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Wojtowicz, R., Otten, V. T., Henricson, A., Crnalic, S. & Nilsson, K. G. (2024). Uncemented trabecular metal high-flex posterior-stabilized monoblock total knee arthroplasty in patients aged 60 years or younger. Knee (Oxford), 46, 99-107
Öppna denna publikation i ny flik eller fönster >>Uncemented trabecular metal high-flex posterior-stabilized monoblock total knee arthroplasty in patients aged 60 years or younger
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2024 (Engelska)Ingår i: Knee (Oxford), ISSN 0968-0160, E-ISSN 1873-5800, Vol. 46, s. 99-107Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: Uncemented trabecular metal (TM) monoblock tibial components in total knee arthroplasty (TKA) have shown excellent clinical results for up to 10 years. However, these studies were performed in highly specialized units, with few surgeons and often excluding knees with secondary osteoarthritis (OA), severe malalignments and previous surgery. The purpose of this study was to investigate implant survivorship and clinical and radiological outcome of the uncemented TM high-flex posterior stabilized (PS) monoblock tibial component in routine clinical practice.

Methods: A retrospective study of 339 knees (282 patients) operated with the implant in routine clinical practice at two hospitals on patients aged 60 years or younger between 2007 and 2015. The operations were performed by 12 surgeons and there were no specific contraindications for use of the implant. Follow up ended in 2020. The status of the implant of deceased patients at death and those not attending follow up was checked with the Swedish Knee Arthroplasty Register. Clinical follow up consisted of clinical investigation, PROMs, and knee X-ray.

Results: Follow up was mean (range) 8.5 (5–13.8) years, and the 8-year survival rate was 0.98 (standard error 0.007). Five patients five knees) were deceased, five knees were revised (none due to aseptic loosening), and 16 patients did not attend the clinical follow up. Forty-four percent of the knees had secondary OA and 45% had had previous operations. 93% were satisfied or very satisfied with the operation and forgotten joint score (FJS) was median (interquartile range) 81 (44–94). Radiographic analysis revealed bone in close contact with the tibial tray and pegs in most cases, and in only 2% of the knees were potential radiolucent lines found.

Conclusion: The results indicate that this uncemented implant performs excellently in routine clinical practice and also in younger patients with secondary OA or previous knee operations.

