Luo Kangjia, Song Yanni, Guan Zilong, Ou Suwen, Ye Jinhua, Ran Songlin, Wang Hufei, Tao Yangbao, Gong Zijian, Ma Tianyi, Jin Yinghu, Huang Rui, Gao Feng, Yu Shan
Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
Front Pharmacol. 2022 Jun 14;13:899725. doi: 10.3389/fphar.2022.899725. eCollection 2022.
KRAS mutation, one of the most important biological processes in colorectal cancer, leads to poor prognosis in patients. Although studies on KRAS have concentrated for a long time, there are currently no ideal drugs against KRAS mutations. Different expression analysis and weighted gene coexpression network analysis was conducted to select candidate genes. Log-rank tests and Cox regression picked out the prognostic genes to build a KRAS-related gene prognostic score (KRGPS). A nomogram based on KRGPS was built to predict survival of clinical patients. Comprehensive analysis showed the prognosis, immune microenvironment and response to immune therapy and chemotherapy in KRGPS subgroups. We collected a KRGPS from the set of two genes GJB6 and NTNG1, with low-KRGSP patients having better progression-free survival (PFS). Low KRGPS is correlated with high infiltration of activated NK cells, plasma cells and activated memory CD4 T cells and that these cells benefit more from immune checkpoint inhibitor therapy. However, high KRGPS is associated with high infiltration of activated mast cells, pathways of immune dysregulation and a high ratio of TP53 and KRAS mutations. KRGPS subgroups are also sensitive to chemotherapy differently. A nomogram, established based on the KRGPS and pathological stage, predict 3- and 5-years PFS well. The KRAS-associated score acts as a promising signature to distinguish prognosis, molecular and immune characteristics, and benefits from immune and chemical therapy. These KRAS-associated genes could be promising targets for drug design.
KRAS 突变是结直肠癌最重要的生物学过程之一，会导致患者预后不良。尽管对 KRAS 的研究已经持续了很长时间，但目前尚无针对 KRAS 突变的理想药物。通过进行不同的表达分析和加权基因共表达网络分析来选择候选基因。对数秩检验和 Cox 回归筛选出预后基因，以构建 KRAS 相关基因预后评分（KRGPS）。基于 KRGPS 构建列线图来预测临床患者的生存率。综合分析显示了 KRGPS 亚组的预后、免疫微环境以及对免疫治疗和化疗的反应。我们从 GJB6 和 NTNG1 这两个基因中收集了一个 KRGPS，低 KRGPS 患者的无进展生存期（PFS）更好。低 KRGPS 与活化的自然杀伤细胞、浆细胞和活化的记忆 CD4 T 细胞的高浸润相关，并且这些细胞从免疫检查点抑制剂治疗中获益更多。然而，高 KRGPS 与活化肥大细胞的高浸润、免疫失调途径以及 TP53 和 KRAS 突变的高比例相关。KRGPS 亚组对化疗的敏感性也不同。基于 KRGPS 和病理分期建立的列线图能很好地预测 3 年和 5 年的 PFS。KRAS 相关评分是区分预后、分子和免疫特征以及从免疫和化疗中获益的一个有前景的指标。这些 KRAS 相关基因可能是药物设计的有前景的靶点。
