BUB1B monoallelic germline variants contribute to prostate cancer predisposition by triggering chromosomal instability.

IF 9 2区 医学 Q1 CELL BIOLOGY Journal of Biomedical Science Pub Date : 2024-07-16 DOI:10.1186/s12929-024-01056-z
Maria P Silva, Luísa T Ferreira, Natércia F Brás, Lurdes Torres, Andreia Brandão, Manuela Pinheiro, Marta Cardoso, Adriana Resende, Joana Vieira, Carlos Palmeira, Gabriela Martins, Miguel Silva, Carla Pinto, Ana Peixoto, João Silva, Rui Henrique, Sofia Maia, Helder Maiato, Manuel R Teixeira, Paula Paulo
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Abstract

Background: Prostate cancer (PrCa) is the most frequently diagnosed cancer in men. Variants in known moderate- to high-penetrance genes explain less than 5% of the cases arising at early-onset (< 56 years) 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 BUB1B variants could be sufficient to fuel chromosomal instability (CIN), potentially triggering (prostate) carcinogenesis.

Methods: To unveil BUB1B 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 pan-cancer role of BUB1B, we used in silico BubR1 molecular modeling, in vitro gene-editing, and ex vivo patients' tumors and peripheral blood lymphocytes.

Results: Rare BUB1B variants were found in ~ 1.9% of the early-onset/familial PrCa cases and in ~ 0.6% of other cancer patients fulfilling criteria for hereditary disease. We further show that BUB1B 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.

Conclusions: Our study shows that different BUB1B variants may uncover a trigger for CIN-driven carcinogenesis, supporting the role of BUB1B as a (pan)-cancer predisposing gene with potential impact on genetic counseling and treatment decision-making.

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BUB1B 单拷贝种系变异通过引发染色体不稳定性导致前列腺癌易感性。
背景:前列腺癌(PrCa)是最常见的男性癌症。在早期发病的病例中,只有不到 5% 的病例是由已知的中高风险基因中的变异引起的(方法:我们对生殖细胞中的 BUB1B 基因进行了定向下一代测序,以揭示新的前列腺癌易感基因:为了揭示 BUB1B 这一新的 PrCa 易感基因,我们对 462 名早发/家族性 PrCa 患者和 1416 名符合其他遗传性癌症综合征基因检测标准的癌症患者的生殖系 DNA 进行了定向下一代测序。为了探索 BUB1B 在癌症中的作用,我们使用了 BubR1 分子建模、体外基因编辑以及患者肿瘤和外周血淋巴细胞:结果:在约 1.9% 的早发性/家族性 PrCa 病例和约 0.6% 符合遗传性疾病标准的其他癌症患者中发现了罕见的 BUB1B 变异。我们进一步发现,BUB1B变异会导致BubR1表达和/或稳定性下降,从而促进染色体过早分离,进而引发CIN,导致对基于紫杉醇的疗法产生耐药性:我们的研究表明,不同的 BUB1B 变体可能会揭示 CIN 致癌的触发因素,从而支持 BUB1B 作为(泛)癌症易感基因的作用,这对遗传咨询和治疗决策具有潜在影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Biomedical Science
Journal of Biomedical Science 医学-医学:研究与实验
CiteScore
18.50
自引率
0.90%
发文量
95
审稿时长
1 months
期刊介绍: The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
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