Anssi Auvinen | Epidemiology
A randomized trial of early detection of clinically significant prostate cancer.
Describes the rationale and design of the population-based ProScreen trial combining PSA kallikrein panel (4Kscore) and MRI for prostate cancer screening, with the aim of assessing the extent of overdiagnosis (detection of clinically insignificant cancer) as well as prostate cancer mortality as the main end-point
Auvinen A, Rannikko A, Taari K, Kujala P, Mirtti T, Kenttämies A, Rinta-Kiikka I, Lehtimäki T, Oksala N, Pettersson K, Tammela TL.
Eur JU Epid 2017;32: 521-527
Steven Bova | PELICAN-Personalized Cancer Medicine
Prostate cancer evolution from multilineage primary to single lineage metastases with implications for liquid biopsy
We infer detailed reconstructions of tumor phylogenies in ten prostate cancer patients with fatal disease and investigate them in conjunction with histopathology and tumor DNA extracted from blood and cerebrospinal ﬂuid. One dominant lineage emerges that initiates and drives systemic metastasis. Routes to metastasis differ between patients, and likely genetic drivers of metastasis distinguish the metastatic lineage from the lineage that remains conﬁned to the prostate. Body ﬂuids capture features of the dominant lineage, and subclonal expansions that occur in the metastatic phase are non-uniformly represented. Cerebrospinal ﬂuid analysis reveals lineages not detected in blood-borne DNA, suggesting possible clinical utility.
Link to whole article: https://rdcu.be/b8eoZ
Woodcock DJ, Riabchenko E, Taavitsainen S, Kankainen M, Gundem G, Brewer DS, Ellonen P, Lepistö M, Golubeva YG, Warner AC, Tolonen TT, Jasu J, Isaacs WB, Emmert-Buck MR, Nykter M, Visakorpi T, Bova GS, Wedge DC.
Nat Commun. 2020 Oct 8;11(1):5070
Kirsi Rautajoki (priorly Granberg) | Cancer Regulation and Immunology
Tumor immune microenvironment analysis reveals three tumor subgroups
Understanding the nature of immunosuppression in malignant tissue is important for successful cancer treatment through immune system modulation. In this study, we uncovered high variability in immune system-related responses and in the composition of the microenvironment across glioblastoma (GBM) cohort, suggesting immunologic diversity. Our analysis identified three GBM subgroups presenting different adaptive immune responses: negative, humoral, and cellular-like. These subgroups and immune cell compositions were associated with typical alterations, such as CDK4 amplifications or inactivating NF1 alterations. All IDH-mutated samples were in the negative group, and they showed lower expression and higher DNA methylation of MHC-I genes.
Luoto S, Hermelo I, Vuorinen E, Hannus P, Kesseli J, Nykter M, Granberg KJ
Teemu Murtola | Pharmacoepidemiology and Chemoprevention
Atorvastatin Versus Placebo for Prostate Cancer Before Radical Prostatectomy-A Randomized, Double-blind, Placebo-controlled Clinical Trial
We tested whether intervention with atorvastatin affects the prostate beneficially compared with placebo in men with prostate cancer in a randomized clinical trial. A total of 160 statin-naïve prostate cancer patients scheduled for radical prostatectomy were randomized to use 80 mg atorvastatin or placebo daily from recruitment to surgery for a median of 27 d. Cholesterol-lowering atorvastatin does not lower prostate cancer proliferation rate compared with placebo overall, but exploratory analyses suggest a benefit in longer exposure.
Murtola TJ, Syvälä H, Tolonen T, Helminen M, Riikonen J, Koskimäki J, Pakarainen T, Kaipia A, Isotalo T, Kujala P, Tammela TLJ.
Eur Urol. 274:697-701, 2018.
Matti Nykter | Computational Biology
Integrative proteogenomics in prostate cancer
We report high-throughput mass spectrometry with integrated genome level analysis on clinical tissue samples of benign prostatic hyperplasia (BPH), untreated primary prostate cancer (PC) and castration resistant prostate cancer (CRPC). Each sample group shows a distinct protein profile. We show that, especially in CRPC, gene copy number, DNA methylation, and RNA expression levels do not reliably predict proteomic changes. Instead, we uncover previously unrecognized molecular and pathway events, for example, several miRNA target correlations present at protein but not at mRNA level. Notably, we identify two metabolic shifts in the citric acid cycle (TCA cycle) during prostate cancer development and progression.
See Research highlight article “Controlling Mutational Chaos” in Nature Reviews Urology.
Pekka Ruusuvuori | Bioimage Informatics
Artificial intelligence for diagnosis and grading of prostate cancer in biopsies
We report pathologist level accuracy for artificial intelligence based detection, length estimation and grading of prostate cancer from histopathological images in a population based diagnostic study in a collaboration study led by researchers at Karolinska Institutet.
Ström, P., Kartasalo, K., Olsson, H., Solorzano, L., Delahunt, B., Berney, D. M., Iczkowski, K. A., Kench, J.G., Kristiansen, G., van der Kwast, T.H., Leite, K.R.M., McKenney, J.K., Oxley, J., Pan, C., Samaratunga, H., Srigley, J.R., Takahashi, H., Tsuzuki, T., Varma, M., Zhou, M., Lindberg, J., Lindskog, C., Ruusuvuori, P., Wählby, C., Grönberg, H., Rantalainen, M., Egevad, L., Eklund M. (2020).
