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Wikström, P., Bergh, A., Josefsson, A., Thysell, E. & Welén, K. (2024). Molekylära subtyper och avancerad prostatacancer: nya möjligheter för anpassad behandling: [Molecular subtypes provide possibilities for precision medicine in a advanced prostate cancer]. Läkartidningen, 121, Article ID 23179.
Open this publication in new window or tab >>Molekylära subtyper och avancerad prostatacancer: nya möjligheter för anpassad behandling: [Molecular subtypes provide possibilities for precision medicine in a advanced prostate cancer]
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2024 (Swedish)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 121, article id 23179Article, review/survey (Refereed) Published
Abstract [en]

Increased molecular knowledge makes it possible to consider not only genetic defects but also expression profiles for precision medicine in advanced prostate cancer. Several prognostic and treatment-predictive classifiers for prostate cancer have been described, such as Prolaris, OncotypeDx, Decipher, Prostatype, PAM50, PCS1-2, and MetA-C, which all build upon transcript profiles. In research studies, the MetA-C classifier has shown clear prognostic information for patients with metastatic disease, in relation to outcome after androgen receptor targeting therapies, and so has immunohistochemical evaluation of tumor cell proliferation (Ki67) and PSA expression. Unfortunately, methods within clinical routine today do not allow molecular subclassification of prostate cancer. To enable comparison of the most promising treatment-predictive biomarkers and to evaluate the health economic value of implementing such precision medicine for prostate cancer, a prospective study is being planned as a joint initiative in Sweden that aims to evaluate and validate biomarkers and to establish a study platform for adaptive biomarker-driven clinical trials (sprintr.se).

Place, publisher, year, edition, pages
Läkartidningen Förlag AB, 2024
National Category
Urology and Nephrology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-224113 (URN)2-s2.0-85191380918 (Scopus ID)
Available from: 2024-05-13 Created: 2024-05-13 Last updated: 2024-05-13Bibliographically approved
Henning, P., Kassem, A., Westerlund, A., Lundberg, P., Engdahl, C., Lionikaite, V., . . . Lerner, U. H. (2024). Toll-like receptor-2 induced inflammation causes local bone formation and activates canonical Wnt signaling. Frontiers in Immunology, 15, Article ID 1383113.
Open this publication in new window or tab >>Toll-like receptor-2 induced inflammation causes local bone formation and activates canonical Wnt signaling
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2024 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 15, article id 1383113Article in journal (Refereed) Published
Abstract [en]

It is well established that inflammatory processes in the vicinity of bone often induce osteoclast formation and bone resorption. Effects of inflammatory processes on bone formation are less studied. Therefore, we investigated the effect of locally induced inflammation on bone formation. Toll-like receptor (TLR) 2 agonists LPS from Porphyromonas gingivalis and PAM2 were injected once subcutaneously above mouse calvarial bones. After five days, both agonists induced bone formation mainly at endocranial surfaces. The injection resulted in progressively increased calvarial thickness during 21 days. Excessive new bone formation was mainly observed separated from bone resorption cavities. Anti-RANKL did not affect the increase of bone formation. Inflammation caused increased bone formation rate due to increased mineralizing surfaces as assessed by dynamic histomorphometry. In areas close to new bone formation, an abundance of proliferating cells was observed as well as cells robustly stained for Runx2 and alkaline phosphatase. PAM2 increased the mRNA expression of Lrp5, Lrp6 and Wnt7b, and decreased the expression of Sost and Dkk1. In situ hybridization demonstrated decreased Sost mRNA expression in osteocytes present in old bone. An abundance of cells expressed Wnt7b in Runx2-positive osteoblasts and ß-catenin in areas with new bone formation. These data demonstrate that inflammation, not only induces osteoclastogenesis, but also locally activates canonical WNT signaling and stimulates new bone formation independent on bone resorption.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2024
Keywords
bone formation, osteoblasts, osteoclasts, toll-like receptors, Wnt signaling
National Category
Dentistry
Identifiers
urn:nbn:se:umu:diva-223835 (URN)10.3389/fimmu.2024.1383113 (DOI)001204953900001 ()38646530 (PubMedID)2-s2.0-85190787237 (Scopus ID)
Funder
Swedish Research CouncilSwedish Dental AssociationSwedish Rheumatism AssociationStiftelsen Konung Gustaf V:s 80-årsfondRegion Västerbotten
Available from: 2024-04-30 Created: 2024-04-30 Last updated: 2024-04-30Bibliographically approved
Wänman, J., Abul-Kasim, K., Semenas, J., Thysell, E., Bergh, A., Wikström, P. & Crnalic, S. (2023). A novel radiographic pattern related to poor prognosis in patients with prostate cancer with metastatic spinal cord compression. European Urology Open Science, 48, 44-53
Open this publication in new window or tab >>A novel radiographic pattern related to poor prognosis in patients with prostate cancer with metastatic spinal cord compression
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2023 (English)In: European Urology Open Science, ISSN 2666-1691, E-ISSN 2666-1683, Vol. 48, p. 44-53Article in journal (Refereed) Published
Abstract [en]

