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- Andersson, Patiyan, 1978-, et al.
(författare)
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Genome-wide analysis of penile cancer using high-density single nucleotide polymorphism arrays
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The availability of genome-wide high-density single nucleotide polymorphism (SNP) arrays makes it possible to in a structured manner study chromosome aberrations in penile cancer where little is known of disruptive genetic events. In this study 19 penile squamous cell carcinomas were analyzed using the 250k NspI SNP array from Affymetrix. We find major regions of frequent copy number gain in chromosome arms 3q, 5p and 8q, and slightly less frequent in 1p, 16q and 20q. The chromosomal regions of most frequent copy number losses were 3p, 4q, 11p and 13q. We identified four candidate genes residing in the major chromosomal regions of aberration. Eight tumours showed copy number gain of the PIK3CA gene located to 3q26.3. Five of the remaining tumours carried an activating mutation of the PIK3CA gene and these tumours showed very few chromosomal aberrations. Collectively, disruption of the PIK3CA gene was found in 13/19 samples, and presence of active phosphorylated AKT was confirmed immunohistochemically in these tumours indicating an active signalling pathway. We found copy number gain of the hTERT gene (5p15.33) in 7 samples and of the Myc gene (8q24.21) in 7 samples. Copy number loss of the tumoursuppressor gene FHIT (3p14.2) was observed in 8 samples, the same 8 samples that showed copy number gain of the PIK3CA gene. In total the PI3K/AKT and RAS/MAPK pathways were found to be activated through mutation or amplification in 64% of the cases, indicating the significance of these pathways in the aetiology of penile cancer.
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| 3. |
- Carlsson, Jessica, 1984-, et al.
(författare)
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Differences in microRNA expression during tumor development in the transition and peripheral zones of the prostate
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ) and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation to the difference in propensity of tumors in the zones of the prostate.Methods:The expression of 667 unique miRNAs was investigated in normal and malignant transition zone and peripheral zone prostate tissues using TaqMan low density arrays for miRNAs. Student’s t-test was used in order to identify differentially expressed miRNAs and hierarchical clustering and principal component analyses were used to note the separation of the tissues. A cross-validation test using the ADtree algorithm was used to test the generality of the identified miRNA signatures.Results:The Student’s t-tests revealed that the major differences in miRNA expression are found between normal and malignant tissues. Hierarchical clustering and PCA based on differentiallyexpressed miRNAs between normal and malignant tissues showed a perfect separation between samples while analyses based on differentially expressed miRNAs between the two zones showed several misplaced samples. A classification and cross-validation procedure confirmedt hese results and several potential miRNA markers were identified.Conclusions:The results of this study indicate that the major differences in the transcription programme are those arising during tumor development, rather than during normal tissue development. In conclusion, tumors arising in the TZ have more unique differentially expressed miRNAs compared to the PZ, indicating that the PZ are more prone to tumor development than the TZ. The results also indicate that separate miRNA expression signatures for diagnosis might be needed for tumors arising in the transition- or peripheral zone.
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| 5. |
- Lycken, Magdalena, 1973-, et al.
(författare)
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Adherence to guidelines for androgen deprivation therapy after radical prostatectomy : Swedish population-based study
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Androgen deprivation therapy (ADT) is a non-curative but essential treatment of prostate cancer with severe side effects. Therefore, both over- and underuse should be avoided. Our aim was to investigate adherence to guidelines for ADT following radical prostatectomy through Swedish population-based data. Methods: We used the database PSA Uppsala/Örebro to study men with localised or locally advanced prostate cancer at diagnosis (clinical stage T1-T3, N0-NX, M0-MX, and prostate-specific antigen (PSA) <50 ng/ml) who underwent radical prostatectomy 1997-2012. Totally 114 men were treated with ADT and selected as cases; 1140 men with no ADT at the index date were selected as controls within four-year strata of time of radical prostatectomy. All men with a PSA doubling time <12 months and/or a biopsy Gleason score of 8-10 were considered to have an indication for ADT according to the European Association of Urology (EAU) guidelines. Results: No indication for ADT was found in 39% of the cases. Among these men, 89% had tumour stage (T-stage) 1-2 at diagnosis, 58% had a biopsy Gleason score 2-6, 98% had an expected remaining lifetime over ten years, 16% received castration, and 84% received antiandrogen monotherapy. Among the controls 5% were found to have an indication for ADT, and 98% of these men had an expected remaining lifetime over ten years.Conclusion: Our results indicate that overtreatment with ADT after radical prostatectomyis common, whereas undertreatment is unusual. Interventions to improve adherence to guidelines are needed to avoid unnecessary side-effects and long treatment durations with ADT.
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| 6. |
- Svensson, Maria A., et al.
(författare)
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A comparative study of ERG status assessment on DNA-, mRNA-, and proteinlevels using unique samples from a Swedish biopsy cohort
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The ERG rearrangement is identified in approximately 50% of prostate cancer (PCa) screened cohorts and is known to be highly specific. This genetic aberration, most commonly leading to the TMPRSS2-ERG fusion, but also SLC45A3-ERG or NDRG1- ERG fusions, all leading to an over expression of a truncated ERG protein. Most studies have applied in situ hybridization (FISH) methods or mRNA based assays to investigate the ERG status. Recently, studies showed that ERG protein levels assessed by ERG antibodies can be used as a surrogate marker for ERG rearrangement. In the current study we investigate ERG status on a series of diagnostic biopsies using DNA-, mRNA- and protein based assays. We formally compare three assay results (i.e. FISH, fusion mRNA and immunohistochemistry) to identify which method could be most appropriate to use when having limited amount of tissue. ERG rearrangement was found in 56% of the cases. Comparing ERG rearrangement status by FISH with ERG over expression and TMPRSS2-ERG fusion transcript we found 95.1% (154/162, Fisher’s exact test 9.50E-36) and 85.2% (138/162, Fisher’s exact test 7.26E-22) concordance, respectively. We show that the ERG antibody highly correlates with the ERG rearrangement with high sensitivity and specificity. We also identified the most common TMPRSS2-ERG isoform in the majority of ERG rearranged cases. These results provide compelling evidence that the ERG antibody can be used to further investigate the role of ERG in PCa.
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| 7. |
- Svensson, Maria A., et al.
(författare)
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ERG rearrangement status and castration resistant prostate cancer : a prospective,population-based study
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Overtreatment is a major concern in prostate cancer (PCa) management, as no adequate prognostic tool exists to separate indolent from aggressive disease at time of diagnosis. Androgen deprivation therapy (ADT) is the standard treatment of locally recurrent or metastatic PCa and although most men respond well to ADT initially, inevitably a resistance to the treatment develops. Men with tumor growth despite the androgen-depleted environment are considered to have castration resistant PCa (CRPC). After developing CRPC, the median survival time is typically less than two years. Since the initial discovery of ERG rearrangement in PCa, several studies have investigated the association between ERG rearrangement and clinical outcome of PCa with discrepant results. Few studies have examined the association between ERG rearrangement and CRPC, despite the fact that the most common fusion partners to ERG are androgen regulated. In this study we investigated the association between ERG status and time to CRPC.We assessed the ERG status in a cohort of 220 men initially managed by watchful waiting and treated with ADT at disease progression. There was no statistically significant association between ERG status and time from start of ADT to CPRC, or start of ADT to PCa-specific death. However, men harboring the ERG rearrangement did have a significantly shorter time between time of diagnosis and start of hormonal treatment, compared to men without the rearrangement (HR: 1.81; 95% CI: 1.23- 2.65), suggesting that ERG rearrangement is indicative of a more aggressive subtype of PCa./p>
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