Rolf I. Skotheim

Dr. Rolf Skotheim
Genome Biology 
Dept. of Cancer Prevention
Institute for Cancer Research
Oslo University Hospital, 
The Norwegian Radium Hospital
rolf.i.skotheim@rr-research.no
Tel +47 22 78 17 27

 

 

ACTIVITIES

Germ cell tumors can develop in both males and females but are far more common among males. In fact, testicular cancer (usually of germ cell origin; TGCT) is the most common cancer type among young and adolescent males, and the incidence has almost quadrupled during the past 50 years. Pluripotent cells in TGCTs may differentiate along embryonic or extraembryonic lineages into various histological subtypes, and as such, the development of this cancer type is a caricature of the early embryogenesis.

We and others have collected strong evidences for this also being the case for the transcriptional and epigenetic programs of these tumours. Genetic studies of embryonal stem cells and their adaptation to culturing have revealed striking similarities to genomic changes in the germ cell tumour genome, in particular embryonal carcinomas. By comparative studies of embryonic stem cells and in vitro cultures of their malignant counterparts, we aim to identify genes with malignancy-specific expression patterns in a stem cell context. The resulting markers will be functionally as well as clinically validated, the latter through the use of large patient series available in our department. Furthermore, the genes with malignancy–specific expression will be interrogated from profiles of isolated side populations from other tumour types, as obtained by the other consortium members.

 

 

GROUP MEMBERS

active in CAST


Sharmini Alagaratnam
Post doc  

Andreas M. Hoff
PhD-student

Anne Cathrine Bakken

 

Ragnhild A. Lothe
Professor, Dept Cancer Prevention, Norwegian Radium Hospital, Oslo University Hospital

 

Project Collaborators

 

Peter W. Andrews
Professor, Dept. Biomedical Science, U of Sheffield

 

Neil Harrison
Post Doc, Dept Biomedical Science, U of Sheffield

 

 

STATUS 2013

We have carried out detailed transcriptome studies of panels of both embryonal carcinoma (EC) and phenotypically similar, but non-malignant, embryonic stem (ES) cell lines. Genome technologies such as exon microarrays and whole-transcriptome RNA-sequencing have been used to identify genes with malignancy specific expression or transcript structures. From the top-most differentially expressed genes and individual exons between EC and ES cells, we have now validated several genes and transcripts that we are in progress of defining their role in cancer. 

We recently published parts of this work in Stem Cells and Development (Alagaratnam et al., 2013). We have as well ongoing work on a particular gene fusion in colorectal cancer, where the gene encoding the Wnt effector TCF4 (alias TCF7L2) is one of the partner genes. We have characterized a clinical colorectal cancer biobank, and found that chimeric RNA molecules involving both VTI1A and TCF7L2 sequences are frequent among cancers, although at low levels. The relevance for the tumourigenesis of this fusion transcript is yet to be determined.

 

SELECTED PUBLICATIONS

 

Kraggerud SM, Hoei-Hansen CE, Alagaratnam S, Skotheim RI, Abeler VM, Rajpert-De Meyts E, Lothe RA. (2013)
Assessment of fusion gene status in sarcomas using a custom made fusion gene microarray.
PLoS One. 8(8):e70649
PubMed 23967081 

Kraggerud SM, Hoei-Hansen CE, Alagaratnam S, Skotheim RI, Abeler VM, Rajpert-De Meyts E, and Lothe RA. (2013)
Molecular characteristics of malignant ovarian germ cell tumors and comparison with testicular counterparts: Implications for pathogenesis.
Endocr Rev. 34(3):339-76.
PubMed 23575763 

Barros-Silva JDPaulo PBakken ACCerveira NLøvf MHenrique RJerónimo CLothe RASkotheim RITeixeira MR (2013)
Novel 5' Fusion Partners of ETV1 and ETV4 in Prostate Cancer
Neoplasia15 (7)720-6
PubMed 23814484

Schumacher FRWang ZSkotheim RIKoster RChung CCHildebrandt MAKratz CPBakken ACTimothy Bishop DCook MBErickson RLFosså SDGreene MH,Jacobs KBKanetsky PAKolonel LNLoud JTKorde LALe Marchand LPablo Lewinger JLothe RAPike MCRahman NRubertone MVSchwartz SM et al. (2013)
Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23
Hum Mol Genet22 (13)2748-53
PubMed 23462292