Background: Prostate cancer spinal bone metastases can have a radiographic profile that mimics multiple myeloma.

Objective: To analyse the presence and prognostic value of myeloma-like prostate cancer bone metastases and its relation to known clinical, molecular, and morphological prognostic markers.

Design, setting, and participants: A cohort of 110 patients with prostate cancer who underwent surgery for metastatic spinal cord compression (MSCC) was analysed. Spinal bone metastases were classified as myeloma like (n = 20) or non–myeloma like (n = 90) based on magnetic resonance imaging prior to surgery. An immunohistochemical analysis of metastasis samples was performed to assess tumour cell proliferation (percentage of Ki67-positive cells) and the expression levels of prostate-specific antigen (PSA) and androgen receptor (AR). The metastasis subtypes MetA, MetB, and MetC were determined from transcriptomic profiling.

Outcome measurements and statistical analysis: Survival curves were compared with the log-rank test. Univariate and multivariate Cox proportional hazard models were used to assess the effects of prognostic variables. Groups were compared using the Mann-Whitney U test for continuous variables and the chi-square test for categorical variables.

Results and limitations: Patients with the myeloma-like metastatic pattern had median survival after surgery for MSCC of 1.7 (range 0.1–33) mo, while the median survival period of those with the non–myeloma-like pattern was 13 (range 0–140) mo (p < 0.001). The myeloma-like appearance had an independent prognostic value for the risk of death after MSCC surgery (adjusted hazard ratio 2.4, p = 0.012). Postoperative neurological function was significantly reduced in the myeloma-like group. No association was found between the myeloma-like pattern and morphological markers of known relevance for this patient group: the transcriptomic subtypes MetA, MetB, and MetC; tumour cell proliferation; and AR and PSA expression.

Conclusions: A myeloma-like metastatic pattern identifies an important subtype of metastatic prostate cancer associated with poor survival and neurological outcomes after surgery for MSCC.

Patient summary: This study describes a novel radiographic pattern of prostate cancer bone metastases and its relation to poor patient prognosis.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Metastatic spinal cord, compression, Myeloma-like prostate cancer, bone metastases, Prostate cancer
National Category
Orthopaedics
Identifiers
urn:nbn:se:umu:diva-202101 (URN)10.1016/j.euros.2022.12.004 (DOI)000973999000001 ()2-s2.0-85144765610 (Scopus ID)
Funder
Swedish Cancer SocietyCancerforskningsfonden i NorrlandRegion Västerbotten
Available from: 2023-01-02 Created: 2023-01-02 Last updated: 2023-09-05Bibliographically approved
Zivanovic, A., Miller, J. T., Munro, S. A., Knutson, T. P., Li, Y., Passow, C. N., . . . Dehm, S. M. (2023). Co-evolution of AR gene copy number and structural complexity in endocrine therapy resistant prostate cancer. NAR Cancer, 5(3), Article ID zcad045.
Open this publication in new window or tab >>Co-evolution of AR gene copy number and structural complexity in endocrine therapy resistant prostate cancer
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2023 (English)In: NAR Cancer, E-ISSN 2632-8674, Vol. 5, no 3, article id zcad045Article in journal (Refereed) Published
Abstract [en]

