Claudin7 and moesin in endometrial Adenocarcinoma; a retrospective study of 265 patients

<p>Abstract</p> <p>Background</p> <p>Metastasis is the main cause of death in cancer and is a multistep process. Moesin (MSN), a member of the ezrin-rdixin-moesin family and Claudin7 (CLDN7), a tight junction protein, both play a role in tumor cell metastasis. Previously, we found an over-expression of MSN and under-expression of CLDN7 at the mRNA level in uterine serous carcinoma in comparison to uterine endometrioid adenocarcinoma. The purpose of this study is to determine the protein expression of MSN and CLDN7 in endometrial cancer (EC) and to evaluate their prognostic value. Two hundred sixty-five patients with EC were retrieved from the archives. MSN and CLDN7 immunostaining were performed on the tissue paraffin sections. The expression of each antibody was reported and then correlated with clinicopathological prognostic factors including age, tumor grade, tumor stage, lympho-vascular involvement, depth of myometrial invasion, overall survival (OS), disease free survival (DFS) and death of disease (DOD).</p> <p>Results</p> <p>MSN and CLDN were expressed in 46% and 52% of overall cases. We observed an association between MSN<it>⁺</it>staining and tumor grade, and serous and clear cell carcinoma subtypes (<it>p </it>< 0.001 each). There was an association between CLDN7⁺staining and low tumor grade and endometrioid adenocarcinoma subtype (<it>p </it>< 0.001 and 0.001 respectively). However, no association between MSN and CLDN7 expression and outcome including OS, DOD, and DFS was found.</p> <p>Conclusion</p> <p>A significant prognostic value of MSN and CLDN7 in predicting disease outcomes in patients with EC was not demonstrated. Nevertheless, the high percentage of EC cases with MSN and CLDN7 immunoexpression, and their association with tumor grade and subtypes, suggests that these proteins might play a role in tumorigenesis of endometrial adenocarcinomas. Future studies are needed to shed light on their mechanistic properties in EC cells.</p

Ovarian Cancer Spheroid Cells with Stem Cell-Like Properties Contribute to Tumor Generation, Metastasis and Chemotherapy Resistance through Hypoxia-Resistant Metabolism

Cells with sphere forming capacity, spheroid cells, are present in the malignant ascites of patients with epithelial ovarian cancer (EOC) and represent a significant impediment to efficacious treatment due to their putative role in progression, metastasis and chemotherapy resistance. The exact mechanisms that underlie EOC metastasis and drug resistance are not clear. Understanding the biology of sphere forming cells may contribute to the identification of novel therapeutic opportunities for metastatic EOC. Here we generated spheroid cells from human ovarian cancer cell lines and primary ovarian cancer. Xenoengraftment of as few as 2000 dissociated spheroid cells into immune-deficient mice allowed full recapitulation of the original tumor, whereas >105 parent tumor cells remained non-tumorigenic. The spheroid cells were found to be enriched for cells with cancer stem cell-like characteristics such as upregulation of stem cell genes, self-renewal, high proliferative and differentiation potential, and high aldehyde dehydrogenase (ALDH) activity. Furthermore, spheroid cells were more aggressive in growth, migration, invasion, scratch recovery, clonogenic survival, anchorage-independent growth, and more resistant to chemotherapy in vitro. 13C-glucose metabolic studies revealed that spheroid cells route glucose predominantly to anaerobic glycolysis and pentose cycle to the detriment of re-routing glucose for anabolic purposes. These metabolic properties of sphere forming cells appear to confer increased resistance to apoptosis and contribute to more aggressive tumor growth. Collectively, we demonstrated that spheroid cells with cancer stem cell-like characteristics contributed to tumor generation, progression and chemotherapy resistance. This study provides insight into the relationship between tumor dissemination and metabolic attributes of human cancer stem cells and has clinical implications for cancer therapy

Complex Segregation Analysis of Pedigrees from the Gilda Radner Familial Ovarian Cancer Registry Reveals Evidence for Mendelian Dominant Inheritance

Familial component is estimated to account for about 10% of ovarian cancer. However, the mode of inheritance of ovarian cancer remains poorly understood. The goal of this study was to investigate the inheritance model that best fits the observed transmission pattern of ovarian cancer among 7669 members of 1919 pedigrees ascertained through probands from the Gilda Radner Familial Ovarian Cancer Registry at Roswell Park Cancer Institute, Buffalo, New York.Using the Statistical Analysis for Genetic Epidemiology program, we carried out complex segregation analyses of ovarian cancer affection status by fitting different genetic hypothesis-based regressive multivariate logistic models. We evaluated the likelihood of sporadic, major gene, environmental, general, and six types of Mendelian models. Under each hypothesized model, we also estimated the susceptibility allele frequency, transmission probabilities for the susceptibility allele, baseline susceptibility and estimates of familial association. Comparisons between models were carried out using either maximum likelihood ratio test in the case of hierarchical models, or Akaike information criterion for non-nested models. When assessed against sporadic model without familial association, the model with both parent-offspring and sib-sib residual association could not be rejected. Likewise, the Mendelian dominant model that included familial residual association provided the best-fitting for the inheritance of ovarian cancer. The estimated disease allele frequency in the dominant model was 0.21.This report provides support for a genetic role in susceptibility to ovarian cancer with a major autosomal dominant component. This model does not preclude the possibility of polygenic inheritance of combined effects of multiple low penetrance susceptibility alleles segregating dominantly

