Institute of Digestive Surgery, Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.
Department of Gastrointestinal, Bariatric and Metabolic Surgery, Research Center for Nutrition, Metabolism & Food Safety, West China-PUMC C.C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
Cancer Med. 2024 Apr;13(7):e6994. doi: 10.1002/cam4.6994.
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.
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.
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.
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.
尽管先前的研究表明，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，但这些发现仍存在争议，尤其是考虑到不同种族背景下可能存在差异。此外，导致 MMR 状态下转移潜能差异的基因调控网络和潜在机制仍有待阐明。
我们从中国西南部收集了 2058 例连续的原发性 CRC 样本，并使用免疫组织化学法评估了 MMR 蛋白（MLH1、MSH2、MSH6 和 PMS2）的表达。为了探讨不同 MMR 状态与复发之间的不一致性，我们进行了荟萃分析。为了深入研究，我们采用加权基因共表达网络分析（WGCNA）、ClueGo 和 iRegulon，确定与 CRC 转移和复发相关的基因表达网络和关键调控分子。最后，我们进行了单变量和多变量 Cox 回归分析，以确定核心调控分子对转移的影响。
在这些样本中，8.2%表现出错配修复缺陷（dMMR），其中 MLH1 和 PSM2 的缺失分别为 40.8%和 63.9%。我们发现了一个独特的 24.3%孤立的 PMS2 缺失而无转移的情况，这与已有的文献结果不同。此外，我们的荟萃分析进一步证实，与功能良好的 MMR（pMMR）相比，dMMR CRC 样本的复发可能性降低。我们确定了两个与远处转移和复发相关的基因表达网络，其中大多数与转移相关的基因位于染色体 8 和 18 上。在转移相关网络中发现了一个 IRF1 正反馈回路，并且 IRF1 被确定为多个数据集的无复发生存期和无远处转移生存期的预测标志物。
地理和种族因素可能影响 MMR 蛋白缺失的特点。我们的研究结果还突出了 CRC 转移中新的基因表达网络和关键调控分子，增强了我们对驱动远处转移的机制的理解。
