背景:需要特异性靶向RAS突变型结直肠癌(CRC)患者的治疗剂。我们通过关联全基因组关联研究和晚期CRC患者的生存数据寻找潜在的药物靶点,这些患者的有丝分裂原活化蛋白激酶激酶(MAPK)通路突变。
方法:来自临床试验COIN和COIN-B的694名患者具有MAPK激活的CRC(分配为KRAS,NRAS或BRAF突变体)。全基因组SNP,进行了基因和基因集分析以确定存活的决定因素.对于RAS蛋白激活剂样2(RASAL2)中的rs12028023,我们通过MAPK通路激活状态研究了其作用(通过与760名没有MAPK激活的CRC的患者进行比较),MAPK基因突变状态,原发性肿瘤的表面积(作为增殖的标志物)和RASAL2上的表达。
结果:在MAGMA全基因组分析中,RASAL2是与存活相关的最显著的基因(P=2.0x10-5)。在前导SNP中携带次要(A)等位基因的患者,与携带主要等位基因的那些相比,RASAL2的内含子1中的rs12028023的存活中位数增加167天。rs12028023通过MAPK激活状态预测存活(PZ检验=2.1x10-3)。此外,rs12028023改善了RAS突变患者的生存率(危险比[HR]=0.62,95%置信区间[CI]=0.5-0.8,P=3.4x10-5),但没有BRAF突变(P=0.87)CRC。rs12028023A-等位基因与原发肿瘤的表面积降低(β=-0.037,标准误差[SE]=0.017,P=3.2x10-2)和培养的成纤维细胞中RASAL2表达降低相关(P=1.6x10-11)。
结论:我们的数据表明RASAL2在MAPK激活的CRC患者中具有预后作用,具有作为治疗靶点的潜力。本文受版权保护。保留所有权利。
Therapeutic agents that specifically target patients with RAS mutant colorectal cancer (CRC) are needed. We sought potential drug targets by relating genome-wide association study and survival data in patients with advanced CRC profiled for mitogen-activated protein kinase (MAPK) pathway mutations.
In total, 694 patients from the clinical trials COIN and COIN-B had MAPK-activated CRCs (assigned as KRAS, NRAS, or BRAF mutant). Genome-wide single nucleotide polymorphism (SNP), gene, and gene-set analyses were performed to identify determinants of survival. For rs12028023 in RAS protein activator-like 2 (
RASAL2), we studied its effect by MAPK pathway activation status (by comparing to 760 patients without MAPK-activated CRCs), MAPK gene mutation status, surface area of the primary tumor (as a marker of proliferation), and expression on
RASAL2.
In MAGMA genome-wide analyses,
RASAL2 was the most significant gene associated with survival (p = 2.0 × 10-5 ). Patients carrying the minor (A) allele in the lead SNP, rs12028023 in intron 1 of
RASAL2, had a median increase in survival of 167 days as compared with patients carrying the major allele. rs12028023 was predictive for survival by MAPK-activation status (pZ-test = 2.1 × 10-3 ). Furthermore, rs12028023 improved survival in patients with RAS mutant (hazard ratio [HR] = 0.62, 95% confidence intervals [CI] = 0.5-0.8, p = 3.4 × 10-5 ) but not BRAF mutant (p = 0.87) CRCs. The rs12028023 A-allele was associated with reduced surface area of the primary tumor (Beta = -0.037, standard error [SE] = 0.017, p = 3.2 × 10-2 ) and reduced
RASAL2 expression in cultured fibroblasts (p = 1.6 × 10-11 ).
Our data demonstrate a prognostic role for RASAL2 in patients with MAPK-activated CRCs, with potential as a therapeutic target.