BACKGROUND RAS,BRAF,and mismatch repair(MMR)/microsatellite instability(MSI)are crucial biomarkers recommended by clinical practice guidelines for colorectal cancer(CRC).However,their characteristics and influencing f...BACKGROUND RAS,BRAF,and mismatch repair(MMR)/microsatellite instability(MSI)are crucial biomarkers recommended by clinical practice guidelines for colorectal cancer(CRC).However,their characteristics and influencing factors in Chinese patients have not been thoroughly described.AIM To analyze the clinicopathological features of KRAS,NRAS,BRAF,and PIK3CA mutations and the DNA MMR status in CRC.METHODS We enrolled 2271 Chinese CRC patients at the China-Japan Friendship Hospital.MMR proteins were tested using immunohistochemical analysis,and the KRAS/NRAS/BRAF/PIK3CA mutations were determined using quantitative polymerase chain reaction.Microsatellite status was determined using an MSI detection kit.Statistical analyses were conducted using SPSS software and logistic regression.RESULTS The KRAS,NRAS,BRAF,and PIK3CA mutations were detected in 44.6%,3.4%,3.7%,and 3.9% of CRC patients,respectively.KRAS mutations were more likely to occur in patients with moderate-to-high differentiation.BRAF mutations were more likely to occur in patients with right-sided CRC,poorly differentiated,or no perineural invasion.Deficient MMR(dMMR)was detected in 7.9% of all patients and 16.8% of those with mucinous adenocarcinomas.KRAS,NRAS,BRAF,and PIK3CA mutations were detected in 29.6%,1.1%,8.1%,and 22.3% of patients with dMMR,respectively.The dMMR was more likely to occur in patients with a family history of CRC,aged<50 years,right-sided CRC,poorly differentiated histology,no perineural invasion,and with carcinoma in situ,stage I,or stage II tumors.CONCLUSION This study analyzed the molecular profiles of KRAS,NRAS,BRAF,PIK3CA,and MMR/MSI in CRC,identifying key influencing factors,with implications for clinical management of CRC.展开更多
Objective:DNA damage response(DDR)genes have low mutation rates,which may restrict their clinical applications in predicting the outcomes of immune checkpoint inhibitor(ICI)treatment.Thus,a systemic analysis of multip...Objective:DNA damage response(DDR)genes have low mutation rates,which may restrict their clinical applications in predicting the outcomes of immune checkpoint inhibitor(ICI)treatment.Thus,a systemic analysis of multiple DDR genes is needed to identify potential biomarkers of ICI efficacy.Methods:A total of 39,631 patients with mutation data were selected from the cBioPortal database.A total of 155 patients with mutation data were obtained from the Fudan University Shanghai Cancer Center(FUSCC).A total of 1,660 patients from the MSK-IMPACT cohort who underwent ICI treatment were selected for survival analysis.A total of 249 patients who underwent ICI treatment from the Dana-Farber Cancer Institute(DFCI)cohort were obtained from a published dataset.The Cancer Genome Atlas(TCGA)level 3 RNA-Seq version 2 RSEM data for gastric cancer were downloaded from cBioPortal.Results:Six MMR and 30 DDR genes were included in this study.Six MMR and 20 DDR gene mutations were found to predict the therapeutic efficacy of ICI,and most of them predicted the therapeutic efficacy of ICI,in a manner dependent on TMB,except for 4 combined DDR gene mutations,which were associated with the therapeutic efficacy of ICI independently of the TMB.Single MMR/DDR genes showed low mutation rates;however,the mutation rate of all the MMR/DDR genes associated with the therapeutic efficacy of ICI was relatively high,reaching 10%–30%in several cancer types.Conclusions:Coanalysis of multiple MMR/DDR mutations aids in selecting patients who are potential candidates for immunotherapy.展开更多