Androgen receptor (AR) inhibition is standard of care for advanced prostate cancer (PC). However, efficacy is limited by progression to castration-resistant PC (CRPC), usually due to AR re-activation via mechanisms that include AR amplification and structural rearrangement. These two classes of AR alterations often co-occur in CRPC tumors, but it is unclear whether this reflects intercellular or intracellular heterogeneity of AR. Resolving this is important for developing new therapies and predictive biomarkers. Here, we analyzed 41 CRPC tumors and 6 patient-derived xenografts (PDXs) using linked-read DNA-sequencing, and identified 7 tumors that developed complex, multiply-rearranged AR gene structures in conjunction with very high AR copy number. Analysis of PDX models by optical genome mapping and fluorescence in situ hybridization showed that AR residing on extrachromosomal DNA (ecDNA) was an underlying mechanism, and was associated with elevated levels and diversity of AR expression. This study identifies co-evolution of AR gene copy number and structural complexity via ecDNA as a mechanism associated with endocrine therapy resistance.

Place, publisher, year, edition, pages
Oxford University Press, 2023
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-214514 (URN)10.1093/narcan/zcad045 (DOI)37636316 (PubMedID)2-s2.0-85170407885 (Scopus ID)
Funder
Swedish Cancer Society, CAN 2018-863Swedish Research Council, 2018-02594
Available from: 2023-09-27 Created: 2023-09-27 Last updated: 2023-09-27Bibliographically approved
Järemo, H., Semenas, J., Halin Bergström, S., Lundholm, M., Thysell, E., Widmark, A., . . . Wikström, P. (2023). Investigating microRNA Profiles in Prostate Cancer Bone Metastases and Functional Effects of microRNA-23c and microRNA-4328. Cancers, 15(9), Article ID 2437.
Open this publication in new window or tab >>Investigating microRNA Profiles in Prostate Cancer Bone Metastases and Functional Effects of microRNA-23c and microRNA-4328
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2023 (English)In: Cancers, ISSN 2072-6694, Vol. 15, no 9, article id 2437Article in journal (Refereed) Published
Abstract [en]

MicroRNAs (miRNAs) are aberrantly expressed in prostate cancer (PC), but comprehensive knowledge about their levels and function in metastatic PC is lacking. Here, we explored the differential expression of miRNA profiles during PC progression to bone metastasis, and further focused on the downregulation of miRNA-23c and -4328 and their impact on PC growth in experimental models. Using microarray screening, the levels of 1510 miRNAs were compared between bone metastases (n = 14), localized PC (n = 7) and benign prostate tissue (n = 7). Differentially expressed miRNAs (n = 4 increased and n = 75 decreased, p < 0.05) were identified, of which miRNA-1, -23c, -143-3p, -143-5p, -145-3p, -205-5p, -221-3p, -222-3p and -4328 showed consistent downregulation during disease progression (benign > localized PC > bone metastases). The downregulation of miRNA-23c and -4328 was confirmed by reverse transcription and quantitative polymerase chain reaction analysis of 67 metastasis, 12 localized PC and 12 benign prostate tissue samples. The stable overexpression of miRNA-23c and -4328 in the 22Rv1 and PC-3 cell lines resulted in reduced PC cell growth in vitro, and in the secretion of high levels of miRNA-23c (but not -4328) in extracellular vesicles. However, no tumor suppressive effects were observed from miRNA-23c overexpression in PC-3 cells subcutaneously grown in mice. In conclusion, bone metastases display a profound reduction of miRNA levels compared to localized PC and benign disease. The downregulation of those miRNAs, including miRNA-23c and -4328, may lead to a loss of tumor suppressive effects and provide biomarker and therapeutic possibilities that deserve to be further explored.

