结直肠癌腹膜转移（PM-CRC）患者的预后较差，对化疗的反应特别差。本研究旨在确定所观察到的临床行为的分子解释，并提出 PM-CRC 的新治疗策略。来自挪威国家队列的肿瘤样本 (230)，正在接受手术和丝裂霉素 C (MMC) 腹腔热灌注化疗 (HIPEC) 治疗 PM -对CRC进行靶向DNA测序，并分析与临床数据的关联。对 30 个样本的子集进行 mRNA 测序，比较携带 BRAF 或 KRAS 突变的肿瘤和野生型肿瘤的基因表达。27% 的患者检测到 BRAF 突变，与 BRAF 突变亚组相比，BRAF 突变亚组的总生存率较差野生型病例（中位时间分别为 16 个月和 36 个月，p < 0.001）。 BRAF 突变与 RNF43/RSPO 畸变和负 Wnt 调节因子的低表达（配体依赖性 Wnt 激活）相关。此外，BRAF 突变与转运溶质载体蛋白（特别是 SLC7A6）和药物代谢酶（CES1 和 CYP3A4）的基因表达变化相关，这些变化可能分别影响 MMC 和伊立替康的疗效。 BRAF 突变的肿瘤还表现出免疫检查点分子的新型嗜丁酸蛋白亚家族成员（BTN1A1 和 BTNL9）表达增加。BRAF 突变经常被检测到，并且与该队列中特别差的生存率相关，可能与配体依赖性 Wnt 激活和改变药物转运和代谢，可能产生对 MMC 和伊立替康的耐药性。针对配体依赖性 Wnt 激活或 BTN 免疫检查点的药物可能代表两种新颖的治疗方法。© 2024。作者。

Patients with peritoneal metastasis from colorectal cancer (PM-CRC) have inferior prognosis and respond particularly poorly to chemotherapy. This study aims to identify the molecular explanation for the observed clinical behavior and suggest novel treatment strategies in PM-CRC.Tumor samples (230) from a Norwegian national cohort undergoing surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC) for PM-CRC were subjected to targeted DNA sequencing, and associations with clinical data were analyzed. mRNA sequencing was conducted on a subset of 30 samples to compare gene expression in tumors harboring BRAF or KRAS mutations and wild-type tumors.BRAF mutations were detected in 27% of the patients, and the BRAF-mutated subgroup had inferior overall survival compared to wild-type cases (median 16 vs 36 months, respectively, p < 0.001). BRAF mutations were associated with RNF43/RSPO aberrations and low expression of negative Wnt regulators (ligand-dependent Wnt activation). Furthermore, BRAF mutations were associated with gene expression changes in transport solute carrier proteins (specifically SLC7A6) and drug metabolism enzymes (CES1 and CYP3A4) that could influence the efficacy of MMC and irinotecan, respectively. BRAF-mutated tumors additionally exhibited increased expression of members of the novel butyrophilin subfamily of immune checkpoint molecules (BTN1A1 and BTNL9).BRAF mutations were frequently detected and were associated with particularly poor survival in this cohort, possibly related to ligand-dependent Wnt activation and altered drug transport and metabolism that could confer resistance to MMC and irinotecan. Drugs that target ligand-dependent Wnt activation or the BTN immune checkpoints could represent two novel therapy approaches.© 2024. The Author(s).