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Häggström, C., Jonsson, H., Björge, T., Nagel, G., Manjer, J., Ulmer, H., . . . Stocks, T. (2020). Linear age-course effects on the associations between body mass index, triglycerides, and female breast and male liver cancer risk: An internal replication study of 800,000 individuals. International Journal of Cancer, 146(1), 58-67
Open this publication in new window or tab >>Linear age-course effects on the associations between body mass index, triglycerides, and female breast and male liver cancer risk: An internal replication study of 800,000 individuals
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2020 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 146, no 1, p. 58-67Article in journal (Refereed) Published
Abstract [en]

Apart from the consistently observed differential association between obesity and breast cancer risk by menopausal status, the associations between obesity and other metabolic imbalances with risks of cancers have not been systematically investigated across the age-course. We created two random 50-50% cohorts from six European cohorts comprising 813,927 individuals. In the "discovery cohort", we used Cox regression with attained age as time-scale and tested interactions between body mass index (BMI), blood pressure, plasma glucose, triglycerides and cholesterol, and attained age in relation to cancer risk. Results with a p-value below 0.05 were additionally tested in the "replication cohort" where a replicated result was considered evidence of a linear interaction with attained age. These findings were investigated by flexible parametric survival models for any age-plateaus in their shape of associations with cancer risk across age. Consistent with other studies, BMI was negatively related to breast cancer risk (n cases = 11,723) among younger (premenopausal) women. However, the association remained negative for several years after menopause and, although gradually weakening over age, the association became positive only at 62 years of age. This linear and positive age-interaction was also found for triglycerides and breast cancer, and for BMI and triglycerides in relation to liver cancer among men (n cases = 444). These findings are unlikely to be due to chance owing to the replication. The linear age-interactions in breast cancer may suggest an influence by other age-related factors than menopause; however, further investigation of age-related effect modifiers in both breast and liver cancer is needed.

Place, publisher, year, edition, pages
WILEY, 2020
Keywords
survival analysis, cohort study, metabolic factors, cancer risk, age interaction
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-398025 (URN)10.1002/ijc.32240 (DOI)000495546500009 ()30815851 (PubMedID)
Funder
Swedish Research Council, 2015-02332
Available from: 2019-12-05 Created: 2019-12-05 Last updated: 2019-12-12Bibliographically approved
Papadimitriou, N., Muller, D., van den Brandt, P. A., Geybels, M., Patel, C. J., Gunter, M. J., . . . Tsilidis, K. K. (2019). A nutrient-wide association study for risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition and the Netherlands Cohort Study. European Journal of Nutrition
Open this publication in new window or tab >>A nutrient-wide association study for risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition and the Netherlands Cohort Study
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2019 (English)In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215Article in journal (Refereed) Published
Abstract [en]

Purpose: The evidence from the literature regarding the association of dietary factors and risk of prostate cancer is inconclusive.

Methods: A nutrient-wide association study was conducted to systematically and comprehensively evaluate the associations between 92 foods or nutrients and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cox proportional hazard regression models adjusted for total energy intake, smoking status, body mass index, physical activity, diabetes and education were used to estimate hazard ratios and 95% confidence intervals for standardized dietary intakes. As in genome-wide association studies, correction for multiple comparisons was applied using the false discovery rate (FDR < 5%) method and suggested results were replicated in an independent cohort, the Netherlands Cohort Study (NLCS).

Results: A total of 5916 and 3842 incident cases of prostate cancer were diagnosed during a mean follow-up of 14 and 20 years in EPIC and NLCS, respectively. None of the dietary factors was associated with the risk of total prostate cancer in EPIC (minimum FDR-corrected P, 0.37). Null associations were also observed by disease stage, grade and fatality, except for positive associations observed for intake of dry cakes/biscuits with low-grade and butter with aggressive prostate cancer, respectively, out of which the intake of dry cakes/biscuits was replicated in the NLCS.

Conclusions: Our findings provide little support for an association for the majority of the 92 examined dietary factors and risk of prostate cancer. The association of dry cakes/biscuits with low-grade prostate cancer warrants further replication given the scarcity in the literature.

