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Article ; Online: Deviating Alternative Splicing as a Molecular Subtype of Microsatellite Stable Colorectal Cancer.

Meier Strømme, Jonas / Johannessen, Bjarne / Skotheim, Rolf I

JCO clinical cancer informatics

2023 Volume 7, Page(s) e2200159

Abstract: Purpose: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Biomarkers to aid in prognostication and treatment decisions are in high demand, and to facilitate their development, a better understanding of the underlying ... ...

Abstract	Purpose: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Biomarkers to aid in prognostication and treatment decisions are in high demand, and to facilitate their development, a better understanding of the underlying biology of the highly heterogeneous disease is needed. Methods: A genome-scale alternative splicing (AS) analysis using RNA-sequencing data from primary microsatellite stable (MSS) CRCs from 127 patients was performed. Splice variant-specific expression levels of individual cancer samples were compared with the total set of samples, and a metric for a tumor sample's global amount of deviating AS was developed. This metric varied considerably across the cohort and ranged from 6 to 282 deviating AS events per tumor sample. A threshold of 45 or more deviating events was set to distinguish cancers with high (n = 44) and low (n = 83) levels of deviating AS. Results: Patients with high amounts of AS deviations had significantly shorter time to relapse compared with patients with fewer deviations ( Conclusion: There is a large variation in the amount of deviating AS among MSS CRCs, and we provide evidence that those with high amounts of deviations represent different cancer biology.
MeSH term(s)	Humans ; Microsatellite Instability ; Alternative Splicing ; Neoplasm Recurrence, Local/genetics ; Colorectal Neoplasms/pathology ; Microsatellite Repeats
Language	English
Publishing date	2023-02-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2473-4276
ISSN (online)	2473-4276
DOI	10.1200/CCI.22.00159
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Article ; Online: Prostate cancer: Molecular aspects, consequences, and opportunities of the multifocal nature.

Skotheim, Rolf I / Bogaard, Mari / Carm, Kristina T / Axcrona, Ulrika / Axcrona, Karol

Biochimica et biophysica acta. Reviews on cancer

2024 Volume 1879, Issue 2, Page(s) 189080

Abstract: Prostate cancer is unique compared to other major cancers due to the presence of multiple primary malignant foci in the majority of patients at the time of diagnosis. Each malignant focus has distinct somatic mutations and gene expression patterns, which ...

Abstract	Prostate cancer is unique compared to other major cancers due to the presence of multiple primary malignant foci in the majority of patients at the time of diagnosis. Each malignant focus has distinct somatic mutations and gene expression patterns, which represents a challenge for the development of prognostic tests for localized prostate cancer. Additionally, the molecular heterogeneity of advanced prostate cancer has important implications for management, particularly for patients with metastatic and locally recurrent cancer. Studies have shown that prostate cancers with mutations in DNA damage response genes are more sensitive to drugs inhibiting the poly ADP-ribose polymerase (PARP) enzyme. However, testing for such mutations should consider both spatial and temporal heterogeneity. Here, we summarize studies where multiregional genomics and transcriptomics analyses have been performed for primary prostate cancer. We further discuss the vast interfocal heterogeneity and how prognostic biomarkers and a molecular definition of the index tumor should be developed. The concept of focal treatments in prostate cancer has been evolving as a demand from patients and clinicians and is one example where there is a need for defining an index tumor. Here, biomarkers must have proven value for individual malignant foci. The potential discovery and implementation of biomarkers that are agnostic to heterogeneity are also explored as an alternative to multisample testing. Thus, deciding upon whole-organ treatment, such as radical prostatectomy, should depend on information from biomarkers which are informative for the whole organ.
MeSH term(s)	Male ; Humans ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology ; Prostate/pathology ; Mutation ; Prostatectomy ; Biomarkers
Chemical Substances	Biomarkers
Language	English
Publishing date	2024-01-24
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2918802-7
ISSN	1879-2561 ; 0304-419X
ISSN (online)	1879-2561
ISSN	0304-419X
DOI	10.1016/j.bbcan.2024.189080
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Zs.A 7162: Show issues

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Article ; Online: Re: Fibroblast Growth Factor Receptor 1 Drives the Metastatic Progression of Prostate Cancer.

