|Transcriptome sequencing reveals PCAT5 as a novel ERG-regulated long non-coding RNA in prostate cancer.
In this study, the transcriptomic differences between untreated prostate cancer and locally recurrent castration-resistant prostate cancer (CRPC) were characterized by next generation sequencing. We identified 145 previously unannotated intergenic long noncoding RNA transcripts (lncRNA) or isoforms that are associated with prostate cancer or CRPC. We defined a novel lncRNA termed PCAT5 as a regulatory target for the transcription factor ERG, which is activated in approximately 50% of human prostate cancer. With genome-wide expression analysis after PCAT5 silencing and in vitro assays we show that PCAT5 affects cell proliferation pathways, cell growth, migration, invasion, colony-forming potential, and apoptosis.
Ylipää A, Kivinummi K, Kohvakka A, Annala M, Latonen L, Scaravilli M, Kartasalo K, Leppänen SP, Karakurt S, Seppälä J, Yli-Harja O, Tammela TLJ, Zhang W, Visakorpi T, Nykter M. Transcriptome sequencing reveals PCAT5 as a novel ERG-regulated long non-coding RNA in prostate cancer. Cancer Res, 75:4026-4031, 2015.
|Gundem G, Van Loo P, Kremeyer B, Alexandrov LB, Tubio JMC, Papaemmanuil E, Brewer DS, Kallio HML, Högnäs G, Annala M, Kivinummi K, Goody V, Latimer C, O’Meara S, Dawson KJ, Isaacs W, Emmert-Buck MR, Nykter M, Foster C, Kote-Jarai Z, Easton D, Whitaker HC; ICGC Prostate Group, Neal DE, Cooper CS, Eeles RA, Visakorpi T, Campbell PJ, McDermott U, Wedge DC, Bova GS. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015 Apr 16;520(7547):353-357. Show in Pubmed.
Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Using whole-genome sequencing, we characterized multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen-deprivation therapy in prostate cancer.
|Tubio JM, Li Y, Ju YS, Martincorena I, Cooke SL, Tojo M, Gundem G, Pipinikas CP, Zamora J, Raine K, Menzies A, Roman-Garcia P, Fullam A, Gerstung M, Shlien A, Tarpey PS, Papaemmanuil E, Knappskog S, Van Loo P, Ramakrishna M, Davies HR, Marshall J, Wedge DC, Teague JW, Butler AP, Nik-Zainal S, Alexandrov L, Behjati S, Yates LR, Bolli N, Mudie L, Hardy C, Martin S, McLaren S, O’Meara S, Anderson E, Maddison M, Gamble S; ICGC Breast Cancer Group; ICGC Bone Cancer Group; ICGC Prostate Cancer Group, Foster C, Warren AY, Whitaker H, Brewer D, Eeles R, Cooper C, Neal D, Lynch AG, Visakorpi T, Isaacs WB, van’t Veer L, Caldas C, Desmedt C, Sotiriou C, Aparicio S, Foekens JA, Eyfjörd JE, Lakhani SR, Thomas G, Myklebost O, Span PN, Børresen-Dale AL, Richardson AL, Van de Vijver M, Vincent-Salomon A, Van den Eynden GG, Flanagan AM, Futreal PA, Janes SM, Bova GS, Stratton MR, McDermott U, Campbell PJ. Mobile DNA in cancer. Extensive transduction of nonrepetitive DNA mediated by L1
retrotransposition in cancer genomes. Science. 2014 Aug 1;345(6196):1251343. Show in Pubmed.Long interspersed nuclear element-1 (L1) retrotransposons are mobile repetitive elements that are abundant in the human genome. In the germ line, neighboring, nonrepetitive sequences are occasionally mobilized by the L1 machinery, a process called 3′ transduction. Because 3′ transductions are potentially mutagenic, together with our ICGC collaborators, studying cancer genomes from 244 patients with 12 different types of cancer including prostate cancer, we found that tumors from 53% of the patients had somatic retrotranspositions, of which 24% were 3′ transductions. The activity of individual L1 elements fluctuated during tumor evolution and correlated with L1 promoter hypomethylation. The 3′ transductions disseminated genes, exons, and regulatory elements to new locations, most often to heterochromatic regions of the genome.
(use A34 tubio transduction.png as figure)
|Bova GS, Kallio HML, Annala M, Kivinummi K, Högnäs G, Häyrynen S, Rantapero T, Kivinen V, Isaacs WB, Tolonen T, Nykter M, Visakorpi T. Integrated clinical, whole genome, and transcriptome analysis of multisampled lethal prostate cancer. Cold Spring Harbor Molecular Case Studies. 2016 May 2(3). Show in Pubmed.
We report the first combined analysis of whole-genome sequence, detailed clinical history, and transcriptome sequence of multiple prostate cancer metastases in a single patient (A21). Whole-genome and transcriptome sequence was obtained from nine anatomically separate metastases, and targeted DNA sequencing was performed in cancerous and noncancerous foci within the primary tumor specimen removed 5 yr before death. Three previously unreported truncal clonal missense mutations (ABCC4 p.R891L, ALDH9A1 p.W89R, and ASNA1 p.P75R) were expressed at the RNA level and assessed as druggable. The truncal status of mutations may be critical for effective actionability and merit further study. Our findings suggest that a large set of deeply analyzed cases could serve as a powerful guide to more effective prostate cancer basic science and personalized cancer medicine clinical trials.
|Högnäs G, Kivinummi K, Kallio HML, Hieta R, Ruusuvuori P, Koskenalho A, Kesseli J, Tammela TLJ, Riikonen J, Ilvesaro J, Kares S, Hirvikoski PP, Laurila M, Mirtti T, Nykter M, Kujala PM, Visakorpi T, Tolonen T, Bova GS. Feasibility of Prostate PAXgene Fixation for Molecular Research and Diagnostic Surgical Pathology: Comparison of Matched Fresh Frozen, FFPE, and PFPE Tissues. Am J Surg Pathol. 2018 Jan;42(1):103-115. Show in Pubmed.
Advances in prostate cancer biology and diagnostics are dependent upon high fidelity integration of clinical, histomorphologic, and molecular phenotypic findings. In this study we compared fresh frozen (FF), formalin-fixed paraffin-embedded (FFPE), and PAXgene-fixed paraffin-embedded (PFPE) tissue preparation methods in radical prostatectomy prostate tissue from 36 patients and did a preliminary test of feasibility of using PFPE tissue in routine prostate surgical pathology diagnostic assessment. Our results suggest that it is feasible to use PFPE tissue for routine robot-assisted laparoscopic prostatectomy (RALP) surgical pathology diagnostics and immunohistochemistry, with the benefit of significantly improved DNA and RNA quality and RNA picogram yield per nucleus as compared to FFPE tissue.