 

Keywords
Diet, Nutrition, Epidemiology, Cohort study, Prostate cancer
National Category
Nutrition and Dietetics
Identifiers
urn:nbn:se:uu:diva-397652 (URN)10.1007/s00394-019-02132-z (DOI)000495235600001 ()31705265 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Note

From WoS: Early access - [The article] have been peer-reviewed and accepted for publication. The article content has been finalized, but it has not been assigned to an issue yet.

Available from: 2019-12-03 Created: 2019-12-03 Last updated: 2019-12-03Bibliographically approved
Sverrisson, I., Folkvaljon, F., Chabok, A., Stattin, P., Smedh, K. & Nikberg, M. (2019). Anastomotic leakage after anterior resection in patients with rectal cancer previously irradiated for prostate cancer. European Journal of Surgical Oncology, 45(3), 341-346
Open this publication in new window or tab >>Anastomotic leakage after anterior resection in patients with rectal cancer previously irradiated for prostate cancer
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2019 (English)In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 45, no 3, p. 341-346Article in journal (Refereed) Published
Abstract [en]

Introduction:

There are little data on the post-operative outcome of anterior resection (AR) for rectal cancer in men who had received radiotherapy for prostate cancer previously. The aim of this study was to assess the rate of anastomotic leakage (AL) after AR in these patients.

Methods:

All men who underwent bowel resection because of rectal cancer between 2000 and 2016 and had been diagnosed previously with prostate cancer were identified by linking the Swedish Colorectal Cancer Registry with the National Prostate Cancer Register. The medical records of men who underwent AR and had previously received radiotherapy for prostate cancer were reviewed.

Results:

In total, 13299 men had undergone a bowel resection for rectal cancer, 188 of whom had previously received radiotherapy for prostate cancer. Among those who had received radiation therapy, 59 men (31%) had an AR: 50 men (85%) received a diverting ileostomy, 42 men (71%) had an American Society of Anesthesiologists score of 1-2 and 36 men (61%) had tumour stage 1-2. AL was found in 12/59 men (20%), one of whom had a re-laparotomy. There was no 90-day mortality.

Conclusions:

In the combined national population-based registries, a minority of patients with rectal cancer had an AR after previous radiotherapy for prostate cancer. These patients were healthy with early cancer stages and, in this selected group of patients, the AL rate was much lower than that reported previously.

Keywords
Rectal cancer, Prostate cancer, Complications, Anastomotic leakage, Radiation therapy
National Category
Surgery Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-381093 (URN)10.1016/j.ejso.2018.11.015 (DOI)000461411100008 ()30503046 (PubMedID)
Available from: 2019-04-15 Created: 2019-04-15 Last updated: 2019-04-15Bibliographically approved
Beckmann, K., Garmo, H., Adolfsson, J., Bosco, C., Johansson, E., Robinson, D., . . . Van Hemelrijck, M. (2019). Androgen Deprivation Therapies and Changes in Comorbidity: A Comparison of Gonadotropin-releasing Hormone Agonists and Antiandrogen Monotherapy as Primary Therapy in Men with High-risk Prostate Cancer. European Urology, 75(4), 676-683
Open this publication in new window or tab >>Androgen Deprivation Therapies and Changes in Comorbidity: A Comparison of Gonadotropin-releasing Hormone Agonists and Antiandrogen Monotherapy as Primary Therapy in Men with High-risk Prostate Cancer
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2019 (English)In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 75, no 4, p. 676-683Article in journal (Refereed) Published
Abstract [en]

Background: Some studies suggest that gonadotropin-releasing hormone (GnRH) agonists are associated with higher risk of adverse events than antiandrogens (AAs) monotherapy. However, it has been unclear whether this is due to indication bias.

Objective: To investigate rates of change in comorbidity for men on GnRH agonists versus AA monotherapy in a population-based register study.

Design, setting, and participants: Men with advanced nonmetastatic prostate cancer (PCa) who received primary AA (n = 2078) or GnRH agonists (n = 4878) and age- and area-matched PCa-free men were selected from Prostate Cancer Database Sweden 3.0. Increases in comorbidity were measured using the Charlson Comorbidity Index (CCI), from 5 yr before through to 5 yr after starting androgen deprivation therapy (ADT).

Outcome measures and statistical methods: Multivariable linear regression was used to determine differences in excess rate of CCI change before and after ADT initiation. Risk of any incremental change in CCI following ADT was assessed using multivariable Cox regression analyses.

