Jonas Langerud

• Langerud, Jonas; Eilertsen, Ina Andrassy; Moosavi, Hossein; Klokkerud, Solveig Margrete Knoph; Reims, Henrik Mikael & Backe, Ingeborg Flåten [Vis alle 13 forfattere av denne artikkelen] (2024). Multiregional transcriptomics identifies congruent consensus subtypes with prognostic value beyond tumor heterogeneity of colorectal cancer. Nature Communications. ISSN 2041-1723. 15(1). doi: 10.1038/s41467-024-48706-2.
• Eide, Peter Andreas Wold; Moosavi, Seyed Hossein; Eilertsen, Ina Andrassy; Brunsell, Tuva Høst; Langerud, Jonas & Berg, Kaja Christine Graue [Vis alle 11 forfattere av denne artikkelen] (2021). Metastatic heterogeneity of the consensus molecular subtypes of colorectal cancer. NPJ GENOMIC MEDICINE. ISSN 2056-7944. 6:59, s. 1–9. doi: 10.1038/s41525-021-00223-7. Fulltekst i vitenarkiv
• Bruun, Jarle; Kryeziu, Kushtrim; Eide, Peter Andreas Wold; Moosavi, Seyed Hossein; Eilertsen, Ina Andrassy & Røsok, Bård Ingvald [Vis alle 21 forfattere av denne artikkelen] (2020). Patient-Derived Organoids from Multiple Colorectal Cancer Liver Metastases Reveal Moderate Intra-patient Pharmacotranscriptomic Heterogeneity. Clinical Cancer Research. ISSN 1078-0432. 26(15), s. 4107–4119. doi: 10.1158/1078-0432.CCR-19-3637. Vis sammendrag

  Abstract Purpose: Molecular tumor heterogeneity may have important implications for the efficacy of targeted therapies in metastatic cancers. Inter-metastatic heterogeneity of sensitivity to anticancer agents has not been well explored in colorectal cancer. Experimental Design: We established a platform for ex vivo pharmacogenomic profiling of patient-derived organoids (PDO) from resected colorectal cancer liver metastases. Drug sensitivity testing (n = 40 clinically relevant agents) and gene expression profiling were performed on 39 metastases from 22 patients. Results: Three drug–response clusters were identified among the colorectal cancer metastases, based primarily on sensitivities to EGFR and/or MDM2 inhibition, and corresponding with RAS mutations and TP53 activity. Potentially effective therapies, including off-label use of drugs approved for other cancer types, could be nominated for eighteen patients (82%). Antimetabolites and targeted agents lacking a decisive genomic marker had stronger differential activity than most approved chemotherapies. We found limited intra-patient drug sensitivity heterogeneity between PDOs from multiple (2–5) liver metastases from each of ten patients. This was recapitulated at the gene expression level, with a highly proportional degree of transcriptomic and pharmacological variation. One PDO with a multi-drug resistance profile, including resistance to EGFR inhibition in a RAS-mutant background, showed sensitivity to MEK plus mTOR/AKT inhibition, corresponding with low-level PTEN expression. Conclusions: Intra-patient inter-metastatic pharmacological heterogeneity was not pronounced and ex vivo drug screening may identify novel treatment options for metastatic colorectal cancer. Variation in drug sensitivities was reflected at the transcriptomic level, suggesting potential to develop gene expression–based predictive signatures to guide experimental therapies.

• Flatin, Bjørnar Tovson Bae; Vedeld, Hege Marie; Pinto, Rita; Langerud, Jonas; Lind, Guro Elisabeth & Lothe, Ragnhild A [Vis alle 8 forfattere av denne artikkelen] (2020). Multiregional assessment of CIMP in primary colorectal cancers: Phenotype concordance but marker variability. International Journal of Cancer. ISSN 0020-7136. s. 1–6. doi: 10.1002/ijc.33425. Fulltekst i vitenarkiv
• Langerud, Jonas; Jarhelle, Elisabeth; Van Ghelue, Marijke; Ariansen, Sarah Louise & Iversen, Nina (2018). Trans-activation-based risk assessment of BRCA1 BRCT variants with unknown clinical significance. Human Genomics. ISSN 1473-9542. 12(51). doi: 10.1186/s40246-018-0183-1. Vis sammendrag

  Background: Deleterious variants in the tumour suppressor BRCA1 are known to cause hereditary breast and ovarian cancer syndrome (HBOC). Missense variants in BRCA1 pose a challenge in clinical care, as their effect on protein functionality often remains unknown. Many of the pathogenic missense variants found in BRCA1 are located in the BRCA1 C-terminal (BRCT) domains, domains that are known to be vital for key functions such as homologous recombination repair, protein-protein interactions and trans-activation (TA). We investigated the TA activity of 12 BRCA1 variants of unknown clinical significance (VUSs) located in the BRCT domains to aid in the classification of these variants. Results: Twelve BRCA1 VUSs were investigated using a modified version of the dual luciferase TA activity assay (TA assay) that yielded increased sensitivity and sample throughput. Variants were classified according to American College of Medical Genetics and Genomics (ACMG) criteria using TA assay results and available data. In combining our TA-assay results and available data, in accordance with the ACMG guidelines for variant classification, we proposed the following variant classifications: c.5100A>G, c.5326C>T, c.5348T>C and c.5477A>T as likely benign (class 2) variants. c.5075A>C, c.5116G>A and c.5513T>G were likely pathogenic (class 4), whereas c.5096G>A likely represents a likely pathogenic variant with moderate penetrance. Variants c.5123C>T, c.5125G>A, c.5131A>C and c. 5504G>A remained classified as VUSs (class 3). Conclusions: The modified TA assay provides efficient risk assessment of rare missense variants found in the BRCA1 BRCT-domains. We also report that increased post-transfection incubation time yielded a significant increase in TA assay sensitivity.

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