Ort, förlag, år, upplaga, sidor
Elsevier, 2024
Nyckelord
Cementless, Posterior stabilized, Total knee arthroplasty, Trabecular metal, Younger person
Nationell ämneskategori
Ortopedi Kirurgi
Identifikatorer
urn:nbn:se:umu:diva-218293 (URN)10.1016/j.knee.2023.11.006 (DOI)2-s2.0-85179469958 (Scopus ID)
Tillgänglig från: 2023-12-22 Skapad: 2023-12-22 Senast uppdaterad: 2023-12-22Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>A novel radiographic pattern related to poor prognosis in patients with prostate cancer with metastatic spinal cord compression
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2023 (Engelska)Ingår i: European Urology Open Science, ISSN 2666-1691, E-ISSN 2666-1683, Vol. 48, s. 44-53Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Elsevier, 2023
Nyckelord
Metastatic spinal cord, compression, Myeloma-like prostate cancer, bone metastases, Prostate cancer
Nationell ämneskategori
Ortopedi
Identifikatorer
urn:nbn:se:umu:diva-202101 (URN)10.1016/j.euros.2022.12.004 (DOI)000973999000001 ()2-s2.0-85144765610 (Scopus ID)
Forskningsfinansiär
CancerfondenCancerforskningsfonden i NorrlandRegion Västerbotten
Tillgänglig från: 2023-01-02 Skapad: 2023-01-02 Senast uppdaterad: 2023-09-05Bibliografiskt granskad
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.
Öppna denna publikation i ny flik eller fönster >>Investigating microRNA Profiles in Prostate Cancer Bone Metastases and Functional Effects of microRNA-23c and microRNA-4328
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2023 (Engelska)Ingår i: Cancers, ISSN 2072-6694, Vol. 15, nr 9, artikel-id 2437Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
MDPI, 2023
Nyckelord
blood vessels, bone metastasis, extracellular vesicles, microarray, microRNA-23c, microRNA-4328, proliferation, prostate cancer, proteomics
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-209116 (URN)10.3390/cancers15092437 (DOI)000986796000001 ()2-s2.0-85159230526 (Scopus ID)
Forskningsfinansiär
Vetenskapsrådet, 2022-00946Cancerfonden, 21-1856Stiftelsen för strategisk forskning (SSF), RB13-0119Cancerforskningsfonden i Norrland, AMP 21-1061Prostatacancerförbundet
Tillgänglig från: 2023-06-07 Skapad: 2023-06-07 Senast uppdaterad: 2023-10-23Bibliografiskt granskad
Morberg, P., Paradowski, P., Röding, F., Juto, H., Sayed-Noor, A., Knutsson, B., . . . Elmqvist, L.-G. (2023). Ortopedisk forskning vid Umeå universitet. Ortopediskt magasin (1), 22-25
Öppna denna publikation i ny flik eller fönster >>Ortopedisk forskning vid Umeå universitet
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2023 (Svenska)Ingår i: Ortopediskt magasin, nr 1, s. 22-25Artikel i tidskrift (Refereegranskat) Published
Ort, förlag, år, upplaga, sidor
Järna: Svensk ortopedisk förening, 2023
Nationell ämneskategori
Ortopedi
Identifikatorer
urn:nbn:se:umu:diva-223207 (URN)
Tillgänglig från: 2024-04-11 Skapad: 2024-04-11 Senast uppdaterad: 2024-04-18Bibliografiskt granskad
Bitar, C., Moberg, I., Krupic, F., Wretenberg, P., Otten, V. T. & Crnalic, S. (2022). 11-Year outcomes in patients with metal-on-metal ASR hip arthroplasty. Journal of Orthopaedics, 32, 98-103
Öppna denna publikation i ny flik eller fönster >>11-Year outcomes in patients with metal-on-metal ASR hip arthroplasty
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2022 (Engelska)Ingår i: Journal of Orthopaedics, ISSN 0972-978X, E-ISSN 2589-9082, Vol. 32, s. 98-103Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: We analysed the long-term revision rate, clinical outcomes and metal ion concentrations in blood over time in patients who had undergone metal-on-metal Articular Surface Replacement (ASR) hip arthroplasty. Methods: A total of 38 patients (43 hips) were included: 24 patients (28 hips) underwent large-head total hip arthroplasty (XL THA), and 14 patients (15 hips) underwent hip resurfacing arthroplasty (HRA). The median follow-up time was 11 (range 7-12) years. Results: None of 15 HRA implants were revised. Nine of 28 XL THA implants (32%) in 8 patients were revised. The Co ion levels significantly increased in the XL THA group (p=0.009) over a median time period of 84 (25-97) months. Conclusion: The levels of Co ions in blood were higher in the patients who had undergone XL THA and increased significantly over time.