Results and limitations: Men on GnRH agonists experienced a greater difference in excess rate of CCI change after starting ADT than men on AA monotherapy (5.6% per yr, p < 0.001). Risk of any new CCI change after ADT was greater for GnRH agonists than for AA (hazard ratio, 1.32; 95% confidence interval, 1.20-144).

Conclusions: Impact on comorbidity was lower for men on AA monotherapy than for men on GnRH agonists. Our results should be confirmed through randomised trials of effectiveness and adverse effects, comparing AA monotherapy and GnRH agonists in men with advanced nonmetastatic PCa who are unsuitable for curative treatment.

Patient summary: Hormone therapies for advanced prostate cancer can increase the risk of other diseases (eg, heart disease, diabetes). This study compared two common forms of hormone therapy and found that the risk of another serious disease was higher for those on gonadotropin-releasing hormone agonists than for those on antiandrogen monotherapy.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2019
Keywords
Androgen deprivation therapy, Antiandrogen monotherapy, Comorbidity, Gonadotropin-releasing hormone agonists, Prostate cancer
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-380435 (URN)10.1016/j.eururo.2018.11.022 (DOI)000461049200041 ()30497883 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2019-04-09Bibliographically approved
Robinson, D., Garmo, H., Van Hemelrijck, M., Damber, J.-E., Bratt, O., Holmberg, L., . . . Adolfsson, J. (2019). Androgen deprivation therapy for prostate cancer and risk of dementia. BJU International, 124(1), 87-92
Open this publication in new window or tab >>Androgen deprivation therapy for prostate cancer and risk of dementia
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2019 (English)In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 124, no 1, p. 87-92Article in journal (Refereed) Published
Abstract [en]

Objectives

To study whether androgen deprivation therapy (ADT), the mainstay treatment for advanced and disseminated prostate cancer, is associated with risk of dementia.

Methods

Risk of dementia in men with prostate cancer primarily managed with ADT or watchful waiting (WW) in the Prostate Cancer Database Sweden, PCBaSe, was compared with that in prostate cancer-free men, matched on birth year and county of residency. We used Cox regression to calculate the hazard ratios (HRs) for Alzheimer's and non-Alzheimer's dementia (vascular dementia, dementia secondary to other diseases or unspecified dementias) for different types and duration of ADT and oral antiandrogens (AAs) as well as for men managed with WW.

Results

A total of 25 967 men with prostate cancer and 121 018 prostate cancer-free men were followed for a median of 4 years. In both groups 6% of the men were diagnosed with dementia. In men with prostate cancer, gonadotropin-releasing hormone agonist treatment ( HR 1.15, 95% confidence interval [CI] 1.07-1.23) and orchiectomy (HR 1.60, 95% CI 1.32-1.93) were associated with an increased risk of dementia, as compared to no treatment in prostate cancer-free men; however, this increase in risk was only observed for non-Alzheimer's dementia and occurred from year 1-4 after start of ADT. No increase in risk for any type of dementia was observed for men treated with AAs or for men on WW.

Conclusion

This population-based cohort study does not support previous observations of an increased risk of Alzheimer's dementia for men on ADT; however, there was a small increase in risk of non-Alzheimer's dementia.

Keywords
androgen deprivation therapy, dementia, #ProstateCancer, #PCSM, #ADT, #Dementia
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-388761 (URN)10.1111/bju.14666 (DOI)000471830900016 ()30637900 (PubMedID)
Funder
Swedish Research Council, 825-2012-5047Swedish Cancer Society, 16-0700Swedish Cancer Society, 16-286Swedish Cancer Society, 16-464
Available from: 2019-08-13 Created: 2019-08-13 Last updated: 2019-08-14Bibliographically approved
Thomsen, F. B., Bosco, C., Garmo, H., Adolfsson, J., Hammar, N., Stattin, P. & Van Hemelrijck, M. (2019). Anti-androgen monotherapy versus gonadotropin-releasing hormone agonists in men with advanced, non-metastatic prostate cancer: a register-based, observational study. Acta Oncologica, 58(1), 110-118
Open this publication in new window or tab >>Anti-androgen monotherapy versus gonadotropin-releasing hormone agonists in men with advanced, non-metastatic prostate cancer: a register-based, observational study
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2019 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 58, no 1, p. 110-118Article in journal (Refereed) Published
Abstract [en]

Background:

In randomised controlled trials, men with advanced, non-metastatic prostate cancer (PCa) treated with anti-androgen monotherapy (AA) had similar all-cause mortality as men treated with gonadotropin-releasing hormone (GnRH) agonists. Using real-world evidence (i.e., observational data), we aimed to further assess the difference in mortality between these two drug categories.