Biallelic germline mutations in the mismatch repair genes, including MLH1, MSH2, MSH6 or PMS2, lead to a recessive constitutional mismatch repair-deficiency (CMMR-D) syndrome characterized by early onset malignancies ...Biallelic germline mutations in the mismatch repair genes, including MLH1, MSH2, MSH6 or PMS2, lead to a recessive constitutional mismatch repair-deficiency (CMMR-D) syndrome characterized by early onset malignancies in children and young adults. Because consanguinity unmasks autosomal recessive disorders, we hypothesized that the frequency of CMMR-D is inflated in the highly consanguineous population of Saudi Arabia. In this study, 371 pediatric and young adult?patient samples from Saudi Arabia that cover the tumor spectrum of CMMR-D syndrome were analyzed for biallelic germline mutations in the MLH1, MSH2, MSH6 and PMS2 with the use of direct genomic sequencing. However, none of the 371 patients involved in the study was found to have biallelic pathological mutations of MLH1, MSH2, MSH6 or PMS2. This result indicates that CMMR-D is exceptionally rare among pediatric cancer patients and adult early onset cancer patients, even in the highly consanguineous Saudi population. Our findings suggest that larger cohorts will be needed, particularly in outbred populations, to determine the frequency of CMMR-D and that routine screening for this syndrome among cancer patients is not warranted.展开更多
目的探讨CpG岛甲基化(CIMP+)结肠癌的临床特点和预后,以及CIMP状态在错配修复缺陷(dMMR)结肠癌的诊断和预后预测中的指导意义。方法以关键词"colorectal cancer""patient"和"CpG Island Methylator Phenotype&...目的探讨CpG岛甲基化(CIMP+)结肠癌的临床特点和预后,以及CIMP状态在错配修复缺陷(dMMR)结肠癌的诊断和预后预测中的指导意义。方法以关键词"colorectal cancer""patient"和"CpG Island Methylator Phenotype"检索基因表达数据库(GEO),得到序列号为GSE39582的数据,共纳入585例结肠癌患者临床资料和肿瘤组织的全转录组测序数据。排除CIMP为缺失值的72例后纳入513例进一步分析,其中男性278例,女性235例,平均年龄(67±13)岁。根据CIMP状态分为CIMP+组(n=93)和CIMP-组(n=420),比较两组临床特点差异,绘制Kaplan-Meier生存曲线比较总生存期和无病生存期差异;提取dMMR亚组71例,分为CIMP+组(n=43)和CIMP-组(n=28),K-M曲线分析两组总生存期和无病生存期差异。组间比较采用t检验、χ^(2)检验或者Mann-WhitneyU非参数检验,生存曲线组间差异性检验采用Long-rank检验。结果CIMP+组患者年龄大于CIMP-组[(70.84±12.60)岁比(66.21±13.08)岁,t=3.18,P=0.002];右半结肠肿瘤起源于CIMP+分子通路途径是左半结肠癌起源于CIMP+的9.3倍(OR=9.3,95%CI:5.2~17.9);BRAF突变型结肠癌起源于CIMP+是BRAF野生型结肠癌起源与CIMP+的215.2倍(OR=215.2,95%CI:53.2~1906.7);dMMR结肠癌患者起源于CIMP+是pMMR患者的12.8倍(OR=12.8,95%CI:7.0~23.9)。CIMP+和CIMP-两组在总生存期和无病生存期方面差异无统计学意义(P=0.590、0.220)。在dMMR结肠癌亚组中,CIMP状态与患者总生存期和无病生存期无相关性(P>0.05)。结论CIMP+结肠癌患病人群多为高龄,肿瘤起源有右半结肠,多合并BRAF基因突变,表现为错配修复缺陷dMMR结肠癌。CIMP状态与结肠癌TNM分期及生存预后无相关性。CIMP+所致dMMR结肠癌与MMR基因突变所致dMMR结肠癌,生存预后无显著差异。展开更多
目的在散发性左、右半肠癌中分别分析错配修复蛋白功能缺失(deficient mismatch repair,dMMR)与临床病理特征的相关性。方法收集昆明医科大学第一附属医院2014年1月至2019年9月经病理证实为腺癌的1922例患者的临床病理资料,分别在散发...目的在散发性左、右半肠癌中分别分析错配修复蛋白功能缺失(deficient mismatch repair,dMMR)与临床病理特征的相关性。方法收集昆明医科大学第一附属医院2014年1月至2019年9月经病理证实为腺癌的1922例患者的临床病理资料,分别在散发性左、右半肠癌中分析dMMR与性别、年龄、体重指数(body mass index,BMI)、民族、血型、术前癌胚抗原(carcino-embryonic antigen,CEA)水平、病理类型、肿瘤分化程度、肿瘤直径、pT分期、pN分期、淋巴结检出数目、远处转移、(union for international cancer control,UICC)UICC分期、脉管侵犯、神经侵犯的关联。结果共有1922例散发性肠癌符合纳入标准,散发性右半肠癌患者占23.99%(461/1922),散发性左半肠癌患者占76.01%(1461/1922)。所有散发性肠癌患者dMMR率为23.47%(451/1922),散发性右半肠癌dMMR率38.83%(179/461);散发性左半肠癌dMMR率18.62%(272/1461)。与既往研究一致的是,所有散发性肠癌的dMMR更多见于年龄<62岁(OR=1.551,P<0.001)、右半肠癌(OR=2.603,P<0.001)、肿瘤直径≥4 cm(OR=1.362,P=0.009)、病理分化程度为中低分化(OR=1.538,P=0.046)、低分化(OR=2.124,P=0.013)及未分化(OR=1.850,P=0.045)、UICC分期Ⅰ~Ⅱ期(OR=1.340,P=0.014)、无神经侵犯者(OR=1.407,P=0.004)。在散发性右半肠癌中,dMMR多见于年龄<62岁(OR=1.888,P=0.001),pT1~T2(OR=3.778,P=<0.001)以及肿瘤直径≥4 cm者(OR=1.856,P=0.012);在散发性左半肠癌中,dMMR多见于年龄<62岁(OR=1.525,P=0.002),肿瘤直径≥4 cm(OR=1.391,P=0.016),无神经侵犯(OR=1.454,P=0.009)。结论不论肠道肿瘤原发部位如何,dMMR均多见于年龄<62岁,肿瘤直径≥4 cm者,而无神经侵犯及pT1~T2分别多见于散发性左半及右半肠癌。展开更多
基金Supported by National High Level Hospital Clinical Research Funding,No.2023-NHLHCRF-YYPPLC-TJ-03.