Chung CCKanetsky PAWang ZHildebrandt MAKoster RSkotheim RIKratz CPTurnbull CCortessis VKBakken ACBishop DTCook MBErickson RLFosså SDJacobs KBKorde LAKraggerud SMLothe RALoud JTRahman NSkinner ECThomas DCWu XYeager MSchumacher FR et al. (2013)
Meta-analysis identifies four new loci associated with testicular germ cell tumor
Nat Genet45 (6)680-5
PubMed 23666239

Alagaratnam SHarrison NBakken ACHoff AMJones MSveen AMoore HDAndrews PWLothe RASkotheim RI (2013)
Transforming pluripotency: an exon-level study of malignancy-specific transcripts in human embryonal carcinoma and embryonic stem cells
Stem Cells Dev22 (7)1136-46
PubMed 23137282

Celestino RSigstad ELøvf MThomassen GOGrøholt KKJørgensen LHBerner ACastro PLothe RABjøro TSobrinho-Simões MSoares PSkotheim RI (2012)
Survey of 548 oncogenic fusion transcripts in thyroid tumors supports the importance of the already established thyroid fusions genes
Genes Chromosomes Cancer51 (12)1154-64
PubMed 22961909

Nyquist KBPanagopoulos IThorsen JHaugom LGorunova LBjerkehagen BFosså AGuriby MNome TLothe RASkotheim RIHeim SMicci F (2012)
Whole-transcriptome sequencing identifies novel IRF2BP2-CDX1 fusion gene brought about by translocation t(1;5)(q42;q32) in mesenchymal chondrosarcoma
PLoS One7 (11)e49705
PubMed 23185413

Camões MJPaulo PRibeiro FRBarros-Silva JDAlmeida MCosta VLCerveira NSkotheim RILothe RAHenrique RJerónimo CTeixeira MR (2012)
Potential downstream target genes of aberrant ETS transcription factors are differentially affected in Ewing's sarcoma and prostate carcinoma
PLoS One7 (11)e49819
PubMed 23185447

Skotheim RIMeza-Zepeda LAHovig ELønning PELothe RAMyklebost O (2012)
[Genome sequencing for personalized cancer treatment]
Tidsskr Nor Laegeforen132 (21)2406-8
PubMed 23160594

Agesen THSveen AMerok MALind GENesbakken ASkotheim RILothe RA (2012)
ColoGuideEx: a robust gene classifier specific for stage II colorectal cancer prognosis
Gut61 (11)1560-7
PubMed 22213796

Sveen AÅgesen THNesbakken AMeling GIRognum TOLiestøl KSkotheim RILothe RA (2012)
ColoGuidePro: a prognostic 7-gene expression signature for stage III colorectal cancer patients
Clin Cancer Res18 (21)6001-10
PubMed 22991413

Cekaite LRantala JKBruun JGuriby MAgesen THDanielsen SALind GENesbakken AKallioniemi OLothe RASkotheim RI (2012)
MiR-9, -31, and -182 deregulation promote proliferation and tumor cell survival in colon cancer
Neoplasia14 (9)868-79
PubMed 23019418

Sveen ABakken ACÅgesen THLind GENesbakken ANordgård OBrackmann SRognum TOLothe RASkotheim RI (2012)
The exon-level biomarker SLC39A14 has organ-confined cancer-specificity in colorectal cancer
Int J Cancer131 (6)1479-85
PubMed 22173985

Paulo PRibeiro FRSantos JMesquita DAlmeida MBarros-Silva JDItkonen HHenrique RJerónimo CSveen AMills IGSkotheim RILothe RATeixeira MR(2012)
Molecular subtyping of primary prostate cancer reveals specific and shared target genes of different ETS rearrangements
Neoplasia14 (7)600-11
PubMed 22904677