Material and Methods:

We emulated a trial using data from Prostate Cancer data Base Sweden 3.0. We specifically focused on men diagnosed in 2006-2012 with high-risk PCa who had no distant metastasis. They either received primary hormonal therapy with AA (n=2078) or GnRH agonists (n=4878) who were followed for a median time of 5 years. Risk of death from PCa and other causes was assessed using competing risk analyses and Cox proportional hazards regression analyses, including propensity score matching.

Results:

The cumulative 5-year PCa mortality was lower for men treated with AA (16% [95% confidence interval, CI, 15-18%]) than men treated with GnRH agonists (22% [95% CI 21-24%]). The 5-year other cause mortality was also lower for men on AA (17% [95% CI 15-19%] compared to men on GnRH agonists (27% [95% CI 25-28%]). In regression analyses, the risk of PCa death was similar, GnRH agonists versus AA (reference), hazard ratio (HR) 1.08 (95% CI 0.95-1.23), but the risk of death from all causes was higher for men on GnRH agonists, HR 1.23 (95% CI 1.13-1.34). Consistent results were seen in the propensity score-matched cohort.

Conclusion:

Our results indicate that the use of AA as primary hormonal therapy in men with high-risk non-metastatic PCa does not increase PCa-specific mortality compared to GnRH. Using AA instead of GnRH agonists may result in shorter time on/exposure to GnRH-treatment, which may reduce the risk of adverse events associated with this treatment.

National Category
Cancer and Oncology Urology and Nephrology Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-379242 (URN)10.1080/0284186X.2018.1529427 (DOI)000459620200015 ()30375907 (PubMedID)
Funder
Swedish Research Council, 825-2012-5047
Available from: 2019-03-19 Created: 2019-03-19 Last updated: 2019-03-19Bibliographically approved
Beckmann, K., Russell, B., Josephs, D., Garmo, H., Häggström, C., Holmberg, L., . . . Adolfsson, J. (2019). Chronic inflammatory diseases, anti-inflammatory medications and risk of prostate cancer: a population-based case-control study. BMC Cancer, 19, Article ID 612.
Open this publication in new window or tab >>Chronic inflammatory diseases, anti-inflammatory medications and risk of prostate cancer: a population-based case-control study
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2019 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, article id 612Article in journal (Refereed) Published
Abstract [en]

Background: Whether chronic inflammation increases prostate cancer risk remains unclear. This study investigated whether chronic inflammatory diseases (CID) or anti-inflammatory medication use (AIM) were associated with prostate cancer risk.

Methods: Fifty-five thousand nine hundred thirty-seven cases (all prostate cancer, 2007-2012) and 279,618 age-matched controls were selected from the Prostate Cancer Database Sweden. CIDs and AIMs was determined from national patient and drug registers. Associations were investigated using conditional logistic regression, including for disease/drug subtypes and exposure length/dose.

Results: Men with a history of any CID had slightly increased risk of any prostate cancer diagnosis (OR: 1.08; 95%CI: 1.04-1.12) but not unfavourable' (high-risk or advanced) prostate cancer. Generally, risk of prostate cancer was highest for shorter exposure times. However, a positive association was observed for asthma >5years before prostate cancer diagnosis (OR: 1.21; 95%CI: 1.05-1.40). Risk of prostate cancer was increased with prior use of any AIMs (OR: 1.26; 95%CI: 1.24-1.29). A positive trend with increasing cumulative dose was only observed for inhaled glucocorticoids (p<0.011).

Conclusion: Detection bias most likely explains the elevated risk of prostate cancer with prior history of CIDs or use of AIMs, given the higher risk immediately after first CID event and lack of dose response. However, findings for length of time with asthma and dose of inhaled glucocorticoids suggest that asthma may increase risk of prostate cancer through other pathways.