Skotheim, Rolf I / Axcrona, Ulrika / Axcrona, Karol

European urology

2022 Volume 81, Issue 4, Page(s) 431

MeSH term(s)	Gene Expression Regulation, Neoplastic ; Humans ; Male ; Prostatic Neoplasms/pathology ; Receptor, Fibroblast Growth Factor, Type 1
Chemical Substances	Receptor, Fibroblast Growth Factor, Type 1 (EC 2.7.10.1)
Language	English
Publishing date	2022-01-11
Publishing country	Switzerland
Document type	Journal Article ; Comment
ZDB-ID	193790-x
ISSN	1873-7560 ; 1421-993X ; 0302-2838
ISSN (online)	1873-7560 ; 1421-993X
ISSN	0302-2838
DOI	10.1016/j.eururo.2021.12.031
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Zs.A 1247: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Re: Spatially Resolved Clonal Copy Number Alterations in Benign and Malignant Tissue.

Axcrona, Karol / Aas, Kirsti / Axcrona, Ulrika / Skotheim, Rolf I

European urology

2022 Volume 83, Issue 2, Page(s) 183

MeSH term(s)	Humans ; DNA Copy Number Variations ; Clone Cells
Language	English
Publishing date	2022-12-01
Publishing country	Switzerland
Document type	Journal Article ; Comment
ZDB-ID	193790-x
ISSN	1873-7560 ; 1421-993X ; 0302-2838
ISSN (online)	1873-7560 ; 1421-993X
ISSN	0302-2838
DOI	10.1016/j.eururo.2022.11.013
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Zs.A 1247: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 294: Show issues

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Article ; Online: ScaR-a tool for sensitive detection of known fusion transcripts: establishing prevalence of fusions in testicular germ cell tumors.

Zhao, Sen / Hoff, Andreas M / Skotheim, Rolf I

NAR genomics and bioinformatics

2020 Volume 2, Issue 1, Page(s) lqz025

Abstract: Bioinformatics tools for fusion transcript detection from RNA-sequencing data are in general developed for identification of novel fusions, which demands a high number of supporting reads and strict filters to avoid false discoveries. As our knowledge of ...

Abstract	Bioinformatics tools for fusion transcript detection from RNA-sequencing data are in general developed for identification of novel fusions, which demands a high number of supporting reads and strict filters to avoid false discoveries. As our knowledge of bona fide fusion genes becomes more saturated, there is a need to establish their prevalence with high sensitivity. We present ScaR, a tool that uses a supervised scaffold realignment approach for sensitive fusion detection in RNA-seq data. ScaR detects a set of 130 synthetic fusion transcripts from simulated data at a higher sensitivity compared to established fusion finders. Applied to fusion transcripts potentially involved in testicular germ cell tumors (TGCTs), ScaR detects the fusions
Language	English
Publishing date	2020-01-13
Publishing country	England
Document type	Journal Article
ISSN	2631-9268
ISSN (online)	2631-9268
DOI	10.1093/nargab/lqz025
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Article ; Online: 'High proliferative cribriform prostate cancer' defines a patient subgroup with an inferior prognosis.

Bogaard, Mari / Skotheim, Rolf I / Maltau, Aase V / Kidd, Susanne G / Lothe, Ragnhild A / Axcrona, Karol / Axcrona, Ulrika

Histopathology

2023 Volume 83, Issue 6, Page(s) 853–869

Abstract: Aims: A cribriform pattern, reactive stroma (RS), PTEN, Ki67 and ERG are promising prognostic biomarkers in primary prostate cancer (PCa). We aim to determine the relative contribution of these factors and the Cancer of the Prostate Risk Assessment ... ...

