Erasmus MC Cancer Institute, Department of Medical Oncology, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands.
Int J Mol Sci. 2022 May 3;23(9):5080. doi: 10.3390/ijms23095080.
Among the structural variants observed in metastatic colorectal cancer (mCRC), deletions (DELs) show a size preference of ~10 kb-1 Mb and are often found in common fragile sites (CFSs). To gain more insight into the biology behind the occurrence of these specific DELs in mCRC, and their possible association with outcome, we here studied them in detail in metastatic lesions of 429 CRC patients using available whole-genome sequencing and corresponding RNA-seq data. Breakpoints of DELs within CFSs are significantly more often located between two consecutive replication origins compared to DELs outside CFSs. DELs are more frequently located at the midpoint of genes inside CFSs with duplications (DUPs) at the flanks of the genes. The median expression of genes inside CFSs was significantly higher than those of similarly-sized genes outside CFSs. Patients with high numbers of these specific DELs showed a shorter progression-free survival time on platinum-containing therapy. Taken together, we propose that the observed DEL/DUP patterns in expressed genes located in CFSs are consistent with a model of transcription-dependent double-fork failure, and, importantly, that the ability to overcome the resulting stalled replication forks decreases sensitivity to platinum-containing treatment, known to induce stalled replication forks as well. Therefore, we propose that our DEL score can be used as predictive biomarker for decreased sensitivity to platinum-containing treatment, which, upon validation, may augment future therapeutic choices.
在转移性结直肠癌 (mCRC) 中观察到的结构变异中，缺失 (DELs) 表现出大小偏好约 10 kb-1 Mb，并且通常在常见的脆性部位 (CFSs) 中发现。为了更深入地了解 mCRC 中这些特定 DEL 发生的生物学基础及其与结局的可能关联，我们在这里使用可用的全基因组测序和相应的 RNA-seq 数据，详细研究了 429 例 CRC 患者的转移性病变中的这些 DEL。CFS 内 DEL 的断点明显比 CFS 外的 DEL 更常位于两个连续复制原点之间。DEL 更频繁地位于 CFS 内基因的中点，而基因侧翼则有重复 (DUP)。CFS 内基因的中位表达明显高于 CFS 外相似大小基因的表达。这些特定 DEL 数量较多的患者在含铂治疗中无进展生存期较短。总之，我们提出观察到的位于 CFS 中的表达基因中的 DEL/DUP 模式与转录依赖性双叉失败模型一致，重要的是，克服由此产生的停滞复制叉的能力降低了对含铂治疗的敏感性，已知含铂治疗也会诱导停滞复制叉。因此，我们提出我们的 DEL 评分可作为对含铂治疗敏感性降低的预测生物标志物，经过验证后，可能会增加未来的治疗选择。
