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Variants in known moderate- to high-penetrance genes explain less than 5% of the cases arising at early-onset (&lt;\u200956\u00a0years) and\/or with familial aggregation of the disease. Considering that BubR1 is an essential component of the mitotic spindle assembly checkpoint, we hypothesized that monoallelic <jats:italic>BUB1B<\/jats:italic> variants could be sufficient to fuel chromosomal instability (CIN), potentially triggering (prostate) carcinogenesis.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>To unveil <jats:italic>BUB1B<\/jats:italic> as a new PrCa predisposing gene, we performed targeted next-generation sequencing in germline DNA from 462 early-onset\/familial PrCa patients and 1,416 cancer patients fulfilling criteria for genetic testing for other hereditary cancer syndromes. To explore the <jats:italic>pan<\/jats:italic>-cancer role of <jats:italic>BUB1B<\/jats:italic>, we used in silico BubR1 molecular modeling, in vitro gene-editing, and ex vivo patients\u2019 tumors and peripheral blood lymphocytes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Rare <jats:italic>BUB1B<\/jats:italic> variants were found in\u2009~\u20091.9% of the early-onset\/familial PrCa cases and in\u2009~\u20090.6% of other cancer patients fulfilling criteria for hereditary disease. We further show that <jats:italic>BUB1B<\/jats:italic> variants lead to decreased BubR1 expression and\/or stability, which promotes increased premature chromatid separation and, consequently, triggers CIN, driving resistance to Taxol-based therapies.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our study shows that different <jats:italic>BUB1B<\/jats:italic> variants may uncover a trigger for CIN-driven carcinogenesis, supporting the role of <jats:italic>BUB1B<\/jats:italic> as a (<jats:italic>pan<\/jats:italic>)-cancer predisposing gene with potential impact on genetic counseling and treatment decision-making.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12929-024-01056-z","type":"journal-article","created":{"date-parts":[[2024,7,16]],"date-time":"2024-07-16T08:01:44Z","timestamp":1721116904000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["BUB1B monoallelic germline variants contribute to prostate cancer predisposition by triggering chromosomal instability"],"prefix":"10.1186","volume":"31","author":[{"given":"Maria P.","family":"Silva","sequence":"first","affiliation":[]},{"given":"Lu\u00edsa T.","family":"Ferreira","sequence":"additional","affiliation":[]},{"given":"Nat\u00e9rcia F.","family":"Br\u00e1s","sequence":"additional","affiliation":[]},{"given":"Lurdes","family":"Torres","sequence":"additional","affiliation":[]},{"given":"Andreia","family":"Brand\u00e3o","sequence":"additional","affiliation":[]},{"given":"Manuela","family":"Pinheiro","sequence":"additional","affiliation":[]},{"given":"Marta","family":"Cardoso","sequence":"additional","affiliation":[]},{"given":"Adriana","family":"Resende","sequence":"additional","affiliation":[]},{"given":"Joana","family":"Vieira","sequence":"additional","affiliation":[]},{"given":"Carlos","family":"Palmeira","sequence":"additional","affiliation":[]},{"given":"Gabriela","family":"Martins","sequence":"additional","affiliation":[]},{"given":"Miguel","family":"Silva","sequence":"additional","affiliation":[]},{"given":"Carla","family":"Pinto","sequence":"additional","affiliation":[]},{"given":"Ana","family":"Peixoto","sequence":"additional","affiliation":[]},{"given":"Jo\u00e3o","family":"Silva","sequence":"additional","affiliation":[]},{"given":"Rui","family":"Henrique","sequence":"additional","affiliation":[]},{"given":"Sofia","family":"Maia","sequence":"additional","affiliation":[]},{"given":"Helder","family":"Maiato","sequence":"additional","affiliation":[]},{"given":"Manuel R.","family":"Teixeira","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8387-2127","authenticated-orcid":false,"given":"Paula","family":"Paulo","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2024,7,16]]},"reference":[{"key":"1056_CR1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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