Matheu ACollado MWise CManterola LCekaite LTye AJCanamero MBujanda LSchedl ACheah KSSkotheim RILothe RALópez de Munain ABriscoe J,Serrano MLovell-Badge R (2012)
Oncogenicity of the developmental transcription factor Sox9
Cancer Res72 (5)1301-15
PubMed 22246670

Paulo PBarros-Silva JDRibeiro FRRamalho-Carvalho JJerónimo CHenrique RLind GESkotheim RILothe RATeixeira MR (2012)
FLI1 is a novel ETS transcription factor involved in gene fusions in prostate cancer
Genes Chromosomes Cancer51 (3)240-9
PubMed 22081504

Ågesen THBerg MClancy TThiis-Evensen ECekaite LLind GENesland JMBakka AMala THauss HJFetveit TVatn MHHovig ENesbakken ALothe RA,Skotheim RI (2011)
CLC and IFNAR1 are differentially expressed and a global immunity score is distinct between early- and late-onset colorectal cancer
Genes Immun12 (8)653-62
PubMed 21716316

Danielsen SACekaite LÅgesen THSveen ANesbakken AThiis-Evensen ESkotheim RILind GELothe RA (2011)
Phospholipase C isozymes are deregulated in colorectal cancer--insights gained from gene set enrichment analysis of the transcriptome
PLoS One6 (9)e24419
PubMed 21909432

Alagaratnam SLind GEKraggerud SMLothe RASkotheim RI (2011)
The testicular germ cell tumour transcriptome
Int J Androl34 (4 Pt 2)e133-50; discussion e150-1
PubMed 21651573

Lind GEDanielsen SAAhlquist TMerok MAAndresen KSkotheim RIHektoen MRognum TOMeling GIHoff GBretthauer MThiis-Evensen ENesbakken A,Lothe RA (2011)
Identification of an epigenetic biomarker panel with high sensitivity and specificity for colorectal cancer and adenomas
Mol Cancer1085
PubMed 21777459

Ribeiro FRPaulo PCosta VLBarros-Silva JDRamalho-Carvalho JJerónimo CHenrique RLind GESkotheim RILothe RATeixeira MR (2011)
Cysteine-rich secretory protein-3 (CRISP3) is strongly up-regulated in prostate carcinomas with the TMPRSS2-ERG fusion gene
PLoS One6 (7)e22317
PubMed 21814574

Sveen AAgesen THNesbakken ARognum TOLothe RASkotheim RI (2011)
Transcriptome instability in colorectal cancer identified by exon microarray analyses: Associations with splicing factor expression levels and patient survival
Genome Med3 (5)32
PubMed 21619627

Løvf MThomassen GOBakken ACCelestino RFioretos TLind GELothe RASkotheim RI (2011)
Fusion gene microarray reveals cancer type-specificity among fusion genes
Genes Chromosomes Cancer50 (5)348-57
PubMed 21305644

Sagona APNezis IPBache KGHaglund KBakken ACSkotheim RIStenmark H (2011)
A tumor-associated mutation of FYVE-CENT prevents its interaction with Beclin 1 and interferes with cytokinesis
PLoS One6 (3)e17086
PubMed 21455500

Costa VLHenrique RDanielsen SADuarte-Pereira SEknaes MSkotheim RIRodrigues AMagalhães JSOliveira JLothe RATeixeira MRJerónimo CLind GE(2010)
Three epigenetic biomarkers, GDF15, TMEFF2, and VIM, accurately predict bladder cancer from DNA-based analyses of urine samples
Clin Cancer Res16 (23)5842-51
PubMed 20975101

Micci FSkotheim RIHaugom LWeimer JEibak AMAbeler VMTrope CGArnold NLothe RAHeim S (2010)
Array-CGH analysis of microdissected chromosome 19 markers in ovarian carcinoma identifies candidate target genes
Genes Chromosomes Cancer49 (11)1046-53
PubMed 20725991

Berg MAgesen THThiis-Evensen EINFAC-study groupMerok MATeixeira MRVatn MHNesbakken ASkotheim RILothe RA (2010)
Distinct high resolution genome profiles of early onset and late onset colorectal cancer integrated with gene expression data identify candidate susceptibility loci
Mol Cancer9100
PubMed 20459617

