| 1. |
- Ma, Yuanjun, et al.
(författare)
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Identification of mutations, gene expression changes and fusion transcripts by whole transcriptome RNAseq in docetaxel resistant prostate cancer cells
- 2016
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Ingår i: SpringerPlus. - : Springer Science and Business Media LLC. - 2193-1801. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Docetaxel has been the standard first-line therapy in metastatic castration resistant prostate cancer. The survival benefit is, however, limited by either primary or acquired resistance. In this study, Du145 prostate cancer cells were converted to docetaxel-resistant cells Du145-R and Du145-RB by in vitro culturing. Next generation RNAseq was employed to analyze these cell lines. Forty-two genes were identified to have acquired mutations after the resistance development, of which thirty-four were found to have mutations in published sequencing studies using prostate cancer samples from patients. Fourteen novel and 2 previously known fusion genes were inferred from the RNA-seq data, and 13 of these were validated by RT-PCR and/or re-sequencing. Four in-frame fusion transcripts could be transcribed into fusion proteins in stably transfected HEK293 cells, including MYH9-EIF3D and LDLR-RPL31P11, which were specific identified or up-regulated in the docetaxel resistant DU145 cells. A panel of 615 gene transcripts was identified to have significantly changed expression profile in the docetaxel resistant cells. These transcriptional changes have potential for further study as predictive biomarkers and as targets of docetaxel treatment.
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| 2. |
- Peng, Zhuochun
(författare)
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Identification, validation and clinical application of a three-gene signature for accurate prognosis prediction and treatment selection of newly diagnosed prostate cancer
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis presents a complete, comprehensive and stepwise approach of translational molecular research. Starting from whole-genome bioinformatics analyses based on the embryonic stem (ES) cell hypothesis, a three-gene signature was identified, validated with the goal of clinical application in order to optimize treatment decision based on improvement of overall survival estimation. In Paper I, we hypothesized that gene signatures of embryonic stem (ES) cells may have prominent importance to determine the tumor subtypes and may be associated with the prognosis of various cancers including prostate cancer (PCa). Using published microarray datasets, 641 embryonic stem cell gene predictors (ESCGPs) were identified. Using gene expression patterns of these 641 ESCGPs tumor subtypes of different cancers can be stratified, particularly for prostate cancer. We further analyzed the gene expression levels of selected ESCGP genes in fresh-frozen fine needle aspiration biopsy samples taken from a Swedish cohort of 189 prostate cancer patients. The registry follow-up period for these patients was up to18 years, where 97.9% patients had overall and cancer-specific survival data. As a result, a three-gene signature (VGLL3, IGFBP3 and F3) was identified sufficient to categorize the patients into high-risk, intermediate-risk and low-risk subtypes directly correlated with the overall and cancer-specific survival. Currently, formalin-fixed paraffin embedded (FFPE) prostate core needle biopsy material is the most common sample material available in clinical practice, on which Gleason grading for prostate cancer diagnosis is usually conducted. Since each patient typically has multiple biopsy samples, and since Gleason grading is an operator dependent procedure known to be difficult, the impact of the operator’s choice of biopsy was evaluated in paper II. We analyzed expression levels of the three-gene signature identified in paper I, using a four multiplex one- step RT-qPCR kit specially designed and optimized for measuring the three-gene expression signature in 127 FFPE prostate core needle biopsy samples taken from 43 patients. Our results show that the assessment of expression levels of two highly expressed genes (IGFBP3 and F3) in prostate cancer tissue is independent of Gleason patterns. These findings indicate that the impact of operator’s choice of biopsy is low. In paper III, we carried out a new cohort study including 241 prostate cancer patients with 6-9 years of registry follow up in order to verify the prognostic value of the three-gene expression signature in FFPE prostate core needle biopsy tissue samples. The cohort consisted of four patient groups with different survival times and cause of death (COD). We observed that supplementing readily available clinical data with gene expression levels of IGFBP3 and F3 in FFPE PCa biopsy tissues could improve survival prediction for PCa patients at time of diagnosis. Based on the above work, a so-called Prostatype test system has been industrially designed and developed for clinical application. It integrates a robust multiplex RT-qPCR kit to measure expression levels of the three-gene signature and, a database of reference patients with accurate clinical documentation using a kNN-algorithm called CPMA (Classification of Prostatic Malignancy Algorithm). The survival prediction in relation to different treatment modalities can greatly assist both clinicians and patients to make an individualized treatment decision.
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| 3. |
- Peng, Zhuochun, et al.
(författare)
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Improving the Prediction of Prostate Cancer Overall Survival by Supplementing Readily Available Clinical Data with Gene Expression Levels of IGFBP3 and F3 in Formalin-Fixed Paraffin Embedded Core Needle Biopsy Material
- 2016
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Background A previously reported expression signature of three genes (IGFBP3, F3 and VGLL3) was shown to have potential prognostic value in estimating overall and cancer-specific survivals at diagnosis of prostate cancer in a pilot cohort study using freshly frozen Fine Needle Aspiration (FNA) samples. Methods We carried out a new cohort study with 241 prostate cancer patients diagnosed from 20042007 with a follow-up exceeding 6 years in order to verify the prognostic value of gene expression signature in formalin fixed paraffin embedded (FFPE) prostate core needle biopsy tissue samples. The cohort consisted of four patient groups with different survival times and death causes. A four multiplex one-step RT-qPCR test kit, designed and optimized for measuring the expression signature in FFPE core needle biopsy samples, was used. In archive FFPE biopsy samples the expression differences of two genes (IGFBP3 and F3) were measured. The survival time predictions using the current clinical parameters only, such as age at diagnosis, Gleason score, PSA value and tumor stage, and clinical parameters supplemented with the expression levels of IGFBP3 and F3, were compared. Results When combined with currently used clinical parameters, the gene expression levels of IGFBP3 and F3 are improving the prediction of survival time as compared to using clinical parameters alone. Conclusion The assessment of IGFBP3 and F3 gene expression levels in FFPE prostate cancer tissue would provide an improved survival prediction for prostate cancer patients at the time of diagnosis.
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| 4. |
- Peng, Zhuochun, et al.
(författare)
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Operator Dependent Choice of Prostate Cancer Biopsy Has Limited Impact on a Gene Signature Analysis for the Highly Expressed Genes IGFBP3 and F3 in Prostate Cancer Epithelial Cells
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:10, s. e109610-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Predicting the prognosis of prostate cancer disease through gene expression analysis is receiving increasing interest. In many cases, such analyses are based on formalin-fixed, paraffin embedded (FFPE) core needle biopsy material on which Gleason grading for diagnosis has been conducted. Since each patient typically has multiple biopsy samples, and since Gleason grading is an operator dependent procedure known to be difficult, the impact of the operator's choice of biopsy was evaluated. Methods: Multiple biopsy samples from 43 patients were evaluated using a previously reported gene signature of IGFBP3, F3 and VGLL3 with potential prognostic value in estimating overall survival at diagnosis of prostate cancer. A four multiplex one-step qRT-PCR test kit, designed and optimized for measuring the signature in FFPE core needle biopsy samples was used. Concordance of gene expression levels between primary and secondary Gleason tumor patterns, as well as benign tissue specimens, was analyzed. Results: The gene expression levels of IGFBP3 and F3 in prostate cancer epithelial cell-containing tissue representing the primary and secondary Gleason patterns were high and consistent, while the low expressed VGLL3 showed more variation in its expression levels. Conclusion: The assessment of IGFBP3 and F3 gene expression levels in prostate cancer tissue is independent of Gleason patterns, meaning that the impact of operator's choice of biopsy is low.
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