Artificial intelligence for diagnosis and grading of prostate cancer in biopsies: a population-based, diagnostic study.
The Lancet Oncology, 21(2), 222-232.
Johanna Schleutker | Genetic Predisposition to Prostate Cancer
Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus
We found an association of the aggressive PCa-associated allele G of rs11672691 with elevated transcript levels of two biologically plausible candidate genes, PCAT19 and CEACAM21, implicated in PCa cell growth and tumor progression. Mechanistically, rs11672691 resides in an enhancer element and alters the binding site of HOXA2, a novel oncogenic transcription factor with prognostic potential in PCa. Remarkably, CRISPR/Cas9-mediated single-nucleotide editing showed the direct effect of rs11672691 on PCAT19 and CEACAM21 expression and PCa cellular aggressive phenotype. Clinical data demonstrated synergistic effects of rs11672691 genotype and PCAT19/CEACAM21 gene expression on PCa prognosis.
Gao P, Xia JH, Sipeky C, Dong XM, Zhang Q, Yang Y, Zhang P, Cruz SP, Zhang K, Zhu J, Lee HM, Suleman S, Giannareas N, Liu S; PRACTICAL Consortium, Tammela TLJ, Auvinen A, Wang X, Huang Q, Wang L, Manninen A, Vaarala MH, Wang L, Schleutker J, Wei GH.
Cell 174(3):576-589, 2018
Alfonso Urbanucci | Genomic Regulation for Precision Cancer Medicine
Chromatin and Epigenetic Dysregulation of Prostate Cancer Development, Progression, and Therapeutic Response
The dysregulation of chromatin and epigenetics has been defined as the overarching cancer hallmark. By disrupting transcriptional regulation in normal cells and mediating tumor progression by promoting cancer cell plasticity, this process has the ability to mediate all defined hallmarks of cancer. In this review, we collect and assess evidence on the contribution of chromatin and epigenetic dysregulation in prostate cancer. We highlight important mechanisms leading to prostate carcinogenesis, the emergence of castration-resistance upon treatment with androgen deprivation therapy, and resistance to antiandrogens. We examine in particular the contribution of chromatin structure and epigenetics to cell lineage commitment, which is dysregulated during tumorigenesis, and cell plasticity, which is altered during tumor progression.
Tapio Visakorpi | Molecular Biology of Prostate Cancer
Androgen receptor and ERG drive the expression of prostate cancer speciﬁc long noncoding RNAs
Long noncoding RNAs (lncRNAs) play pivotal roles in cancer development and progression, and some function in a highly cancer-speciﬁc manner. Here, we investigated a group of lncRNAs that we previously identiﬁed to be aberrantly expressed in prostate cancer, called TPCATs. We report that the majority of TPCATs investigated here are strongly associated with androgen receptor and other cooperative TFs, most importantly with ERG, in fusion-positive tumors. We found that the expression of many of the TPCATs was regulated by these TFs. In addition, three of the TPCATs were independently associated with PC progression, most notably EPCART that we also found to promote the migration and proliferation of the PC cells in vitro. Together, these ﬁndings demonstrate that EPCART has functions relevant for PC progression.
Kohvakka, A., Sattari, M., Shcherban, A., Annala, M., Urbanucci, A., Kesseli, J., Tammela, T., Kivinummi, K., Latonen, L., Nykter, M., Visakorpi, T. AR and ERG drive the expression of prostate cancer specific long noncoding RNAs.
Oncogene 39, 5241–5251 (2020).
Nonmetastatic Castration-Resistant Prostate Cancer and Survival with Darolutamide.
In this double-blind, placebo-controlled trial, we randomly assigned 1509 men, in a 2:1 ratio, to receive darolutamide (955 patients) or placebo (554 patients) while they continued to receive androgen-deprivation therapy. After the results of the primary end-point analysis were found to be positive, unblinding of the treatment assignments occurred, and patients in the placebo group were permitted to cross over to receive open-label darolutamide treatment.Among men with nonmetastatic, castration-resistant prostate cancer, the percentage of patients who were alive at 3 years was significantly higher among those who received darolutamide than among those who received placebo. The incidence of adverse events was similar in the two groups. (Funded by Bayer HealthCare and Orion Pharma; ARAMIS ClinicalTrials.gov number.
Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Le Berre MA, Petrenciuc O, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators.
Teemu Tolonen | Histopathology
Extraprostatic extension (pT3a) in prostate biopsy is an under-recognized feature indicating high risk disease
Extraprostatic extension (EPE+) in a needle biopsy may be more common than previously thought. Approximately one of six high grade prostate cancers harbor EPE+ in core biopsies. EPE+ is associated with highly adverse features of prostate cancer, making its reporting obligatory. More studies are needed to establish the predictive and prognostic value of EPE+ in needle biopsies
Tolonen TT, Riikonen J, Tammela TLJ, Koivusalo L, Haapasalo H, Kujala P, Kaipia A. Extraprostatic extension (pT3a) in prostate biopsy is an under-recognized feature indicating high risk disease.
Ann Diagn Pathol. 2018 Aug;35:80-84