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As the known susceptibility genes, such as <jats:italic>BRCA1<\/jats:italic> and <jats:italic>BRCA2<\/jats:italic>, explain only a fraction of this, additional predisposing genes and related biological mechanisms are actively being searched for. We have recently identified a recurrent <jats:italic>MCPH1<\/jats:italic> germline mutation, p.Arg304ValfsTer3, as a breast cancer susceptibility allele. <jats:italic>MCPH1<\/jats:italic> encodes a multifunctional protein involved in maintenance of genomic integrity and it is also somatically altered in various cancer types, including breast cancer. Additionally, biallelic <jats:italic>MCPH1<\/jats:italic> mutations are causative for microcephaly and at cellular level premature chromosome condensation. To study the molecular mechanisms leading to cancer predisposition and malignant conversion, here we have modeled the effect of <jats:italic>MCPH1<\/jats:italic> p.Arg304ValfsTer3 mutation using gene\u2010edited MCF10A breast epithelial cells. As a complementary approach, we also sought for additional potential cancer driver mutations in <jats:italic>MCPH1<\/jats:italic> p.Arg304ValfsTer3 carrier breast tumors. We show that mutated MCPH1 de\u2010regulates transcriptional programs related to invasion and metastasis and leads to downregulation of histone genes. These global transcriptional changes are mirrored by significantly increased migration and invasion potential of the cells as well as abnormal chromosomal condensation both before and after mitosis. These findings provide novel molecular insights to MCPH1 tumor suppressor functions and establish a role in regulation of transcriptional programs related to malignant conversion and chromosomal assembly. The <jats:italic>MCPH1<\/jats:italic> p.Arg304ValfsTer3 carrier breast tumors showed recurrent tumor suppressor gene <jats:italic>TP53<\/jats:italic> mutations, which were also significantly over\u2010represented in breast tumors with somatically inactivated <jats:italic>MCPH1<\/jats:italic>.<\/jats:p>","DOI":"10.1002\/ijc.32234","type":"journal-article","created":{"date-parts":[[2019,2,27]],"date-time":"2019-02-27T04:25:22Z","timestamp":1551241522000},"page":"2070-2081","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Tumor suppressor MCPH1 regulates gene expression profiles related to malignant conversion and chromosomal assembly"],"prefix":"10.1002","volume":"145","author":[{"given":"Anna","family":"Tervasm\u00e4ki","sequence":"first","affiliation":[{"name":"Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu University of Oulu  Oulu 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