Cancer genomics

Goals:

Molecular tumor profiling by early implementation of next-generation sequencing technology and advanced computational infrastructure
Identification of new tumor biomarkers

Background:

The project was seeded by an initiative launched by a national committee, on which Professor Lothe was member. The committee had mandate to propose a thematic area for public clinical studies, and one such proposal, "treatment based on tumor genome profile", aligned with contemporary globally renowned cancer research strategies such as the UK Stratified Medicine Programme. In alignment with this initiative, The Norwegian Cancer Genomics Consortium (NCGC) was funded by the Research Council of Norway for the period 2012-19. The consortium was led by Professor Ola Myklebost, and Professors Lothe and Skotheim were among principal investigators and work package leaders. The computational infrastructure established in our group as part of this study was a stepping stone for development of Services for Sensitive Data (TSD) at the University of Oslo, which is currently the largest national resource for secure handling of sensitive data. In parallel, “Cancer - a national priority area” was established by the national health regions, with Professors Lothe and Lønning (U of Bergen) as the appointed leaders. The purpose was to arrange national meetings, Losby I (2014), II (2015) (TV2 interview) and III (2016), and introduce oncologists to cancer genomics. These initiatives have been part of the underpinning research essential for the establishment of precision cancer medicine in Norway. In addition, we obtained additional funding through the Centre of Excellence in Cancer Biomedicine (2007-17), where Lothe served as co-director.

Outcomes:

We established the lab protocol and computational analyses in our first RNA seq publication in 2013 (Nome et al., Transl Oncol 2013). NCGC contributed amongst others to exome/transcriptome sequencing of tumor-normal pairs of nine major cancer types, of which we were responsible for three of them: colorectal cancer, prostate cancer, and ovarian cancer (Sveen et al. Genome Med 2017 & 2021; Berg KCG et al. Mol Cancer 2017; Løvf et al. Eur Urol 2018; Sveen et al. JCI Insight 2024). We have performed technical comparisons of microarrays and sequencing for gene expression analyses (Eilertsen et al., Cancer Lett 2019).

The dedicated subproject, focused on structural DNA and RNA variants, has led to identification of novel fusion transcripts and alternative splicing variants. These variants serve as potential biomarkers for cancer detection and prognostic evaluation of testicular, colorectal, and prostate cancers (20 publications). We also developed various bioinformatics tools, including ScaR for sensitive detection of fusion transcripts from RNA-seq data (Zhao et al. NAR Genomics & Bioinformatics 2020), and chimeraviz for visualization of fusion genes (Lågstad et al. Bioinformatics 2017). We have used methylome sequencing to detect epigenetic biomarkers with high sensitivity and specificity for early detection of bladder cancer (Pharo et al. Clin Epigenetics, 2022). Mutation sequencing is incorporated for analyses of predictive biomarkers in the EVIDENT functional oncology trial of colorectal cancer.

Selected publications:

Evolutionary mode and timing of dissemination of high-grade serous carcinomas
Sveen A, Johannessen B, Klokkerud SM, Kraggerud SM, Meza-Zepeda LA, Bjørnslett M, Bischof K, Myklebost O, Taskén K, Skotheim RI, Dørum A, Davidson B, Lothe RA (2024)
JCI Insight (in press)

BladMetrix: a novel urine DNA methylation test with high accuracy for detection of bladder cancer in hematuria patients
Pharo HD, Jeanmougin M, Ager-Wick E, Vedeld HM, Sørbø AK, Dahl C, Larsen LK, Honne H, Brandt-Winge S, Five MB, Monteiro-Reis S, Henrique R, Jeronimo C, Steven K, Wahlqvist R, Guldberg P, Lind GE (2022)
Clin Epigenetics, 14 (1), 115

The expressed mutational landscape of microsatellite stable colorectal cancers
Sveen A, Johannessen B, Eilertsen IA, Røsok BI, Gulla M, Eide PW, Bruun J, Kryeziu K, Meza-Zepeda LA, Myklebost O, Bjørnbeth BA, Skotheim RI, Nesbakken A, Lothe RA (2021)
Genome Med, 13 (1), 142

ScaR-a tool for sensitive detection of known fusion transcripts: establishing prevalence of fusions in testicular germ cell tumors
Zhao S, Hoff AM, Skotheim RI (2020)
NAR Genom Bioinform, 2 (1), lqz025

Technical differences between sequencing and microarray platforms impact transcriptomic subtyping of colorectal cancer
Eilertsen IA, Moosavi SH, Strømme JM, Nesbakken A, Johannessen B, Lothe RA, Sveen A (2019)
Cancer Lett, 469, 246-255

Multifocal Primary Prostate Cancer Exhibits High Degree of Genomic Heterogeneity
Løvf M, Zhao S, Axcrona U, Johannessen B, Bakken AC, Carm KT, Hoff AM, Myklebost O, Meza-Zepeda LA, Lie AK, Axcrona K, Lothe RA, Skotheim RI (2018)
Eur Urol, 75 (3), 498-505

Multilevel genomics of colorectal cancers with microsatellite instability-clinical impact of JAK1 mutations and consensus molecular subtype 1
Sveen A, Johannessen B, Tengs T, Danielsen SA, Eilertsen IA, Lind GE, Berg KCG, Leithe E, Meza-Zepeda LA, Domingo E, Myklebost O, Kerr D, Tomlinson I, Nesbakken A, Skotheim RI, Lothe RA (2017)
Genome Med, 9 (1), 46

Multi-omics of 34 colorectal cancer cell lines - a resource for biomedical studies
Berg KCG, Eide PW, Eilertsen IA, Johannessen B, Bruun J, Danielsen SA, Bjørnslett M, Meza-Zepeda LA, Eknæs M, Lind GE, Myklebost O, Skotheim RI, Sveen A, Lothe RA (2017)
Mol Cancer, 16 (1), 116

chimeraviz: a tool for visualizing chimeric RNA
Lågstad S, Zhao S, Hoff AM, Johannessen B, Lingjærde OC, Skotheim RI (2017)
Bioinformatics, 33 (18), 2954-2956

Common fusion transcripts identified in colorectal cancer cell lines by high-throughput RNA sequencing
Torfinn Nome, Gard Os Thomassen, Jarle Bruun, Terje Ahlquist, Anne C Bakken, Andreas M Hoff, Torleiv Rognum, Arild Nesbakken, Susanne Lorenz, Jinchang Sun, João Diogo Barros-Silva, Guro E Lind, Ola Myklebost, Manuel R Teixeira, Leonardo A Meza-Zepeda, Ragnhild A Lothe, Rolf I Skotheim (2013)
Transl Oncol, 6 (5), 546-53