Comprehensive analysis of 20q13 genes in ovarian cancer identifies ADRM1 as amplification target

Abstract

Approximately 25,000 ovarian cancers are diagnosed in the US annually, and 75% of cases are in the advanced stage when they are largely incurable. There is a critical need for improved early detection tools and development of novel treatments. Because chromosome band 20q13 is a commonly DNA amplified region in ovarian cancer and increase in 20q13 copy number may be an early event, we examined the DNA amplification and RNA expression pattern of 239 microarray probes mapping to this region with the goal of identifying gene(s) associated with ovarian cancer. Using Agilent expression microarray analysis and FISH to tumor tissue arrays, we narrowed the candidates to 19 genes that were consistently overexpressed in a subset of tumors amplified for both ZNF217 and TPD54, although, interestingly the candidates do not include these two amplified genes. Unsupervised clustering of 225 ovarian samples with respect to RNA expression of these 19 genes allowed identification of a 20q-amplified subset of 51 (23%) tumors and this subset was significantly correlated with poor outcome. Of the 19 candidate genes in this subset, ADRM1 overexpression was the most highly correlated with amplification, was amplified in a higher percentage of tumors than ZNF217 and TPD54, and was significantly upregulated with respect to stage, recurrence and metastasis. In addition, overexpression of ADRM1 correlates significantly with shorter time to recurrence and overall survival. Functional analysis is now warranted to determine whether ADRM1 is a target for early screening and/or therapy for ovarian cancer.

Gene Expression: Protein Interaction Systems Network Modeling Identifies Transformation-Associated Molecules and Pathways in Ovarian Cancer

“…All three amplifications seem to be early events during transformation; however, regulatory mechanisms seemed to be in place in untransformed cells because the node gene expression was significantly lower than in transformed cells. 6q, 8q, and 20q copy number changes are reported in ovarian cancer (17,18); 6q21-25 amplification in cisplatinresistant ovarian cancer (19) suggests SYNCRIP to be a useful predictive biomarker. LAMA5 has been identified as a predictor of amplification and biomarker for cervical cancer (20).…”

“…Bivalent and trivalent combinations of histone modifications are also reported in cancer (29). In an ongoing study, we have profiled the epigenetic status of genes in the A4 cell model on a genome-wide scale through Me-DIP for DNA methylation and ChIP-on-chip for histone methylation (K4, K9, and K27) from which we extracted data relating to SeOvCa genes MAL, MEST, PTGIS, PAPSS2, EFEMP1, and FBN1 because these are reported to be epigenetically regulated in human malignancies (18,(30)(31)(32)(33)(34)(35)(36). The transformed state was strikingly associated with hypomethylated promoters of the upregulated genes (MAL and MEST); this was further supported by two activation K4 marks upstream of the MAL transcription start site (TSS) and an enriched K4-K9 bivalent mark upstream of the MEST-TSS (Fig.…”

Knockdown of Adhesion-Regulating Molecule 1 Inhibits Proliferation in HL60 Cells

“…Together with other clinical studies [11][12][13][14][15][16][17][18] indicating that ADRM1 is overexpressed in several cancers, including ovarian, cervical, breast, prostate, bladder and colon cancer, other metastatic carcinomas, progressive malignant stages and cancers with poor prognoses, we hypothesized that the ADRM1 gene may also play a role in acute leukemia (AL) and that the inhibition of ADRM1 gene expression could be a potential therapeutic strategy for AL.…”

A possible connection between adhesion regulating molecule 1 overexpression and nuclear factor kappa B activity in hepatocarcinogenesis

“…Immunoreactivity was evaluated independently by two observers, who were blinded to the patients' clinicopathologic data. The staining intensities were scored as: none, weak, moderate, and strong, as previously described (12). Discrepancies were rechecked and final decisions were reached by consensus.…”

“…Studies show that ADRM1 is commonly overexpressed in tumors of different sources including liver, lung, colon, bladder, kidney, stomach and ovary (10,11). ADRM1 is also identified as an amplification target in ovarian cancer, and its overexpression is significantly associated with earlier recurrence and worse survival (12).…”