Place, publisher, year, edition, pages
BMC, 2019
Keywords
Prostate cancer, Chronic inflammatory disease, Autoimmune disease, Anti-inflammatory medication
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-390092 (URN)10.1186/s12885-019-5846-3 (DOI)000472477600005 ()31226970 (PubMedID)
Funder
Swedish Cancer Society, 2013/472
Available from: 2019-08-05 Created: 2019-08-05 Last updated: 2019-12-12Bibliographically approved
Loeb, S., Folkvaljon, Y., Bratt, O., Robinson, D. & Stattin, P. (2019). Defining Intermediate Risk Prostate Cancer Suitable for Active Surveillance. Journal of Urology, 201(2), 292-299
Open this publication in new window or tab >>Defining Intermediate Risk Prostate Cancer Suitable for Active Surveillance
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2019 (English)In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 201, no 2, p. 292-299Article in journal (Refereed) Published
Abstract [en]

Purpose: Active surveillance of intermediate risk prostate cancer is controversial. Many active surveillance programs are limited to men with Grade Group 1 (Gleason 6) disease and prostate specific antigen less than 10 ng/ml. However, recent guidelines state that active surveillance can be considered in cases of limited Grade Group 2 (Gleason 3 thorn 4) despite limited data on outcomes. We compared prostatectomy outcomes between prostate cancer subgroups of intermediate risk vs low risk.

Materials and Methods: We performed an observational study in the National Prostate Cancer Register of Sweden, which includes 98% of prostate cancer cases nationwide. From 2009 to 2012 radical prostatectomy was performed in 5,087 men with low risk prostate cancer (Grade Group 1, prostate specific antigen less than 10 ng/ml and cT2 or less) and intermediate risk prostate cancer (Grade Group 2, prostate specific antigen 10 to 20 ng/ml or T2). We compared upgrading and up staging between the groups based on the CAPRA (Cancer of the Prostate Risk Assessment) scores and published active surveillance criteria. Results were validated in an independent data set of cases diagnosed from 2013 to 2016.

Results: Men with Grade Group 1, prostate specific antigen 10 to 15 ng/ml and prostate specific antigen density less than 0.15 ng/ml/cm3 did not significantly differ in upgrading or adverse pathology findings compared to men with low risk prostate cancer. Prostate specific antigen greater than 15 ng/ml or Grade Group 2 was associated with a significantly greater risk of aggressive prostate cancer. Men with low risk CAPRA scores (0 to 2) and Grade Group 2 disease were at almost threefold increased risk of upgrading and twofold increased risk of adverse pathology compared to men with low risk CAPRA, Grade Group 1 disease.

Conclusions: Expanding the prostate specific antigen threshold to 15 ng/ml for Grade Group 1 prostate cancer would allow more men to elect active surveillance. This is unlikely to compromise outcomes, particularly if prostate specific antigen density is low. In contrast, caution should be exercised in offering active surveillance to men with prostate specific antigen greater than 15 ng/ml or Grade Group 2 prostate cancer.

Keywords
prostatic neoplasms, neoplasm grading, prostate-specific antigen, watchful waiting, Sweden
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-375806 (URN)10.1016/j.juro.2018.09.042 (DOI)000455997500079 ()30240688 (PubMedID)
Funder
Swedish Research Council, 825-2012-5047Swedish Cancer Society, 16-0700NIH (National Institute of Health), K07CA178258
Available from: 2019-02-13 Created: 2019-02-13 Last updated: 2019-02-13Bibliographically approved
Lundström, K.-J., Söderström, L., Jernow, H., Stattin, P. & Nordin, P. (2019). Epidemiology of hydrocele and spermatocele; incidence, treatment and complications. Scandinavian journal of urology, 53(2-3), 134-138
Open this publication in new window or tab >>Epidemiology of hydrocele and spermatocele; incidence, treatment and complications
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2019 (English)In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 53, no 2-3, p. 134-138Article in journal (Refereed) Published
Abstract [en]

