulation through antagomirs. Moreover, observations of the pathological reductions in tumor-suppressive miRs have inspired the concept of “miR replacement therapy” to enhance the amount of these miRs, thereby restoring them to normal levels. However, the clinical applicability of miR-based therapies is severely limited by the lack of effective delivery systems. Therefore, to understand the role of this new class of regulators, we need to identify the mRNA targets regulated by individual miRs as well as to develop specific, efficient, and safe delivery systems for therapeutic miRs