Sagona APNezis IPPedersen NMLiestøl KPoulton JRusten TESkotheim RIRaiborg CStenmark H (2010)
PtdIns(3)P controls cytokinesis through KIF13A-mediated recruitment of FYVE-CENT to the midbody
Nat Cell Biol12 (4)362-71
PubMed 20208530

Brekke HRRibeiro FRKolberg MAgesen THLind GEEknaes MHall KSBjerkehagen Bvan den Berg ETeixeira MRMandahl NSmeland SMertens FSkotheim RILothe RA (2010)
Genomic changes in chromosomes 10, 16, and X in malignant peripheral nerve sheath tumors identify a high-risk patient group
J Clin Oncol28 (9)1573-82
PubMed 20159821

Burum-Auensen ESkotheim RISchjølberg ARRøislien JLothe RAClausen OP (2010)
Spindle proteins are differentially expressed in the various histological subtypes of testicular germ cell tumors
J Carcinog91
PubMed 20411023

Brekke HRKolberg MSkotheim RIHall KSBjerkehagen BRisberg BDomanski HAMandahl NLiestøl KSmeland SDanielsen HEMertens FLothe RA (2009)
Identification of p53 as a strong predictor of survival for patients with malignant peripheral nerve sheath tumors
Neuro Oncol11 (5)514-28
PubMed 19182148

Godmann MGashaw IEildermann KSchweyer SBergmann MSkotheim RIBehr R (2009)
The pluripotency transcription factor Krüppel-like factor 4 is strongly expressed in intratubular germ cell neoplasia unclassified and seminoma
Mol Hum Reprod15 (8)479-88
PubMed 19505997

Alagaratnam SHardy JRLothe RASkotheim RIByrne JA (2009)
TPD52, a candidate gene from genomic studies, is overexpressed in testicular germ cell tumours
Mol Cell Endocrinol306 (1-2)75-80
PubMed 19041365

Micci FWeimer JHaugom LSkotheim RIGrunewald RAbeler VMSilins ILothe RATrope CGArnold NHeim S (2009)
Reverse painting of microdissected chromosome 19 markers in ovarian carcinoma identifies a complex rearrangement map
Genes Chromosomes Cancer48 (2)184-93
PubMed 18973136

Skotheim RIThomassen GOEken MLind GEMicci FRibeiro FRCerveira NTeixeira MRHeim SRognes TLothe RA (2009)
A universal assay for detection of oncogenic fusion transcripts by oligo microarray analysis
Mol Cancer85
PubMed 19152679

Ahlquist TLind GECosta VLMeling GIVatn MHoff GSRognum TOSkotheim RIThiis-Evensen ELothe RA (2008)
Gene methylation profiles of normal mucosa, and benign and malignant colorectal tumors identify early onset markers
Mol Cancer794
PubMed 19117505

Kilpinen SAutio ROjala KIljin KBucher ESara HPisto TSaarela MSkotheim RIBjörkman MMpindi JPHaapa-Paananen SVainio PEdgren HWolf MAstola JNees MHautaniemi SKallioniemi O (2008)
Systematic bioinformatic analysis of expression levels of 17,330 human genes across 9,783 samples from 175 types of healthy and pathological tissues
Genome Biol9 (9)R139
PubMed 18803840

Lind GEAhlquist TKolberg MBerg MEknaes MAlonso MAKallioniemi AMeling GISkotheim RIRognum TOThiis-Evensen ELothe RA (2008)
Hypermethylated MAL gene - a silent marker of early colon tumorigenesis
J Transl Med613
PubMed 18346269

Almstrup KLeffers HLothe RASkakkebaek NESonne SBNielsen JERajpert-De Meyts ESkotheim RI (2007)
Improved gene expression signature of testicular carcinoma in situ
Int J Androl30 (4)292-302; discussion 303
PubMed 17488342

Kleivi KLind GEDiep CBMeling GIBrandal LTNesland JMMyklebost ORognum TOGiercksky KESkotheim RILothe RA (2007)
Gene expression profiles of primary colorectal carcinomas, liver metastases, and carcinomatoses
Mol Cancer62
PubMed 17201907

 

 

Rolf I. Skotheim laboratory