Original Article Higher than expected frequencies of non-ovarian cancers within a large familial ovarian cancer registry

Abstract: Our objective was to determine whether the frequencies of non-ovarian cancers (NOC) within families in a large Familial Ovarian Cancer Registry (FOCR) are significantly different from the frequencies listed in the SEER database. The FOCR was established in 1981. Registry members are families with two or more first degree relatives who have a diagnosis of ovarian cancer, three or more cases of cancer on one side of the family with at least one being ovarian, at least one female with two or more primary cancers in which one is ovary, or a history of two or more cancers in the family with at least one being ovarian cancer diagnosed before the age of 45. The data was analyzed to find relative rates of 10 of the most common cancers found within the database, with the exception of ovarian and breast. These include bladder, CNS, cervical, colorectal, liver, lung, pancreas, prostate, stomach, and uterine. Cancers were further stratified by age at diagnosis, and compared to information in the SEER database. There are 2,671 pedigrees and a total of 50,454 individuals within the FOCR. There are 1,938 families with two or more relatives with ovarian cancer, accounting for 4,816 individuals with ovarian cancer. The total number of individuals with ovarian cancer is 5,421. Of these individuals with ovarian cancer, 2,249 have been verified with testing or physician correspondence. The frequencies of the NOCs within the registry were higher than that of the general population as described in the SEER database. In particular, the overall frequencies of cancers of the bladder, cervix, prostate, and uterus were higher within the FOCR at 2.3, 7.4, 25.2, and 11.9 per 1,000 respectively. Furthermore, diagnoses of both cervical and uterine cancers tended to occur at an earlier age within the FOCR. The overall frequencies of cancers of the bladder, cervix, prostate, and uterus are higher in the FOCR compared with a general population database. Future studies on segregation analysis and genome-wide linkage studies are warranted on families with NOC within the Familial Ovarian Cancer Registry

Surgical-pathological findings in type 1 and 2 endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study on GOG-210 protocol

To report clinical and pathologic relationships with disease spread in endometrial cancer patients

Nonsteroidal Anti-inflammatory Drugs and Endometrial Carcinoma Mortality and Recurrence

Background: Recent data suggest that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with reductions in endometrial cancer risk, yet very few have examined whether their use is related to prognosis among endometrial cancer patients

Gene Expression Profiles in Stage I Uterine Serous Carcinoma in Comparison to Grade 3 and Grade 1 Stage I Endometrioid Adenocarcinoma

Endometrial cancer is the most common gynecologic malignancy in the developed countries. Clinical studies have shown that early stage uterine serous carcinoma (USC) has outcomes similar to early stage high grade endometrioid adenocarcinoma (EAC-G3) than to early stage low grade endometrioid adenocarcinoma (EAC-G1). However, little is known about the origin of these different clinical outcomes. This study applied the whole genome expression profiling to explore the expression difference of stage I USC (n = 11) relative to stage I EAC-G3 (n = 11) and stage I EAC-G1 (n = 11), respectively.We found that the expression difference between USC and EAC-G3, as measured by the number of differentially expressed genes (DEGs), is consistently less than that found between USC and EAC-G1. Pathway enrichment analyses suggested that DEGs specific to USC vs. EAC-G3 are enriched for genes involved in signaling transduction, while DEGs specific to USC vs. EAC-G1 are enriched for genes involved in cell cycle. Gene expression differences for selected DEGs are confirmed by quantitative RT-PCR with a high validation rate.This data, although preliminary, indicates that stage I USC is genetically similar to stage I EAC-G3 compared to stage I EAC-G1. DEGs identified from this study might provide an insight in to the potential mechanisms that influence the clinical outcome differences between endometrial cancer subtypes. They might also have potential prognostic and therapeutic impacts on patients diagnosed with uterine cancer

rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97-1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03-1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 x 10(-28)), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.Peer reviewe

Microarray Analysis Reveals Distinct Gene Expression Profiles Among Different Tumor Histology, Stage and Disease Outcomes in Endometrial Adenocarcinoma

Endometrial cancer is the most common gynecologic malignancy in developed countries and little is known about the underlying mechanism of stage and disease outcomes. The goal of this study was to identify differentially expressed genes (DEG) between late vs. early stage endometrioid adenocarcinoma (EAC) and uterine serous carcinoma (USC), as well as between disease outcomes in each of the two histological subtypes.Gene expression profiles of 20 cancer samples were analyzed (EAC = 10, USC = 10) using the human genome wide illumina bead microarrays. There was little overlap in the DEG sets between late vs. early stages in EAC and USC, and there was an insignificant overlap in DEG sets between good and poor prognosis in EAC and USC. Remarkably, there was no overlap between the stage-derived DEGs and the prognosis-derived DEGs for each of the two histological subtypes. Further functional annotation of differentially expressed genes showed that the composition of enriched function terms were different among different DEG sets. Gene expression differences for selected genes of various stages and outcomes were confirmed by qRT-PCR with a high validation rate.This data, although preliminary, suggests that there might be involvement of distinct groups of genes in tumor progression (late vs. early stage) in each of the EAC and USC. It also suggests that these genes are different from those involved in tumor outcome (good vs. poor prognosis). These involved genes, once clinically verified, may be important for predicting tumor progression and tumor outcome