Latvian Biomedical Research and Study Centre, LV-1067 Riga, Latvia.
R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, 03022 Kyiv, Ukraine.
Genes (Basel). 2019 Jul 19;10(7):551. doi: 10.3390/genes10070551.
Near-triploid human tumors are frequently resistant to radio/chemotherapy through mechanisms that are unclear. We recently reported a tight association of male tumor triploidy with XXY karyotypes based on a meta-analysis of 15 tumor cohorts extracted from the Mitelman database. Here we provide a conceptual framework of the digyny-like origin of this karyotype based on the germline features of malignant tumors and adaptive capacity of digyny, which supports survival in adverse conditions. Studying how the recombinatorial reproduction via diploidy can be executed in primary cancer samples and HeLa cells after DNA damage, we report the first evidence that diploid and triploid cell sub-populations constitutively coexist and inter-change genomes via endoreduplicated polyploid cells generated through genotoxic challenge. We show that irradiated triploid HeLa cells can enter tripolar mitosis producing three diploid sub-subnuclei by segregation and pairwise fusions of whole genomes. Considering the upregulation of meiotic genes in tumors, we propose that the reconstructed diploid sub-cells can initiate pseudo-meiosis producing two "gametes" (diploid "maternal" and haploid "paternal") followed by digynic-like reconstitution of a triploid stemline that returns to mitotic cycling. This process ensures tumor survival and growth by (1) DNA repair and genetic variation, (2) protection against recessive lethal mutations using the third genome.
近三倍体人类肿瘤常通过不明机制对放化疗产生耐药性。我们最近根据从 Mitelman 数据库中提取的 15 个肿瘤队列的荟萃分析报告了男性肿瘤三倍体与 XXXX 核型之间的紧密关联。在这里，我们基于恶性肿瘤的种系特征和杂种的适应能力提供了这种核型的雌雄同体起源的概念框架，这支持了在不利条件下的生存。研究通过二倍体的重组繁殖如何在原发性癌症样本和 DNA 损伤后的 HeLa 细胞中执行，我们报告了第一个证据，即二倍体和三倍体细胞亚群通过通过遗传毒性挑战产生的内复制多倍体细胞持续共存并交换基因组。我们表明，受照射的三倍体 HeLa 细胞可以通过整个基因组的分离和成对融合进入三极有丝分裂，产生三个二倍体亚核。考虑到肿瘤中减数分裂基因的上调，我们提出重构的二倍体亚细胞可以启动假减数分裂，产生两个“配子”（二倍体“母本”和单倍体“父本”），然后通过类似雌雄同体的方式重建返回有丝分裂循环的三倍体干细胞系。这个过程通过以下方式确保肿瘤的存活和生长：(1) DNA 修复和遗传变异；(2) 利用第三个基因组保护隐性致死突变。