Abstract	Aims: A cribriform pattern, reactive stroma (RS), PTEN, Ki67 and ERG are promising prognostic biomarkers in primary prostate cancer (PCa). We aim to determine the relative contribution of these factors and the Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) score in predicting PCa prognosis. Methods and results: We included 475 patients who underwent radical prostatectomy (2010-12, median follow-up = 8.7 years). Cribriform pattern was identified in 57% of patients, PTEN loss in 55%, ERG expression in 51%, RS in 39% and high Ki67 in 9%. In patients with multiple samples from the same malignant focus and either PTEN loss or high Ki67, intrafocal heterogeneity for PTEN and Ki67 expression was detected in 55% and 89%, respectively. In patients with samples from two or more foci, interfocal heterogeneity was detected in 46% for PTEN and 6% for Ki67. A cribriform pattern and Ki67 were independent predictors of biochemical recurrence (BCR) and clinical recurrence (CR), whereas ERG expression was an independent predictor of CR. Besides CAPRA-S, a cribriform pattern provided the highest relative proportion of explained variation for predicting BCR (11%), and Ki67 provided the highest relative proportion of explained variation for CR (21%). In patients with a cribriform pattern, high Ki67 was associated with a higher risk of BCR [hazard ratio (HR) = 2.83, P < 0.001] and CR (HR = 4.35, P < 0.001). Conclusions: High Ki67 in patients with a cribriform pattern identifies a patient subgroup with particularly poor prognosis, which we termed 'high proliferative cribriform prostate cancer'. These results support reporting a cribriform pattern in pathology reports, and advocate implementing Ki67.
MeSH term(s)	Male ; Humans ; Ki-67 Antigen ; Biomarkers, Tumor/metabolism ; Prognosis ; Prostatic Neoplasms/pathology ; Prostate/pathology ; Prostatectomy/methods ; Neoplasm Grading
Chemical Substances	Ki-67 Antigen ; Biomarkers, Tumor
Language	English
Publishing date	2023-07-28
Publishing country	England
Document type	Journal Article
ZDB-ID	131914-0
ISSN	1365-2559 ; 0309-0167
ISSN (online)	1365-2559
ISSN	0309-0167
DOI	10.1111/his.15012
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Zs.A 1328: Show issues

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Article ; Online: Evolutionary mode and timing of dissemination of high-grade serous carcinomas.

Sveen, Anita / Johannessen, Bjarne / Klokkerud, Solveig Mk / Kraggerud, Sigrid M / Meza-Zepeda, Leonardo A / Bjørnslett, Merete / Bischof, Katharina / Myklebost, Ola / Taskén, Kjetil / Skotheim, Rolf I / Dørum, Anne / Davidson, Ben / Lothe, Ragnhild A

JCI insight

2024 Volume 9, Issue 3

Abstract: Dissemination within the peritoneal cavity is a main determinant of poor patient outcomes from high-grade serous carcinomas (HGSCs). The dissemination process is poorly understood from a cancer evolutionary perspective. We reconstructed the evolutionary ... ...

Abstract	Dissemination within the peritoneal cavity is a main determinant of poor patient outcomes from high-grade serous carcinomas (HGSCs). The dissemination process is poorly understood from a cancer evolutionary perspective. We reconstructed the evolutionary trajectories across a median of 5 tumor sites and regions from each of 23 patients based on deep whole-exome sequencing. Polyclonal cancer origin was detected in 1 patient. Ovarian tumors had more complex subclonal architectures than other intraperitoneal tumors in each patient, which indicated that tumors developed earlier in the ovaries. Three common modes of dissemination were identified, including monoclonal or polyclonal dissemination of monophyletic (linear) or polyphyletic (branched) subclones. Mutation profiles of initial or disseminated clones varied greatly among cancers, but recurrent mutations were found in 7 cancer-critical genes, including TP53, BRCA1, BRCA2, and DNMT3A, and in the PI3K/AKT1 pathway. Disseminated clones developed late in the evolutionary trajectory models of most cancers, in particular in cancers with DNA damage repair deficiency. Polyclonal dissemination was predicted to occur predominantly as a single and rapid wave, but chemotherapy exposure was associated with higher genomic diversity of disseminated clones. In conclusion, we described three common evolutionary dissemination modes across HGSCs and proposed factors associated with dissemination diversity.
MeSH term(s)	Female ; Humans ; Mutation ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Carcinoma
Language	English
Publishing date	2024-01-04
Publishing country	United States
Document type	Journal Article
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.170423
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Article ; Online: Complex Polygenic Nature of Testicular Germ Cell Cancer Suggests Multifactorial Aetiology.

Rajpert-De Meyts, Ewa / Skotheim, Rolf I

European urology

2018 Volume 73, Issue 6, Page(s) 832–833

MeSH term(s)	Humans ; Male ; Neoplasms, Germ Cell and Embryonal ; Testicular Neoplasms
Language	English
Publishing date	2018-03-09
Publishing country	Switzerland
Document type	Editorial ; Comment
ZDB-ID	193790-x
ISSN	1873-7560 ; 1421-993X ; 0302-2838
ISSN (online)	1873-7560 ; 1421-993X
ISSN	0302-2838
DOI	10.1016/j.eururo.2018.02.023
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Zs.A 1247: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: In situ expression of ERG protein in the context of tumor heterogeneity identifies prostate cancer patients with inferior prognosis.