Place, publisher, year, edition, pages
MDPI, 2023
Keywords
blood vessels, bone metastasis, extracellular vesicles, microarray, microRNA-23c, microRNA-4328, proliferation, prostate cancer, proteomics
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-209116 (URN)10.3390/cancers15092437 (DOI)000986796000001 ()2-s2.0-85159230526 (Scopus ID)
Funder
Swedish Research Council, 2022-00946Swedish Cancer Society, 21-1856Swedish Foundation for Strategic Research, RB13-0119Cancerforskningsfonden i Norrland, AMP 21-1061Prostatacancerförbundet
Available from: 2023-06-07 Created: 2023-06-07 Last updated: 2023-10-23Bibliographically approved
Spyratou, V., Freyhult, E., Bergh, A., Thellenberg-Karlsson, C., Wikström, P., Welén, K. & Josefsson, A. (2023). Ki67 and prostate specific antigen are prognostic in metastatic hormone naïve prostate cancer. Acta Oncologica, 6212, 1698-1706
Open this publication in new window or tab >>Ki67 and prostate specific antigen are prognostic in metastatic hormone naïve prostate cancer
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2023 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 6212, p. 1698-1706Article in journal (Refereed) Published
Abstract [en]

Background: For metastatic hormone naïve prostate cancer patients, androgen deprivation therapy (ADT) with escalation therapy including docetaxel and/or androgen targeting drugs is the standard therapy. However, de-escalation is preferable to avoid unnecessary side effects, especially from docetaxel, but markers to identify these patients are lacking. The purpose of the present study was to investigate the potential of PSA and Ki67 immunoreactive scores as prognostic and treatment-predictive markers.

Material and methods: Prostate biopsies from 92 patients with metastatic hormone naïve PC (PSA > 80 ng/mL or clinical metastases) were immunohistochemically evaluated for PSA and Ki67. Gene expression analysis was performed with Clariom D microarrays to identify the phenotypic profile associated with the immunohistochemistry scores of biopsies. Cox regression analysis for progression free survival after ADT adjustment for age, ISUP, and serum PSA and Kaplan-Meier analyses were performed to assess prognostic values of Ki67, PSA, and the Ki67/PSA ratio.

Results: The immunohistochemical score for PSA was the strongest prognostic factor for progression-free and overall survival after ADT. Consequently, the ratio between Ki67 and PSA displayed a stronger prognostic value than Ki67 itself. Further, mRNA expression data analysis showed an association between high Ki67/PSA ratio, cell-cycle regulation, and DNA damage repair. In an exploratory sub-analysis of 12 patients treated with early docetaxel as addition to ADT and matched controls, a high Ki67/PSA ratio showed potential to identify those who benefit from docetaxel.

Conclusion: PSA and Ki67 immunoreactive scores are prognostic in the metastatic hormone-sensitive setting, with PSA being superior. The combination of Ki67 and PSA did not give additional prognostic value. The results suggest immunohistochemical scoring of PSA to have potential to improve identification of patients responding well to ADT alone.

Place, publisher, year, edition, pages
Taylor & Francis, 2023
Keywords
androgen deprivation therapy, biomarker, docetaxel, Metastatic prostate cancer, prostate specific antigen
National Category
Urology and Nephrology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-214585 (URN)10.1080/0284186X.2023.2254480 (DOI)001068664400001 ()37713321 (PubMedID)2-s2.0-85171153075 (Scopus ID)
Funder
Swedish Research Council, 2022-00946Swedish Cancer Society, 19-0054Swedish Cancer Society, 19-0053Swedish Cancer Society, 20-1055Swedish Cancer Society, 21-1856Knut and Alice Wallenberg Foundation, 2020.0235Prostatacancerförbundet
Available from: 2023-09-28 Created: 2023-09-28 Last updated: 2024-02-01Bibliographically approved
Dudka, I., Lundquist, K., Wikström, P., Bergh, A. & Gröbner, G. (2023). Metabolomic profiles of intact tissues reflect clinically relevant prostate cancer subtypes. Journal of Translational Medicine, 21(1), Article ID 860.
Open this publication in new window or tab >>Metabolomic profiles of intact tissues reflect clinically relevant prostate cancer subtypes
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2023 (English)In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 21, no 1, article id 860Article in journal (Refereed) Published
Abstract [en]

