【作者】 张翔；

【导师】 蔡辉；

【作者基本信息】 兰州大学 ， 临床医学·外科学（专业学位）， 2024， 硕士

【摘要】 背景:在大多数实体瘤中RAS/BRAF各位点突变存在不同的生物学特征,近些年来,一些研究开始关注结直肠癌RAS/BRAF不同位点突变的预后差异,但是结论有所争议。结果:共纳入1027例结直肠癌患者,RAS/BRAF突变发生率为58.4%,超突变被定义为MSI-H(Microsatellite Instability-High,高度微卫星不稳定性)或POLE(Polymerase Epsilon,聚合酶ε)患者,在非超突变队列中,I-III期结直肠癌中只有KRASG13D突变和较高发生频率以及较差的无病生存期相关,在转移性结直肠癌的队列中,我们评估了RAS/BRAF各突变位点的一线治疗无进展生存时间,然后根据无进展生存期将突变患者重新分成4组,分别为组1(野生组)、组2(RAS低风险突变组)、组3(RAS高风险突变组)、组4(BRAFV600E方法:回顾性分析2017-03到2022-09在浙江大学附属第一医院诊断为IIV期的结直肠癌,通过电子病历收集临床病理信息,以及第二代测序数据,对部分患者的石蜡标本进行PD-L1(Programmed Death-Ligand 1,编程死亡配体1)的检测。对生存数据进行KM分析,对不同的组之间使用Log-rank检测,多因素分析采用COX回归分析。组)。我们发现,这四组患者在临床病理特征、转移部位和PD-L1表达方面存在显著差异,这可能是导致预后不同的一个原因。此外,我们还观察到,高风险突变组的患者可能从加强的三药联合治疗方案中获益(hazard ratio[HR]=2.54;95%confidence interval[CI],1.36-5.12;p=0.009)。结论:在非超突变的结直癌患者中,RAS/BRAF各等位基因突变的预后风险在局部和转移性结直肠癌中是不同的,在I-III期结直肠癌中KRASG13D突变似乎是独立预后标记物。在IV期结直肠癌中,KRASG13D/G12C/G12V突变根据预后风险分层被定义为高风险突变亚组,并可以从三药强化治疗方案中获益。更多还原

【Abstract】 Background: In most solid tumors,mutations at various sites of RAS/BRAF have different biological characteristics.In recent years,some studies have begun to focus on the prognosis of colorectal cancer with different site mutations of RAS/BRAF,but the conclusions are controversial.Method: A retrospective analysis was conducted on patients diagnosed with Stage I-IV colorectal cancer from March 2017 to September 2022 at the First Affiliated Hospital of Zhejiang University.Clinical and pathological information was collected through electronic medical records,along with second-generation sequencing data.PDL1(Programmed Death-Ligand 1)testing was performed on paraffin specimens of some patients.Survival data were analyzed using KM analysis,differences between groups were tested using Log-rank test,and multivariate analysis was performed using COX regression analysis.Results: A total of 1027 patients with colorectal cancer were included,with a mutation rate of RAS/BRAF of 58.4%.Hypermutation was defined as patients with MSI-H(Microsatellite Instability-High)or POLE(Polymerase Epsilon).In the nonhypermutant cohort,only the KRASG13 D mutation was related to a higher occurrence rate and poorer disease-free survival in Stage I-III colorectal cancer.In the metastatic colorectal cancer cohort,we evaluated the progression-free survival of various mutation sites of RAS/BRAF,and then reclassified the mutated patients into four groups according to their progression-free survival,namely Group 1(wild-type group),Group2(RAS low-risk mutation group),Group 3(RAS high-risk mutation group),and Group4(BRAFV600E group).We found significant differences among these four groups in clinical pathological characteristics,metastasis sites,and PD-L1 expression,which may be a reason for different prognoses.Additionally,we observed that patients in the highrisk mutation group may benefit from enhanced triplet combination therapy(hazard ratio [HR],2.54;95% confidence interval [CI],1.36-5.12;p=0.009).Conclusion: In non-hypermutated colorectal cancer patients,the prognostic risk of mutations in each allele of RAS/BRAF is different in localized and metastatic colorectal cancer,and the KRASG13 D mutation appears to be an independent prognostic marker in stage I-III colorectal cancer.In stage IV colorectal cancer,KRASG13D/G12C/G12 V mutations are defined as a high-risk mutation subgroup based on prognostic risk stratification and can benefit from a three-drug intensive regimen.更多还原