Objectives: To estimate the incidence of men seeking specialized care and receiving treatment for hydro or spermatocele complaints. Also, to determine the risk of complications of treatment. Materials and methods: The total number of men living in Sweden each year from 2005 to 2014 was used to calculate incidence and age distribution of adult (>= 18 years) men seeking specialized healthcare with either hydro or spermatocele. This was done by using nationwide registries, mandatory by law. They contain information on primary or discharge diagnosis, procedure codes and antibiotic prescriptions. Also, complication rates comparing aspiration (with or without sclerotherapy) and conventional surgery were analysed. Results: The incidence of men with either hydro or spermatocele diagnosis in specialized healthcare was similar to 100/100,000 men. The treatment incidence was 17/100,000 men. Orchiectomy was used as primary treatment in 2.4% of cases. The risk of experiencing a complication was clinically and statistically significantly increased with conventional surgery as compared with aspiration, 17.5% (1607/9174) vs 4.6% (181/3920), corresponding to relative risk of 3.79 (95% CI = 3.27-4.40). Hematoma and infections were the most common complications. Conclusion: Hydro and spermatoceles are common, affecting elderly men. Aspiration seems advantageous with respect to complications and can be recommended due to the benign course of the disease. The indication for conventional surgery might be questioned such as the use of orchiectomy as primary treatment.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2019
Keywords
Testicular hydrocele, spermatocele, incidence, postoperative complications
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-396078 (URN)10.1080/21681805.2019.1600582 (DOI)000465949700001 ()30990342 (PubMedID)
Available from: 2019-10-30 Created: 2019-10-30 Last updated: 2019-10-30Bibliographically approved
Thysell, E., Vidman, L., Ylitalo, E. B., Jernberg, E., Crnalic, S., Iglesias-Gato, D., . . . Wikstrom, P. (2019). Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor. Molecular Oncology, 13(8), 1763-1777
Open this publication in new window or tab >>Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor
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2019 (English)In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 13, no 8, p. 1763-1777Article in journal (Refereed) Published
Abstract [en]

Bone metastasis is the lethal end-stage of prostate cancer (PC), but the biology of bone metastases is poorly understood. The overall aim of this study was therefore to explore molecular variability in PC bone metastases of potential importance for therapy. Specifically, genome-wide expression profiles of bone metastases from untreated patients (n = 12) and patients treated with androgen-deprivation therapy (ADT, n = 60) were analyzed in relation to patient outcome and to morphological characteristics in metastases and paired primary tumors. Principal component analysis and unsupervised classification were used to identify sample clusters based on mRNA profiles. Clusters were characterized by gene set enrichment analysis and related to histological and clinical parameters using univariate and multivariate statistics. Selected proteins were analyzed by immunohistochemistry in metastases and matched primary tumors (n = 52) and in transurethral resected prostate (TUR-P) tissue of a separate cohort (n = 59). Three molecular subtypes of bone metastases (MetA-C) characterized by differences in gene expression pattern, morphology, and clinical behavior were identified. MetA (71% of the cases) showed increased expression of androgen receptor-regulated genes, including prostate-specific antigen (PSA), and glandular structures indicating a luminal cell phenotype. MetB (17%) showed expression profiles related to cell cycle activity and DNA damage, and a pronounced cellular atypia. MetC (12%) exhibited enriched stroma-epithelial cell interactions. MetB patients had the lowest serum PSA levels and the poorest prognosis after ADT. Combined analysis of PSA and Ki67 immunoreactivity (proliferation) in bone metastases, paired primary tumors, and TUR-P samples was able to differentiate MetA-like (high PSA, low Ki67) from MetB-like (low PSA, high Ki67) tumors and demonstrate their different prognosis. In conclusion, bone metastases from PC patients are separated based on gene expression profiles into molecular subtypes with different morphology, biology, and clinical outcome. These findings deserve further exploration with the purpose of improving treatment of metastatic PC.

Keywords
bone metastasis, gene expression, gene set enrichment analysis, morphology, survival, unsupervised cluster analysis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-393124 (URN)10.1002/1878-0261.12526 (DOI)000478600200009 ()31162796 (PubMedID)
Funder
Swedish Research Council, 2015-02393 WikstromSwedish Foundation for Strategic Research , RB13-0119Swedish Foundation for Strategic Research , WikstromSwedish Cancer Society, CAN 2016/824Swedish Cancer Society, CAN 2013/1324Swedish Cancer Society, CAN2016/387Swedish Cancer Society, CAN 2015/732
Available from: 2019-09-24 Created: 2019-09-24 Last updated: 2019-09-24Bibliographically approved
Projects
PCA BASE SWEDEN Prostate cancer studies on large databases in Sweden [2008-05910_VR]; Umeå UniversityProstate cancer research in large Swedish databases. PCBaSe Sweden [2010-05950_VR]; Umeå UniversityPrediction and clinical outcomes in prostate cancer. Studies in large databases [2010-07112_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-8306-0687

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