Background: Prostate cancer (PC) is a heterogenous multifocal disease ranging from indolent to lethal states. For improved treatment-stratification, reliable approaches are needed to faithfully differentiate between high- and low-risk tumors and to predict therapy response at diagnosis.

Methods: A metabolomic approach based on high resolution magic angle spinning nuclear magnetic resonance (HR MAS NMR) analysis was applied on intact biopsies samples (n = 111) obtained from patients (n = 31) treated by prostatectomy, and combined with advanced multi- and univariate statistical analysis methods to identify metabolomic profiles reflecting tumor differentiation (Gleason scores and the International Society of Urological Pathology (ISUP) grade) and subtypes based on tumor immunoreactivity for Ki67 (cell proliferation) and prostate specific antigen (PSA, marker for androgen receptor activity).

Results: Validated metabolic profiles were obtained that clearly distinguished cancer tissues from benign prostate tissues. Subsequently, metabolic signatures were identified that further divided cancer tissues into two clinically relevant groups, namely ISUP Grade 2 (n = 29) and ISUP Grade 3 (n = 17) tumors. Furthermore, metabolic profiles associated with different tumor subtypes were identified. Tumors with low Ki67 and high PSA (subtype A, n = 21) displayed metabolite patterns significantly different from tumors with high Ki67 and low PSA (subtype B, n = 28). In total, seven metabolites; choline, peak for combined phosphocholine/glycerophosphocholine metabolites (PC + GPC), glycine, creatine, combined signal of glutamate/glutamine (Glx), taurine and lactate, showed significant alterations between PC subtypes A and B.

Conclusions: The metabolic profiles of intact biopsies obtained by our non-invasive HR MAS NMR approach together with advanced chemometric tools reliably identified PC and specifically differentiated highly aggressive tumors from less aggressive ones. Thus, this approach has proven the potential of exploiting cancer-specific metabolites in clinical settings for obtaining personalized treatment strategies in PC.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
Mtabolomics, Prostate cancer, Subtype, HR MAS NMR, Biomarker
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-217520 (URN)10.1186/s12967-023-04747-7 (DOI)38012666 (PubMedID)2-s2.0-85178355279 (Scopus ID)
Funder
Swedish Research Council, 2022-00946Swedish Research Council, 2021-06146Swedish Cancer Society, 21-1856Swedish Cancer Society, 22-2041The Kempe FoundationsKnut and Alice Wallenberg Foundation, “NMR for Life” ProgrammeScience for Life Laboratory, SciLifeLabUmeå University
Available from: 2023-12-06 Created: 2023-12-06 Last updated: 2023-12-18Bibliographically approved
Thysell, E., Köhn, L., Semenas, J., Järemo, H., Freyhult, E., Lundholm, M., . . . Wikström, P. (2022). Clinical and biological relevance of the transcriptomic-based prostate cancer metastasis subtypes MetA-C. Molecular Oncology (4)
Open this publication in new window or tab >>Clinical and biological relevance of the transcriptomic-based prostate cancer metastasis subtypes MetA-C
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2022 (English)In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, no 4Article in journal (Refereed) Published
Abstract [en]

