A fluorescence-based sensor screen identifies MED12 as a potential microsatellite instability regulator in colon cancer
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
Abstract Inactivation of the DNA mismatch repair (MMR) system, due to (epi)genetic alterations of MMR genes, increases the frequency of mutations across the genome, creating a phenotype known as microsatellite instability (MSI). Cancers with this phenotype have been associated with a better prognosis for some time, but only since recently it has been recognised as a predictive biomarker of response to immunotherapy. Because MSI tumours accumulate more insertions and/or deletions in coding regions of the genome containing microsatellites, there is an increase in neoantigens resulting from reading frame shifts, which promotes immunogenicity. To investigate if additional genes exist that can cause an MSI phenotype, we developed a fluorescence-based sensor to identify genes whose inactivation increases the rate of frameshift mutations on microsatellite sequences in cancer cells. Using genome-scale CRISPR/Cas9 screens, we identified MED12 as a potential new regulator of microsatellite instability. Consistent with this, we found that MED12 mutant colon cancers that lack mutations in the known MMR genes are more likely to be of the MSI phenotype.
Authors 12
-
The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 2, 066 CX Amsterdam, The Netherlands
-
The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 2, 066 CX Amsterdam, The Netherlands
-
The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 2, 066 CX Amsterdam, The Netherlands
-
The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 2, 066 CX Amsterdam, The Netherlands
-
The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 2, 066 CX Amsterdam, The Netherlands
-
The Netherlands Cancer Institute · Sanquin · Oncode Institute · Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
Department of Hematopoiesis, Sanquin Research, Landsteiner Laboratory
Division of Cancer Immunology, Oncode Institute, The Netherlands Cancer Institute
University of Amsterdam, Oncode Institute
Department of Hematopoiesis, Sanquin Research, Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Oncode Institute, Amsterdam, The Netherlands
Division of Cancer Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 11, 1066 CX Amsterdam, The Netherlands
-
Berlin Institute of Health at Charité - Universitätsmedizin Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Berlin Institute of Health at Charité – Universitätsmedizin Berlin. BIH Biomedical Innovation Academy, BIH Charité (Junior) (Digital) Clinician Scientist Program
Charité Comprehensive Cancer Center, Charité – Universitätsmedizin Berlin
Charité – Universitätsmedizin Berlin
Department of Hematology, Oncology, and Tumor Immunology
Berlin Institute of Health at Charité – Universitätsmedizin Berlin. BIH Biomedical Innovation Academy, BIH Charité (Junior) (Digital) Clinician Scientist Program, Charitéplatz 1, 10117 Berlin, Germany
Charité Comprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Berlin, Germany
Department of Hematology, Oncology, and Tumor Immunology, Campus Charité Mitte, Charité – Universitätsmedizin Berlin, Berlin, Germany
-
The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 2, 066 CX Amsterdam, The Netherlands
-
Leiden University Medical Center
Affiliation as printed
Department of Dermatology, Leiden University Medical Center
Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands
-
The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Division of Cancer Immunology, Oncode Institute, The Netherlands Cancer Institute
Division of Cancer Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 11, 1066 CX Amsterdam, The Netherlands
-
The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 2, 066 CX Amsterdam, The Netherlands
-
René Bernards corresponding
The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 2, 066 CX Amsterdam, The Netherlands
Cited by 0 stored of 0
No patents citing this paper on Lens.org (checked 2026-10-11).