TY - JOUR T1 - Novel germline variant in the histone demethylase and transcription regulator KDM4C induces a multi-cancer phenotype JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2021-107747 SP - jmedgenet-2021-107747 AU - Riku Katainen AU - Iikki Donner AU - Maritta Räisänen AU - Davide Berta AU - Anna Kuosmanen AU - Eevi Kaasinen AU - Marja Hietala AU - Lauri A Aaltonen Y1 - 2021/07/18 UR - http://jmg.bmj.com/content/early/2021/07/18/jmedgenet-2021-107747.abstract N2 - Background Genes involved in epigenetic regulation are central for chromatin structure and gene expression. Specific mutations in these might promote carcinogenesis in several tissue types.Methods We used exome, whole-genome and Sanger sequencing to detect rare variants shared by seven affected individuals in a striking early-onset multi-cancer family. The only variant that segregated with malignancy resided in a histone demethylase KDM4C. Consequently, we went on to study the epigenetic landscape of the mutation carriers with ATAC, ChIP (chromatin immunoprecipitation) and RNA-sequencing from lymphoblastoid cell lines to identify possible pathogenic effects.Results A novel variant in KDM4C, encoding a H3K9me3 histone demethylase and transcription regulator, was found to segregate with malignancy in the family. Based on Roadmap Epigenomics Project data, differentially accessible chromatin regions between the variant carriers and controls enrich to normally H3K9me3-marked chromatin. We could not detect a difference in global H3K9 trimethylation levels. However, carriers of the variant seemed to have more trimethylated H3K9 at transcription start sites. Pathway analyses of ChIP-seq and differential gene expression data suggested that genes regulated through KDM4C interaction partner EZH2 and its interaction partner PLZF are aberrantly expressed in mutation carriers.Conclusions The apparent dysregulation of H3K9 trimethylation and KDM4C-associated genes in lymphoblastoid cells supports the hypothesis that the KDM4C variant is causative of the multi-cancer susceptibility in the family. As the variant is ultrarare, located in the conserved catalytic JmjC domain and predicted pathogenic by the majority of available in silico tools, further studies on the role of KDM4C in cancer predisposition are warranted.Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Data that potentially allow identification of individuals must be protected and thus, sequencing data produced in this study cannot be deposited to public databases. Roadmap epigenomics ChIP-seq and DNase hotspot data provided in LOLA Core and Extended databases was downloaded from http://cloud.databio.org/regiondb/. ER -