| 1. |
- Lapointe, Jacques, et al.
(author)
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Gene expression profiling identifies clinically relevant subtypes of prostate cancer
- 2004
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 101:3, s. 811-816
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Journal article (peer-reviewed)abstract
- Prostate cancer, a leading cause of cancer death, displays a broad range of clinical behavior from relatively indolent to aggressive metastatic disease. To explore potential molecular variation underlying this clinical heterogeneity, we profiled gene expression in 62 primary prostate tumors, as well as 41 normal prostate specimens and nine lymph node metastases, using cDNA microarrays containing ≈26,000 genes. Unsupervised hierarchical clustering readily distinguished tumors from normal samples, and further identified three subclasses of prostate tumors based on distinct patterns of gene expression. High-grade and advanced stage tumors, as well as tumors associated with recurrence, were disproportionately represented among two of the three subtypes, one of which also included most lymph node metastases. To further characterize the clinical relevance of tumor subtypes, we evaluated as surrogate markers two genes differentially expressed among tumor subgroups by using immunohistochemistry on tissue microarrays representing an independent set of 225 prostate tumors. Positive staining for MUC1, a gene highly expressed in the subgroups with "aggressive" clinicopathological features, was associated with an elevated risk of recurrence (P = 0.003), whereas strong staining for AZGP1, a gene highly expressed in the other subgroup, was associated with a decreased risk of recurrence (P = 0.0008). In multivariate analysis, MUC1 and AZGP1 staining were strong predictors of tumor recurrence independent of tumor grade, stage, and preoperative prostate-specific antigen levels. Our results suggest that prostate tumors can be usefully classified according to their gene expression patterns, and these tumor subtypes may provide a basis for improved prognostication and treatment stratification.
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| 2. |
- Li, Chunde
(author)
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Tracking functional changes in the cancer genome : a molecular genetic analysis of renal and prostatic carcinomas using PCR based techniques by a candidate chromosome and candidate gene approach
- 1999
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Doctoral thesis (other academic/artistic)abstract
- Renal cell carcinoma (RCC) is the most common malignancy occurring in the adult kidney. Prostatic carcinoma is the most common male malignancy in most Western countries. Several environmental factors have been suggested to contributed to the tumor genesis but the involvement of genetic factors is also recognized. Here we applied a variety of molecular genetic techniques to characterize somatic and constitutional genetic alterations in patients with these types of tumors. Von Hippel-Lindau disease (VHL) is an autosomal dominant disorder predisposing to the development of RCC. The disease is caused by the germline mutations of the VHL gene located in chromosomal region 3p25. Using PCR /direct DNA sequencing and Southern blot analysis, 7 germline mutations were identified in 10 VHL families (Paper 1). We further showed the importance of VHL mutation analysis both in prognosis of patient and presymptomatic diagnosis of VHL mutation carriers. Particular note was emphasized on the selection of kidney donors from relatives of a possible VHL patient affected by bilateral RCCs. Somatic deletions of the long arm of chromosome 10 were demonstrated in 24% of the RCC analyzed (Paper 2). As the deletion included the PTEN/MMAC 1 gene, mutation analysis was carried out using PCR/direct DNA sequencing. Three single base changes were identified in 3/6 tumors showing loss of the PTEN/MMAC1 region. A homozygous deletion coupled with absent PTEN/MMAC1 expression was detected in the RCC line UOK147. The result suggests the possible importance of PTEN/MMAC1 gene mutation in clinical prognosis of a subset of RCCs. Using PCR/LOH analysis we detected LOH of 13q markers in 18/36 prostatic carcinomas analyzed (Paper 3). Two important regions of deletion were defined, which did not included the Rb I locus at 13q14 or the BRCA2 locus at 13q12. Mutation analysis of the BRCA2 gene in six tumors did not reveal any important mutations. Immunohistochemical analysis of the same tumor materials showed that frequent aberrant pRb expression was correlated with a tetraploid DNA content but not concordant with the loss of the Rb1 gene. The data suggest the existence of yet unidentified tumor suppressor genes on 13q that are important for prostate cancer development. In the same set of prostatic carcinomas, 16q deletions were demonstrated in 75% of tumors (Paper4). Extensive deletions were found in all the metastases while small deletions were also present in 54% of primary tumors. Four important deleted regions were identified and the presence of the terminal 16q deletion was closely correlated with grade, stage and metastases. The location of tandemly arranged classical cadherin genes was coincident with the four important deleted regions. We chose the CDH I gene at 16q22.1 that encodes the E-cadherin protein as the first candidate gene. Mutation analysis of all the 16 coding exons did not find any mutations in the ten tumors showing LOH at the CDH I region. In addition, we also detected frequent reduced or absent E-cadherin expression in the same set of materials. The finding suggests that chromosome 16q deletions are important in the development of prostate cancer metastasis and could potentially be used as a prognostic marker. Using a modified PCR/LOH analysis in sporadic prostatic carcinomas, we found two possible deletions at the putative prostate cancer susceptibility locus HPCX on Xq27-28 (Paper 5). These deletions caused a complete loss of the DNA sequences in the region. The findings further support the importance of this locus in sporadic tumors. The association between the CAG repeats polymorphism in the androgen receptor gene and prostatic carcinomas was analyzed in Swedish and Japanese populations (Paper 6). Both sporadic and familial prostatic carcinomas in Sweden showed association with short CAG repeats whereas sporadic prostatic carcinomas in Japan showed association with long repeats. In both populations the allele AR(CAG)22 showed negative correlation with prostatic carcinomas, and the alleles AR(CAG)21 and AR(CAG)23 showed positive correlation. Compared to Swedish populations, Japanese males more frequently carried AR(CAG)22 and less frequently AR(CAG)21 and AR(CAG)23. This difference in allelic distribution may be part of the genetic background that determines a dramatically lower incidence of clinical prostate cancer in Japan. The present study may contribute to a better understanding of the genetic mechanism for the development of renal and prostatic carcinoma. The results also present the potential of molecular genetic analysis in clinical diagnosis and prognosis of these two common types of urological malignancies.
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| 3. |
- Ma, Yuanjun, et al.
(author)
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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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In: SpringerPlus. - : Springer Science and Business Media LLC. - 2193-1801. ; 5
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Journal article (peer-reviewed)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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| 4. |
- Peng, Zhuochun, et al.
(author)
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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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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:1
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Journal article (peer-reviewed)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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| 5. |
- Peng, Zhuochun, et al.
(author)
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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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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:10, s. e109610-
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Journal article (peer-reviewed)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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