Background Little is known about epigenetic silencing of genes by promoter hypermethylation in renal cell carcinoma (RCC). The aim of this study was to identify prognostic methylation markers in surgically treated clear cell RCC (ccRCC). Methods Methylation patterns were assayed using the Infinium HumanMethylation450 BeadChip array on pairs of ccRCC and normal tissue from 12 patients. Using quantitative PSQ analysis, tumor-specific hypermethylated genes were validated in 25 independent cohorts and their clinical relevance was also verified in 152 independent cohorts. Results Using genome-wide methylation array, Zinc finger protein 278 ( ZNF278 ), Family with sequence similarity 155 member A ( FAM155A ) and Dipeptidyl peptidase 6 ( DPP6 ) were selected for tumor-specific hypermethylated genes in primary ccRCC. The promoter methylation of these genes occurred more frequently in ccRCC than normal kidney in independent validation cohort. The hypermethylation of three genes were associated with advanced tumor stage and high grade tumor in ccRCC. During median follow-up of 39.2 (interquartile range, 15.4–79.1) months, 22 (14.5%) patients experienced distant metastasis. Multivariate analysis identified the methylation status of these three genes, either alone, or in a combined risk score as an independent predictor of distant metastasis. Conclusion The promoter methylation of ZNF278 , FAM155A and DPP6 genes are associated with aggressive tumor phenotype and early development of distant metastasis in patients with surgically treated ccRCC. These potential methylation markers, either alone, or in combination, could provide novel targets for development of individualized therapeutic and prevention regimens.
Very young breast cancer patients are more common in Asian countries than Western countries and are thought to have worse prognosis than older patients. The aim of the current study was to identify molecular characteristics of young patients with estrogen receptor ( ER )‐positive breast cancer by analyzing mutations and copy number variants ( CNV ), and by applying expression profiling. The whole exome and transcriptome of 47 Korean young breast cancer ( KYBR ) patients (age <35) were analyzed. Genomic profiles were constructed using mutations, CNV and differential gene expression from sequencing data. Pathway analyses were also performed using gene sets to identify biological processes. Our data were compared with young ER + breast cancer patients in The Cancer Genome Atlas ( TCGA ) dataset. TP 53 , PIK 3 CA and GATA 3 were highly recurrent somatic mutation genes. APOBEC ‐associated mutation signature was more frequent in KYBR compared with young TCGA patients. Integrative profiling was used to classify our patients into 3 subgroups based on molecular characteristics. Group A showed luminal A‐like subtype and IGF 1R signal dysregulation. Luminal B patients were classified into groups B and C, which showed chromosomal instability and enrichment for APOBEC 3A/B deletions, respectively. Group B was characterized by 11q13 ( CCND 1) amplification and activation of the ubiquitin‐mediated proteolysis pathway. Group C showed 17q12 ( ERBB 2) amplification and lower ER and progesterone receptor expression. Group C was also distinguished by immune activation and lower epithelial‐mesenchyme transition ( EMT ) degree compared with group B. This study showed that integrative genomic profiling could classify very young patients with breast cancer into molecular subgroups that are potentially linked to different clinical characteristics.
The present study aimed to identify novel methylation markers of clear cell renal cell carcinoma (ccRCC) using microarray methylation analysis and evaluate their prognostic relevance in patient samples. To identify cancer-specific methylated biomarkers, microarray profiling of ccRCC samples from our institute (n=12) and The Cancer Genome Atlas (TCGA) database (n=160) were utilized, and the prognostic relevance of candidate genes were investigated in another TCGA dataset (n=153). For validation, pyrosequencing analyses with ccRCC samples from our institute (n=164) and another (n=117) were performed and the potential clinical application of selected biomarkers was examined. We identified 22 CpG island loci that were commonly hypermethylated in ccRCC. Kaplan-Meier analysis of TCGA data indicated that only 4/22 loci were significantly associated with disease progression. In the internal validation set, Kaplan-Meier analysis revealed that hypermethylation of two loci, zinc finger protein 492 (ZNF492) and G protein-coupled receptor 149 (GPR149), was significantly associated with shorter time-to-progression. Multivariate Cox regression models revealed that hypermethylation of ZNF492 [hazard ratio (HR), 5.44; P=0.001] and GPR149 (HR, 7.07; P<0.001) may be independent predictors of tumor progression. Similarly, the methylation status of these two genes was significantly associated with poor outcomes in the independent external validation cohort. Collectively, the present study proposed that the novel methylation markers ZNF492 and GPR149 could be independent prognostic indicators in patients with ccRCC.
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In this study, an integrated deep learning framework was developed for classifying the periodontitis stages of each individual tooth using dental panoramic radiographs. Based on actual patient panoramic radiographs data, the bone loss by periodontitis and cementoenamel junction boundaries were detected, while the tooth number and tooth length were identified using data from AIHub, an open database platform. The two factors were integrated to classify and to evaluate the periodontitis staging on dental panoramic radiography. Periodontitis is classified into four stages based on the criteria of the radiographic bone level, as suggested at the relevant international conference in 2017. For the integrated deep learning framework developed in this study, the classification performance was evaluated by comparing the results of dental specialists, which indicated that the integrated framework had an accuracy of 0.929, with a recall and precision of 0.807 and 0.724, respectively, in average across all four stages. The novel framework was thus shown to exhibit a relatively high level of performance, and the findings in this study are expected to assist dental specialists with detecting the periodontitis stage and subsequent effective treatment. A systematic application will be developed in the future, to provide ancillary data for diagnosis and basic data for the treatment and prevention of periodontal disease.
