背景:虽然先前的研究表明结直肠癌(CRC)中不同错配修复(MMR)状态的远处转移潜能存在差异,他们的发现仍然没有定论,特别是考虑到不同种族背景的潜在差异。此外,基因调控网络和导致MMR状态间转移潜能差异的潜在机制尚未阐明.
方法:我们从中国西南部收集了2058个连续的原发性CRC样本,并使用免疫组织化学评估了MMR蛋白(MLH1,MSH2,MSH6和PMS2)的表达。为了探索不同MMR状态和复发之间的不一致,我们进行了荟萃分析.为了更深入地研究,我们采用加权基因共表达网络分析(WGCNA),ClueGo,还有iRegulon,精确定位与CRC转移和复发相关的基因表达网络和关键调控分子。最后,应用单变量和多变量Cox回归分析来确定核心调节分子对转移的影响.
结果:在样本中,8.2%显示MMR不足(dMMR),MLH1和PSM2的损失分别为40.8%和63.9%,分别。发现了一个独特的24.3%的PMS2孤立损失,没有并发转移,与既定文献不同的结果。此外,与熟练MMR(pMMR)相比,我们的荟萃分析进一步巩固了dMMRCRC样本中降低的复发可能性.确定了两个与远处转移和复发相关的基因表达网络,大多数与转移相关的基因位于8号和18号染色体上。在转移相关网络中发现了IRF1正反馈回路,IRF1被确定为多个数据集的无复发和无远处转移生存的预测标志物。
结论:地理和种族因素可能影响MMR蛋白丢失的特殊性。我们的发现还强调了新的基因表达网络和CRC转移中的关键调控分子。增强我们对驱动远处转移的机制的理解。
BACKGROUND: While previous studies have indicated variability in distant metastatic potential among different mismatch repair (MMR) states in colorectal cancer (CRC), their findings remain inconclusive, especially considering potential differences across various ethnic backgrounds. Furthermore, the gene regulatory networks and the underlying mechanisms responsible for these variances in metastatic potential across MMR states have yet to be elucidated.
METHODS: We collected 2058 consecutive primary CRC samples from the South West of China and assessed the expression of MMR proteins (MLH1, MSH2, MSH6, and PMS2) using immunohistochemistry. To explore the inconsistencies between different MMR statuses and recurrence, we performed a meta-analysis. To delve deeper, we employed Weighted Gene Co-expression Network Analysis (WGCNA), ClueGo, and iRegulon, pinpointing gene expression networks and key regulatory molecules linked to metastasis and recurrence in CRC. Lastly, both univariate and multivariate Cox regression analyses were applied to determine the impact of core regulatory molecules on metastasis.
RESULTS: Of the samples, 8.2% displayed deficient MMR (dMMR), with losses of MLH1 and PSM2 observed in 40.8% and 63.9%, respectively. A unique 24.3% isolated loss of PMS2 without concurrent metastasis was identified, a result that diverges from established literature. Additionally, our meta-analysis further solidifies the reduced recurrence likelihood in dMMR CRC samples compared to proficient MMR (pMMR). Two gene expression networks tied to distant metastasis and recurrence were identified, with a majority of metastasis-related genes located on chromosomes 8 and 18. An IRF1 positive feedback loop was discerned in the metastasis-related network, and IRF1 was identified as a predictive marker for both recurrence-free and distant metastasis-free survival across multiple datasets.
CONCLUSIONS: Geographical and ethnic factors might influence peculiarities in MMR protein loss. Our findings also highlight new gene expression networks and crucial regulatory molecules in CRC metastasis, enhancing our comprehension of the mechanisms driving distant metastasis.