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Somatic PRDM2 c.4467delA mutations in colorectal cancers control histone methylation and tumor growth
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyangsi, Republic of Korea.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 58, p. 98646-98659Article in journal (Refereed) Published
Abstract [en]

The chromatin modifier PRDM2/RIZ1 is inactivated by mutation in several forms of cancer and is a putative tumor suppressor gene. Frameshift mutations in the C-terminal region of PRDM2, affecting (A)8 or (A)9 repeats within exon 8, are found in one third of colorectal cancers with microsatellite instability, but the contribution of these mutations to colorectal tumorigenesis is unknown. To model somatic mutations in microsatellite unstable tumors, we devised a general approach to perform genome editing while stabilizing the mutated nucleotide repeat. We then engineered isogenic cell systems where the PRDM2 c.4467delA mutation in human HCT116 colorectal cancer cells was corrected to wild-type by genome editing. Restored PRDM2 increased global histone 3 lysine 9 dimethylation and reduced migration, anchorage-independent growth and tumor growth in vivo. Gene set enrichment analysis revealed regulation of several hallmark cancer pathways, particularly of epithelial-to-mesenchymal transition (EMT), with VIM being the most significantly regulated gene. These observations provide direct evidence that PRDM2 c.4467delA is a driver mutation in colorectal cancer and confirms PRDM2 as a cancer gene, pointing to regulation of EMT as a central aspect of its tumor suppressive action.

Place, publisher, year, edition, pages
2017. Vol. 8, no 58, p. 98646-98659
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-345974DOI: 10.18632/oncotarget.21713ISI: 000419392300074000419392300074OAI: oai:DiVA.org:uu-345974DiVA, id: diva2:1190047
Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-03-16Bibliographically approved
In thesis
1. Targeting allelic loss in colorectal cancer
Open this publication in new window or tab >>Targeting allelic loss in colorectal cancer
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Targeted cancer therapy exploits molecular differences between tumor and normal cells to selectively kill cancer cells. Whereas targeting of activated oncogenes has proved clinically useful, few current therapies exploit loss-of-function mutations in tumor suppressor genes or in the genome at large. This thesis explores the consequences of allelic loss affecting tumor suppressor genes and passenger genes in colorectal cancer (CRC), aiming to identify vulnerabilities that can be exploited for therapy. 

In Paper I we used genome editing to model inactivation of PRDM2 and showed that PRDM2 loss impacts cell growth and invasiveness, potentially mediated by genes involved in epithelial-to-mesenchymal transition. We confirmed the role of PRDM2 as a tumor suppressor gene in CRC and proved that c.4467delA inactivating mutations constitute a driver event in CRC.

In Paper II we investigated whether the reduced allelic diversity resulting from loss of heterozygosity (LOH) in cancers could be exploited for therapy. We identified target genes by mapping prevalent alleles frequently lost in cancer and investigated NAT2 loss in CRC. Drug discovery efforts identified a compound selectively toxic to tumor cells with reduced NAT2 activity, providing proof of concept for LOH targeting by small molecule drugs.

In Paper III, we aimed to widen the cohort of CRC patients eligible for NAT2 allele-selective chemotherapy. We determined NAT2 slow acetylator frequencies and LOH events in two independent cohorts by next-generation sequencing and genomic arrays. Next, we demonstrated enhanced response to allele-selective chemotherapy of tumor cells encoding additional prevalent NAT2 slow acetylator alleles, and developed a method for detection of NAT2 allelic loss suitable for clinical use.

In Paper IV, we extended the search of therapeutic target genes by mining loss-of-function (LoF) alleles retained in tumors after LOH. This effort identified a prevalent splice site disruption in CYP2D6 as a putative target and motivated the development of cell model systems to identify compounds targeting CYP2D6 loss in cancer cells.

In Paper V we characterized a set of 56 microsatellite stable CRCs by whole-genome sequencing in an attempt to understand the genetic causes leading to genomic instability and colorectal tumorigenesis. We confirmed the mutation frequencies of known CRC genes and identified for the first time the contribution of an unknown mutational process in 10% of the analyzed tumors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 50
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1443
Keywords
colorectal cancer, gene editing, loss of heterozygosity, targeted therapy, whole genome sequencing
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-345970 (URN)978-91-513-0274-4 (ISBN)
Public defence
2018-05-04, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:00 (English)
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Available from: 2018-04-10 Created: 2018-03-13 Last updated: 2018-04-24

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Pandzic, TatjanaRendo, VerónicaLarsson, ChatarinaLarsson, JimmyStoimenov, IvayloKundu, SnehangshuAli, Muhammad AkhtarHellström, MatsHe, LiqunSjöblom, Tobias

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Pandzic, TatjanaRendo, VerónicaLarsson, ChatarinaLarsson, JimmyStoimenov, IvayloKundu, SnehangshuAli, Muhammad AkhtarHellström, MatsHe, LiqunSjöblom, Tobias
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