Kidd, Susanne G / Bogaard, Mari / Carm, Kristina T / Bakken, Anne Cathrine / Maltau, Aase M V / Løvf, Marthe / Lothe, Ragnhild A / Axcrona, Karol / Axcrona, Ulrika / Skotheim, Rolf I

Molecular oncology

2022 Volume 16, Issue 15, Page(s) 2810–2822

Abstract: Prognostic biomarkers for prostate cancer are needed to improve prediction of disease course and guide treatment decisions. However, biomarker development is complicated by the common multifocality and heterogeneity of the disease. We aimed to determine ... ...

Abstract	Prognostic biomarkers for prostate cancer are needed to improve prediction of disease course and guide treatment decisions. However, biomarker development is complicated by the common multifocality and heterogeneity of the disease. We aimed to determine the prognostic value of candidate biomarkers transcriptional regulator ERG and related ETS family genes, while considering tumor heterogeneity. In a multisampled, prospective, and treatment-naïve radical prostatectomy cohort from one tertiary center (2010-2012, median follow-up 8.1 years), we analyzed ERG protein (480 patients; 2047 tissue cores), and RNA of several ETS genes in a subcohort (165 patients; 778 fresh-frozen tissue samples). Intra- and interfocal heterogeneity was identified in 29% and 33% (ERG protein) and 39% and 27% (ETS RNA) of patients, respectively. ERG protein and ETS RNA was identified exclusively in a nonindex tumor in 31% and 32% of patients, respectively. ERG protein demonstrated independent prognostic value in predicting biochemical (P = 0.04) and clinical recurrence (P = 0.004) and appeared to have greatest prognostic value for patients with Grade Groups 4-5. In conclusion, when heterogeneity is considered, ERG protein is a robust prognostic biomarker for prostate cancer.
MeSH term(s)	Biomarkers, Tumor/genetics ; Humans ; Male ; Prospective Studies ; Prostatectomy ; Prostatic Neoplasms/diagnosis ; Prostatic Neoplasms/genetics ; RNA ; Trans-Activators/genetics ; Trans-Activators/metabolism ; Transcriptional Regulator ERG/genetics
Chemical Substances	Biomarkers, Tumor ; ERG protein, human ; Trans-Activators ; Transcriptional Regulator ERG ; RNA (63231-63-0)
Language	English
Publishing date	2022-06-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2415106-3
ISSN	1878-0261 ; 1574-7891
ISSN (online)	1878-0261
ISSN	1574-7891
DOI	10.1002/1878-0261.13225
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Article: TIN: An R Package for Transcriptome Instability Analysis.

Johannessen, Bjarne / Sveen, Anita / Skotheim, Rolf I

Cancer informatics

2015 Volume 14, Page(s) 109–112

Abstract: Alternative splicing is a key regulatory mechanism for gene expression, vital for the proper functioning of eukaryotic cells. Disruption of normal pre-mRNA splicing has the potential to cause and reinforce human disease. Owing to rapid advances in high- ... ...

Abstract	Alternative splicing is a key regulatory mechanism for gene expression, vital for the proper functioning of eukaryotic cells. Disruption of normal pre-mRNA splicing has the potential to cause and reinforce human disease. Owing to rapid advances in high-throughput technologies, it is now possible to identify novel mRNA isoforms and detect aberrant splicing patterns on a genome scale, across large data sets. Analogous to the genomic types of instability describing cancer genomes (eg, chromosomal instability and microsatellite instability), transcriptome instability (TIN) has recently been proposed as a splicing-related genome-wide characteristic of certain solid cancers. We present the R package TIN, available from Bioconductor, which implements a set of methods for TIN analysis based on exon-level microarray expression profiles. TIN provides tools for estimating aberrant exon usage across samples and for analyzing correlation patterns between TIN and splicing factor expression levels.
Language	English
Publishing date	2015-09-20
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2202739-7
ISSN	1176-9351
ISSN	1176-9351
DOI	10.4137/CIN.S31363
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