Purpose: To evaluate the possible mechanisms influencing the infiltration of CD8 T lymphocytes into the tumor epithelium of advanced-stage serous ovarian cancers. Experimental Design: Immunohistochemical localization of CD8 T lymphocytes was done on a homogeneous population of 184 high-grade, advanced-stage serous ovarian cancer tissue specimens. Microarray analysis was done on microdissected tumor epithelium from 38 specimens to identify genes up-regulated or down-regulated in specimens with differing numbers of tumor-infiltrating CD8 T lymphocytes. Quantitative real-time PCR and immunohistochemistry were used to validate a candidate gene. Univariate and multivariate survival analyses were done combining CD8 T lymphocytenumberand HLA-DMBexpressionwithstandardprognostic factors. Results: Marked CD8 T lymphocyte infiltration of the tumor epithelium is associated with a 20-month improvement in median overall survival. Additionally, when combined with cytoreduction status and age, CD8 T lymphocyte status is an independent prognostic factor for survival. Microarray analysis showed HLA-DMB, a component of the MHC II antigen presentation machinery, to be differentially expressed in specimens with an abundance of tumor-infiltrating CD8 T lymphocytes. This relationship was validated at both mRNA and protein levels. As well, high HLA-DMB expression in the tumor epithelium was associated with a significant improvement in median overall survival in both univariate and multivariate analyses. Conclusions: Tumor cell expression of HLA-DMB is associated with increased numbers of tumor-infiltrating CD8 T lymphocytes and both are associated with improved survival in advanced-stage serous ovarian cancer.
The detection of differentially expressed (DE) genes, that is, genes whose expression levels vary between two or more classes representing different experimental conditions (say, diseases), is one of the most commonly studied problems in bioinformatics. For example, the identification of DE genes between distinct disease phenotypes is an important first step in understanding and developing treatment drugs for the disease. We present a novel approach to the problem of detecting DE genes that is based on a test statistic formed as a weighted (normalized) cluster-specific contrast in the mixed effects of the mixture model used in the first instance to cluster the gene profiles into a manageable number of clusters. The key factor in the formation of our test statistic is the use of gene-specific mixed effects in the cluster-specific contrast. It thus means that the (soft) assignment of a given gene to a cluster is not crucial. This is because in addition to class differences between the (estimated) fixed effects terms for a cluster, gene-specific class differences also contribute to the cluster-specific contributions to the final form of the test statistic. The proposed test statistic can be used where the primary aim is to rank the genes in order of evidence against the null hypothesis of no DE. We also show how a P-value can be calculated for each gene for use in multiple hypothesis testing where the intent is to control the false discovery rate (FDR) at some desired level. With the use of publicly available and simulated datasets, we show that the proposed contrast-based approach outperforms other methods commonly used for the detection of DE genes both in a ranking context with lower proportion of false discoveries and in a multiple hypothesis testing context with higher power for a specified level of the FDR.
BACKGROUND: ARID1A (AT-rich interactive domain 1A gene) has recently been identified as a novel tumor suppressor gene and one of the driver genes in endometrial carcinogenesis. Approximately 30% to 40% of endometrial carcinomas harbor mutations in the ARID1A gene, which results in complete loss of ARID1A protein expression. Although ARID1A aberrations are not restricted to endometrial cancer, the authors hypothesized that it might be a useful marker of malignancy in peritoneal washings for patients with endometrial cancer. METHODS: The cytology archive of Brigham and Women's Hospital was searched to identify cell blocks from peritoneal washings that contained malignant or benign endometrial epithelium. From 2006 through 2013, 17 cases of endometrial carcinoma (EMCA) and 16 cases of endometriosis were identified. Surgical pathology reports and follow-up data were used to confirm the diagnoses. Immunohistochemistry for ARID1A was performed, and slides were scored as 0 (complete loss of staining) or 1 (retained staining) by 2 independent pathologists. The discordant cases were resolved by consensus. The two-tailed Fisher exact probability test was used to calculate statistical significance. RESULTS: Complete loss of ARID1A expression was found in 8 of 17 EMCA cases (47%) and none of the 16 endometriosis cases (0%) (P 5.024). The concordance among the pathologists on first review was high (96.7%). CONCLUSIONS: The results of the current study demonstrated that ARID1A can be used in peritoneal washings to confirm malignancy in patients with EMCA. Complete loss of ARID1A expression by immunohistochemistry is highly specific for carcinoma, but retained expression is not informative. Cancer (Cancer Cytopathol) 2015;123:253-7.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.