Ort, förlag, år, upplaga, sidor
Elsevier BV, 2022
Nationell ämneskategori
Ortopedi
Identifikatorer
urn:nbn:se:umu:diva-203187 (URN)10.1016/j.jor.2022.05.015 (DOI)000807305100011 ()2-s2.0-85131094702 (Scopus ID)
Tillgänglig från: 2023-01-17 Skapad: 2023-01-17 Senast uppdaterad: 2024-01-22Bibliografiskt granskad
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)
Öppna denna publikation i ny flik eller fönster >>Clinical and biological relevance of the transcriptomic-based prostate cancer metastasis subtypes MetA-C
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2022 (Engelska)Ingår i: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, nr 4Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2022
Nyckelord
MetA-C, Metastasis, Prognosis, Prostate cancer, Subtypes, Transcriptomic
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-190463 (URN)10.1002/1878-0261.13158 (DOI)000734478400001 ()34889043 (PubMedID)2-s2.0-85121666619 (Scopus ID)
Tillgänglig från: 2021-12-16 Skapad: 2021-12-16 Senast uppdaterad: 2023-10-23Bibliografiskt granskad
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.
Öppna denna publikation i ny flik eller fönster >>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 (Engelska)Ingår i: Cancers, ISSN 2072-6694, Vol. 14, nr 21, artikel-id 5195Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
MDPI, 2022
Nyckelord
androgen receptor, bone metastases, ERG, Ki67, metastatic subtypes, PDGFRB, prostate cancer, PSA, SDF1, smooth muscle actin
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-201227 (URN)10.3390/cancers14215195 (DOI)000880962300001 ()36358614 (PubMedID)2-s2.0-85141664487 (Scopus ID)
Forskningsfinansiär
Stiftelsen för strategisk forskning (SSF), RB13-0119Cancerfonden, 19 0053Cancerfonden, 19 0054Cancerfonden, 21 1856Knut och Alice Wallenbergs Stiftelse, KAW 2015.0114Vetenskapsrådet, 2018-02594Cancerforskningsfonden i Norrland, 22-2302Cancerforskningsfonden i Norrland, 21-2258
Tillgänglig från: 2022-12-05 Skapad: 2022-12-05 Senast uppdaterad: 2022-12-05Bibliografiskt granskad
Otten, V., Wästerlund, D., Lindbjörn, J., Mertens, C., Mukka, S., Crnalic, S. & Nilsson, K. G. (2022). Evaluation of a new cemented highly cross-linked all-polyethylene cup: a prospective and randomised study assessing wear and fixation characteristics using radiostereometric analysis. HIP International, 32(6), 779-786
Öppna denna publikation i ny flik eller fönster >>Evaluation of a new cemented highly cross-linked all-polyethylene cup: a prospective and randomised study assessing wear and fixation characteristics using radiostereometric analysis
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2022 (Engelska)Ingår i: HIP International, ISSN 1120-7000, E-ISSN 1724-6067, Vol. 32, nr 6, s. 779-786Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

BACKGROUND AND PURPOSE: The aim of this prospective, randomised and controlled study was to evaluate the wear and fixation properties of a new cemented highly cross-linked all-polyethylene (HXLPE) cup in comparison with a conventional cemented ultra-high molecular weight polyethylene (ConvPE) cup using radiostereometric analysis (RSA).

PATIENTS AND METHODS: A total of 58 patients (58 hips) with primary osteoarthritis (OA) were enrolled in a randomised controlled trial to receive either a ConvPE cup (control) or HXLPE cup (intervention) with identical geometry. The subjects were randomised in a 1:1 ratio. The primary endpoint was proximal wear measured as femoral head penetration into the cup, secondary outcomes were 3D-wear and annual proximal wear from 1 to 5 years. Cup fixation was measured as movement of the cup in relation to the acetabular bone with proximal migration being the primary outcome measure, 3D-migration and change in inclination as secondary outcomes. The patients were followed for 5 years with RSA performed postoperatively, at 3, 12, 24, and 60 months.

RESULTS: The HXLPE displayed a lower median proximal femoral head penetration compared to ConvPE, with a median difference at 2 years of -0.07 mm (95% CI, -0.10 to -0.04 mm), and -0.19 mm (95% CI, -0.27 to -0.15 mm) at 5 years. Annual proximal wear between 1 and 5 years was 0.03 mm/year for HXLPE and 0.06 mm/year for ConvPE (mean difference 0.05 mm, [95% CI, 0.03-0.07 mm]). Proximal migration, 3D migration and change in inclination was numerically slightly higher for HXLPE, albeit not statistically significant.

CONCLUSIONS: Compared to ConvPE, the HXLPE cup displayed significantly lower polyethylene wear. Cup migration was not statistically significant different.

CLINICALTRIALS.GOV IDENTIFIER: NCT04322799.