To improve treatment of metastatic prostate cancer, the biology of metastases needs to be understood. We recently described three subtypes of prostate cancer bone metastases (MetA-C), based on differential gene expression. The aim of this study was to verify the clinical relevance of these subtypes, and to explore their biology and relations to genetic drivers. Freshly-frozen metastasis samples were obtained as hormone-naive (n=17), short-term castrated (n=21) or castration resistant (n=65) from a total of 67 patients. Previously published sequencing data from 573 metastasis samples was also analyzed. Through transcriptome profiling and sample classification based on a set of predefined MetA-C-differentiating genes, we found that most metastases were heterogeneous for the MetA-C subtypes. Overall, MetA was the most common subtype, while MetB was significantly enriched in castration-resistant samples and in liver metastases, and consistently associated with poor prognosis. By gene set enrichment analysis, the phenotype of MetA was described by high androgen response, protein secretion and adipogenesis, MetB by high cell cycle activity and DNA repair, and MetC by epithelial-to-mesenchymal transition and inflammation. The MetB subtype demonstrated single-nucleotide variants of RB transcriptional corepressor 1 (RB1) and loss of 21 genes at chromosome 13, including RB1, but provided independent prognostic value to those genetic aberrations. In conclusion, a distinct set of gene transcripts can be used to classify prostate cancer metastases into the subtypes MetA-C. The MetA-C subtypes show diverse biology, organ tropism and prognosis. The MetA-C classification may be used independently, or in combination with genetic markers, primarily to identify MetB patients in need of complementary therapy to conventional androgen-receptor-targeting treatments.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
Keywords
MetA-C, Metastasis, Prognosis, Prostate cancer, Subtypes, Transcriptomic
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-190463 (URN)10.1002/1878-0261.13158 (DOI)000734478400001 ()34889043 (PubMedID)2-s2.0-85121666619 (Scopus ID)
Available from: 2021-12-16 Created: 2021-12-16 Last updated: 2023-10-23Bibliographically approved
Wikström, P., Halin Bergström, S., Josefsson, A., Semenas, J., Nordstrand, A., Thysell, E., . . . Bergh, A. (2022). Epithelial and stromal characteristics of primary tumors predict the bone metastatic subtype of prostate cancer and patient survival after androgen-deprivation therapy. Cancers, 14(21), Article ID 5195.
Open this publication in new window or tab >>Epithelial and stromal characteristics of primary tumors predict the bone metastatic subtype of prostate cancer and patient survival after androgen-deprivation therapy
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2022 (English)In: Cancers, ISSN 2072-6694, Vol. 14, no 21, article id 5195Article in journal (Refereed) Published
Abstract [en]

Prostate cancer (PC) bone metastases can be divided into transcriptomic subtypes, by us termed MetA-C. The MetB subtype, constituting about 20% of the cases, is characterized by high cell cycle activity, low androgen receptor (AR) activity, and a limited response to standard androgen deprivation therapy (ADT). Complementary treatments should preferably be introduced early on if the risk of developing metastases of the MetB subtype is predicted to behigh. In this study, we therefore examined if the bone metastatic subtype and patient outcome after ADT could be predicted by immunohistochemical analysis of epithelial and stromal cell markers in primary tumor biopsies obtained at diagnosis (n = 98). In this advanced patient group, primary tumor International Society of Urological Pathology (ISUP) grade was not associated with outcome or metastasis subtype. In contrast, high tumor cell Ki67 labeling (proliferation) in combination with low tumor cell immunoreactivity for PSA, and a low fraction of AR positive stroma cells in the primary tumors were prognostic for poor survival after ADT. Accordingly, the same tissue markers were associated with developing metastases enriched for the aggressive MetB subtype. The development of the contrasting MetA subtype, showing the best response to ADT, could be predicted by the opposite staining pattern. We conclude that outcome after ADT and metastasis subtype can, at least to some extent, be predicted by analysis of primary tumor characteristics, such as tumor cell proliferation and PSA expression, and AR expression in stromal cells.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
androgen receptor, bone metastases, ERG, Ki67, metastatic subtypes, PDGFRB, prostate cancer, PSA, SDF1, smooth muscle actin
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-201227 (URN)10.3390/cancers14215195 (DOI)000880962300001 ()36358614 (PubMedID)2-s2.0-85141664487 (Scopus ID)
Funder
Swedish Foundation for Strategic Research, RB13-0119Swedish Cancer Society, 19 0053Swedish Cancer Society, 19 0054Swedish Cancer Society, 21 1856Knut and Alice Wallenberg Foundation, KAW 2015.0114Swedish Research Council, 2018-02594Cancerforskningsfonden i Norrland, 22-2302Cancerforskningsfonden i Norrland, 21-2258
Available from: 2022-12-05 Created: 2022-12-05 Last updated: 2022-12-05Bibliographically approved
Bovinder Ylitalo, E., Thysell, E., Landfors, M., Brattsand, M., Jernberg, E., Crnalic, S., . . . Wikström, P. (2021). A novel DNA methylation signature is associated with androgen receptor activity and patient prognosis in bone metastatic prostate cancer. Clinical Epigenetics, 13(1), Article ID 133.
Open this publication in new window or tab >>A novel DNA methylation signature is associated with androgen receptor activity and patient prognosis in bone metastatic prostate cancer
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2021 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 13, no 1, article id 133Article in journal (Refereed) Published
Abstract [en]

