Hatakeyama Keiichi, Nagashima Takeshi, Ohnami Sumiko, Ohnami Shumpei, Maruyama Koji, Ohshima Keiichi, Shimoda Yuji, Naruoka Akane, Kenmotsu Hirotsugu, Urakami Kenichi, Akiyama Yasuto, Yamaguchi Ken
Cancer Multiomics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.
Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.
Cancer Sci. 2025 Oct;116(10):2882-2892. doi: 10.1111/cas.70159. Epub 2025 Aug 6.
Whole-genome analyses have revealed that large-scale structural variations (SVs) such as whole-genome duplication (WGD) occur early in the development of many cancers. However, the diversity of chromosomal abnormalities within tumors before and after WGD remains poorly understood. Here, we analyzed various types of Japanese tumor genomes via whole-genome sequencing and examined the diversity of WGD by focusing on large SVs at the chromosomal level. WGD was detected in 52% of cases, while the frequency of chromothripsis (CT) was 20%. Although aneuploidy via deletion of chromosome arms was common in many cancers, in rare ovarian cancers, all chromosomes were near-haploidy before WGD. Minor allele analysis revealed that many non-mutated ohnolog genes drifted down chromosome arms after WGD and returned to normal ploidy, but only 17p, including TP53, which is also an ohnolog, underwent loss of heterozygosity due to arm deletion before WGD in most cancers. TP53 mutations were frequently detected in WGD and CT-positive tumors, and these SVs strongly correlated with homologous recombination deficiency scores. Furthermore, these tumors had many mutations that continued to generate neoantigens and resulted in worse survival outcomes. Diversity analysis of tumors with WGD will provide a new perspective on structural abnormalities in tumor genomes.
全基因组分析表明，诸如全基因组复制（WGD）之类的大规模结构变异（SVs）在许多癌症的发展早期就会出现。然而，WGD前后肿瘤内染色体异常的多样性仍知之甚少。在此，我们通过全基因组测序分析了各种类型的日本肿瘤基因组，并通过关注染色体水平上的大型SVs来研究WGD的多样性。在52%的病例中检测到WGD，而染色体碎裂（CT）的频率为20%。尽管通过染色体臂缺失导致的非整倍体在许多癌症中很常见，但在罕见的卵巢癌中，所有染色体在WGD之前都接近单倍体状态。次要等位基因分析显示，许多未发生突变的同源基因在WGD后沿染色体臂向下漂移并恢复到正常倍性，但在大多数癌症中，只有包括同样作为同源基因的TP53在内的17号染色体短臂在WGD之前因臂缺失而发生杂合性缺失。TP53突变在WGD和CT阳性肿瘤中经常被检测到，并且这些SVs与同源重组缺陷评分密切相关。此外，这些肿瘤有许多持续产生新抗原的突变，导致生存结果更差。对具有WGD的肿瘤进行多样性分析将为肿瘤基因组的结构异常提供新的视角。