Ort, förlag, år, upplaga, sidor
Sage Publications, 2022
Nyckelord
Highly cross-linked polyethylene, RCT, RSA, migration, wear
Nationell ämneskategori
Ortopedi
Identifikatorer
urn:nbn:se:umu:diva-180299 (URN)10.1177/1120700021989991 (DOI)000631213800001 ()33566703 (PubMedID)2-s2.0-85101002186 (Scopus ID)
Tillgänglig från: 2021-02-16 Skapad: 2021-02-16 Senast uppdaterad: 2022-12-30Bibliografiskt granskad
Kruse, M., Mohammed, J., Sayed-Noor, A., Wolf, O., Holmgren, G., Nordström, R., . . . Mukka, S. (2022). Peri-implant femoral fractures in hip fracture patients treated with osteosynthesis: a retrospective cohort study of 1965 patients. European Journal of Trauma and Emergency Surgery, 48, 293-298
Öppna denna publikation i ny flik eller fönster >>Peri-implant femoral fractures in hip fracture patients treated with osteosynthesis: a retrospective cohort study of 1965 patients
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2022 (Engelska)Ingår i: European Journal of Trauma and Emergency Surgery, ISSN 1863-9933, E-ISSN 1863-9941, Vol. 48, s. 293-298Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

BACKGROUND AND PURPOSE: There are few studies on incidence rates, treatment and outcomes for peri-implant femoral fractures (PIFF) in the proximity of osteosynthesis. The purpose of this study was to investigate the incidence of PIFF following osteosynthesis of proximal femoral fractures.

PATIENTS AND METHODS: This retrospective cohort study comprised a consecutive series of hip fracture patients aged 50 years or older and operated with osteosynthesis between 2003 and 2015. Patients were followed-up until 2018, removal of implants or death, for a mean of 4 years (range 0-15). Data on age, sex, housing, hip complications, and reoperations were recorded. The risk of PIFFs was assessed using Cox proportional hazards regression analysis. In patients with two fractures during the study period, only the first fracture was included.

RESULTS: A total of 1965 osteosynthesis procedures were performed, of which 382 were cephalomedullary nails (CMN), 933 sliding hip devices (SHD) and 650 pins. Mean age was 80 years (range 50-104), 65% of patients were women. A total of 41 PIFFs occurred during the study period. The cumulative incidence of peri-implant fractures was 0.8% for CMN, 2.7% (HR 2.995% CI, 0.87-9.6, p = 0.08) for SHD and 2.0% (HR 2.3 95% CI, 0.6-8.1, p = 0.2) for pins. PIFFs occurred after a mean of 27 months (range 0-143). The 1-year mortality was 34% following PIFF. The majority was treated surgically (66%, 27/41) and the reoperation rate was 15% (4/27).

CONCLUSION: In this retrospective cohort study, in contrast to previous reports, we found a tendency to a higher cumulative incidence of PIFFs for SHD compared to modern CMN. Our results show cumulative incidences of PIFFs comparable to those described for periprosthetic femur fractures after hip arthroplasty for femoral neck fracture.

Ort, förlag, år, upplaga, sidor
Springer, 2022
Nyckelord
Complication, Hip fracture, Internal fixation, Peri-implant hip fracture, Removal of hardware
Nationell ämneskategori
Ortopedi
Identifikatorer
urn:nbn:se:umu:diva-179074 (URN)10.1007/s00068-020-01596-7 (DOI)000610486500001 ()33484277 (PubMedID)2-s2.0-85099585582 (Scopus ID)
Tillgänglig från: 2021-01-25 Skapad: 2021-01-25 Senast uppdaterad: 2023-03-24Bibliografiskt granskad
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.
Öppna denna publikation i ny flik eller fönster >>A novel DNA methylation signature is associated with androgen receptor activity and patient prognosis in bone metastatic prostate cancer
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2021 (Engelska)Ingår i: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 13, nr 1, artikel-id 133Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
BioMed Central, 2021
Nyckelord
Androgen receptor, DNA methylation, Gene expression, MetA, Metastasis, MetB, MetC, Prognosis, Prostate cancer, Subtypes
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-185893 (URN)10.1186/s13148-021-01119-0 (DOI)000670704300001 ()34193246 (PubMedID)2-s2.0-85109041809 (Scopus ID)
Tillgänglig från: 2021-07-12 Skapad: 2021-07-12 Senast uppdaterad: 2023-09-05Bibliografiskt granskad
Organisationer
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0001-5875-4946

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