Background: The aim of the current study was to investigate the role of Circular RNA(circRNA) circASS1 in breast cancer(BC) cells, and this may be a novel therapy and a potential diagnostic biomarker or targeted treatment of BC. Methods: We analyzed the expression profile of human circRNAs in two BC cell lines: MCF-7, MDA-MB-231 by the circRNAs microarray, and we found the dysregulated circRNA: circASS1. Then the expression of circASS1 in breast cancer cells were identified. Next, measure of the abilities of invasion and migration were carried out by overexpressing circASS1 or silencing circASS1 in MDA-MB-231 and MCF-7, respectively. Luciferase Assay System were also carried out to detect harbored miRNA. Then, measure of the abilities of invasion and migration were carried out by overexpressing miR-4443 mimics. At last, the expression of circASS1's parental gene, ASS1 in gain-of-function and loss-of-function experiments were also quantitative analyzed. Results: Compared with MCF-7, the expression level of circASS1 in MDA-MB-231 is down-regulated. What is more, the results show overexpression of circASS1 could suppress invasion and migration in MDA-MB-231. On the contrary, silence of circASS1 could promote invasion and migration in MCF-7. miR-4443 could be captured by circASS1 according to Luciferase Assay System results, which could promote the ability of invasion and migration in MCF-7. Last, the expression of ASS1 is up-regulated in loss-of-function experiments, while down-regulated in gain-of-function experiments. Western blotting showed ASS1 up-regulated in loss-of-function experiments. Conclusions: CircASS1 suppresses invasion and migration capacity of BC cells by increasing expression of ASS1 and circASS1 could harbor miR-4443, suggesting that circASS1 could be a potential target in BC treatment and a prospective prognostic biological marker in BC.
Objective: The molecular profile of primary breast cancer has been studied associated with drug responses. Metastatic triple-negative breast cancer (mTNBC) is heterogeneous disease and there is no effective therapeutic target. We investigated the genomic profiles of mTNBC to find potential drug targets. Methods: Metastatic breast cancer samples were collected for genomic analysis (fresh tissue, n=17; FFPE, n=28). We conducted both whole-exome sequencing and RNA-seq for these samples and validated genomic variants by Sanger sequencing. We built up pipelines for somatic mutation, copy number alteration, mRNA expression, and fusion gene analysis. Precise somatic mutations were additionally filtered out for FFPE without matched normal. In addition, we investigated the differences of genomic profiles of mTNBC with those of primary breast cancer from TCGA data. Results: Most of somatic mutation profiles of mTNBC were similar with those of primary cancer. However, there were some specific alterations that were not found in primary tumor. TP53 (>40 %) was concordantly discovered with primary TNBC, but KDM6A (>20 %) was highly recurrent than other breast datasets. We ascertained the diversity of immune cell activity from mRNA expression analysis, and additional pathways also represented the variance within our mTNBC population, which was differentiated from those of primary breast cancer. In addition, we found two novel FGFR1/2 fusion in two cases and validated it by RT-PCR and Western blot. Conclusion: We found specific genomic profiles of mTNBC that were distinct from those of primary tumor. Novel structural variants discovered in our dataset could be potential therapeutic targets for mTNBC patients. Citation Format: Wooyeong Jang, Jihyun Kim, Hanna Yang, Youngmee Kwon, Keun Seok Lee, Sung Hoon Sim, Sun-Young Kong, Kyounghee An, In Hae Park, Charny Park. The genomic profile investigation of metastatic triple-negative breast cancer for precision medicine achievement [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4279.
Objective: The heterogeneity of triple negative breast cancer (TNBC) confers the difficulties in chemotherapy and induces poor outcome. Subtype classification of TNBC using gene expression profile could achieve to identify molecular markers to suggest therapeutic guidance. Methods: In this study, we collected gene expression profiles of 957 TNBC patients from GEO and integrated into one meta-data using meta analysis. We identified subtypes using nonnegative matrix factorization (NMF) and explored for comprehensive characteristics of consensus molecular subtype (CMS) by investigating key pathway activity, tumor microenvironment, stemness and so on. In addition, we computed the drug response score (DRscore) from MSigDB chemical perturbation signature gene set and examined drug associations with key pathways of CMS. Drug candidates were validated from independent two data sets; our patients’ expression profile (n = 38) and biobank TNBC organoids (n=64). Results: We classified four different TNBC subtypes displaying gene expression patterns including mesenchymal-like (MSL), luminal-AR (LAR), immunomodulatory (IM), and stem-like (SL). MSL were activated pathways with epithelial-to-mesenchymal (EMT) and TGF-beta signaling whereas SL was up-regulation of cell cycle and WNT signaling pathway. The LAR subtype was activated of androgen and estrogen receptor pathway. Although metastatic TNBC generally shared equal activity of key pathways with primary, coagulation, toll-like receptors, TNF, and Jak-STAT signaling pathways were dysregulated in metastasis. Especially, SPP1 gene expression to induce metastasis was associated with poor prognosis. DRscores were discriminative in CMS of meta-data and biobank expression profile. We found subtype-specific 18 drugs as therapeutic candidates and these drugs were also correlated with key pathways. In a case of cisplatin, DRscores appear resistant in MSL while response in SL. Our patients’ expression profiles were shown to consistent result as well as biobank. Conclusion: These finding might facilitate understanding heterogeneity of TNBC. Our novel approach to explore drug response suggested functional intervention landscape of drug response without in-vivo experiment. Taken together, we propose biomarkers for diagnosis and also suggest therapeutic strategy depending on CMS. Citation Format: Jihyun Kim, Doyeong Yu, Jiyoon Noh, Wooyeong Jang, Hanna Yang, Youngmee Kwon, Keun Seok Lee, Sung Hoon Sim, Sun-Young Kong, In Hae Park, Charny Park. Consensus molecular subtype of triple negative breast cancer to implicate in chemotherapy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3424.
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