Background: Patients with metastatic prostate cancer (PC) are treated with androgen deprivation therapy (ADT) that initially reduces metastasis growth, but after some time lethal castration-resistant PC (CRPC) develops. A better understanding of the tumor biology in bone metastases is needed to guide further treatment developments. Subgroups of PC bone metastases based on transcriptome profiling have been previously identified by our research team, and specifically, heterogeneities related to androgen receptor (AR) activity have been described. Epigenetic alterations during PC progression remain elusive and this study aims to explore promoter gene methylation signatures in relation to gene expression and tumor AR activity.

Materials and methods: Genome-wide promoter-associated CpG methylation signatures of a total of 94 tumor samples, including paired non-malignant and malignant primary tumor areas originating from radical prostatectomy samples (n = 12), and bone metastasis samples of separate patients with hormone-naive (n = 14), short-term castrated (n = 4) or CRPC (n = 52) disease were analyzed using the Infinium Methylation EPIC arrays, along with gene expression analysis by Illumina Bead Chip arrays (n = 90). AR activity was defined from expression levels of genes associated with canonical AR activity.

Results: Integrated epigenome and transcriptome analysis identified pronounced hypermethylation in malignant compared to non-malignant areas of localized prostate tumors. Metastases showed an overall hypomethylation in relation to primary PC, including CpGs in the AR promoter accompanied with induction of AR mRNA levels. We identified a Methylation Classifier for Androgen receptor activity (MCA) signature, which separated metastases into two clusters (MCA positive/negative) related to tumor characteristics and patient prognosis. The MCA positive metastases showed low methylation levels of genes associated with canonical AR signaling and patients had a more favorable prognosis after ADT. In contrast, MCA negative patients had low AR activity associated with hypermethylation of AR-associated genes, and a worse prognosis after ADT.

Conclusions: A promoter methylation signature classifies PC bone metastases into two groups and predicts tumor AR activity and patient prognosis after ADT. The explanation for the methylation diversities observed during PC progression and their biological and clinical relevance need further exploration.

Place, publisher, year, edition, pages
BioMed Central, 2021
Keywords
Androgen receptor, DNA methylation, Gene expression, MetA, Metastasis, MetB, MetC, Prognosis, Prostate cancer, Subtypes
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-185893 (URN)10.1186/s13148-021-01119-0 (DOI)000670704300001 ()34193246 (PubMedID)2-s2.0-85109041809 (Scopus ID)
Available from: 2021-07-12 Created: 2021-07-12 Last updated: 2023-09-05Bibliographically approved
Projects
Biomarkers for aggressive prostate cancer [2009-04892_VR]; Umeå UniversityBiomarkers for Prostate Cancer Prognosis and Prediction of Therapy Response [2012-02179_VR]; Umeå UniversityBiomarkers for prostate cancer prognosis and prediction of therapy response [2015-02393_VR]; Umeå UniversityBiomarkers for improved prognostics and therapeutics of aggressive prostate cancer [2018-02594_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-6347-1999

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