文摘BACKGROUND RAS,BRAF,and mismatch repair(MMR)/microsatellite instability(MSI)are crucial biomarkers recommended by clinical practice guidelines for colorectal cancer(CRC).However,their characteristics and influencing factors in Chinese patients have not been thoroughly described.AIM To analyze the clinicopathological features of KRAS,NRAS,BRAF,and PIK3CA mutations and the DNA MMR status in CRC.METHODS We enrolled 2271 Chinese CRC patients at the China-Japan Friendship Hospital.MMR proteins were tested using immunohistochemical analysis,and the KRAS/NRAS/BRAF/PIK3CA mutations were determined using quantitative polymerase chain reaction.Microsatellite status was determined using an MSI detection kit.Statistical analyses were conducted using SPSS software and logistic regression.RESULTS The KRAS,NRAS,BRAF,and PIK3CA mutations were detected in 44.6%,3.4%,3.7%,and 3.9% of CRC patients,respectively.KRAS mutations were more likely to occur in patients with moderate-to-high differentiation.BRAF mutations were more likely to occur in patients with right-sided CRC,poorly differentiated,or no perineural invasion.Deficient MMR(dMMR)was detected in 7.9% of all patients and 16.8% of those with mucinous adenocarcinomas.KRAS,NRAS,BRAF,and PIK3CA mutations were detected in 29.6%,1.1%,8.1%,and 22.3% of patients with dMMR,respectively.The dMMR was more likely to occur in patients with a family history of CRC,aged<50 years,right-sided CRC,poorly differentiated histology,no perineural invasion,and with carcinoma in situ,stage I,or stage II tumors.CONCLUSION This study analyzed the molecular profiles of KRAS,NRAS,BRAF,PIK3CA,and MMR/MSI in CRC,identifying key influencing factors,with implications for clinical management of CRC.
基金This work was supported by the National Key R&D Program of China(Grant No.2018YFC1313300)the National Natural Science Foundation of China(Grant No.81572331).
文摘Objective:DNA damage response(DDR)genes have low mutation rates,which may restrict their clinical applications in predicting the outcomes of immune checkpoint inhibitor(ICI)treatment.Thus,a systemic analysis of multiple DDR genes is needed to identify potential biomarkers of ICI efficacy.Methods:A total of 39,631 patients with mutation data were selected from the cBioPortal database.A total of 155 patients with mutation data were obtained from the Fudan University Shanghai Cancer Center(FUSCC).A total of 1,660 patients from the MSK-IMPACT cohort who underwent ICI treatment were selected for survival analysis.A total of 249 patients who underwent ICI treatment from the Dana-Farber Cancer Institute(DFCI)cohort were obtained from a published dataset.The Cancer Genome Atlas(TCGA)level 3 RNA-Seq version 2 RSEM data for gastric cancer were downloaded from cBioPortal.Results:Six MMR and 30 DDR genes were included in this study.Six MMR and 20 DDR gene mutations were found to predict the therapeutic efficacy of ICI,and most of them predicted the therapeutic efficacy of ICI,in a manner dependent on TMB,except for 4 combined DDR gene mutations,which were associated with the therapeutic efficacy of ICI independently of the TMB.Single MMR/DDR genes showed low mutation rates;however,the mutation rate of all the MMR/DDR genes associated with the therapeutic efficacy of ICI was relatively high,reaching 10%–30%in several cancer types.Conclusions:Coanalysis of multiple MMR/DDR mutations aids in selecting patients who are potential candidates for immunotherapy.
文摘Biallelic germline mutations in the mismatch repair genes, including MLH1, MSH2, MSH6 or PMS2, lead to a recessive constitutional mismatch repair-deficiency (CMMR-D) syndrome characterized by early onset malignancies in children and young adults. Because consanguinity unmasks autosomal recessive disorders, we hypothesized that the frequency of CMMR-D is inflated in the highly consanguineous population of Saudi Arabia. In this study, 371 pediatric and young adult?patient samples from Saudi Arabia that cover the tumor spectrum of CMMR-D syndrome were analyzed for biallelic germline mutations in the MLH1, MSH2, MSH6 and PMS2 with the use of direct genomic sequencing. However, none of the 371 patients involved in the study was found to have biallelic pathological mutations of MLH1, MSH2, MSH6 or PMS2. This result indicates that CMMR-D is exceptionally rare among pediatric cancer patients and adult early onset cancer patients, even in the highly consanguineous Saudi population. Our findings suggest that larger cohorts will be needed, particularly in outbred populations, to determine the frequency of CMMR-D and that routine screening for this syndrome among cancer patients is not warranted.
文摘目的探讨CpG岛甲基化(CIMP+)结肠癌的临床特点和预后,以及CIMP状态在错配修复缺陷(dMMR)结肠癌的诊断和预后预测中的指导意义。方法以关键词"colorectal cancer""patient"和"CpG Island Methylator Phenotype"检索基因表达数据库(GEO),得到序列号为GSE39582的数据,共纳入585例结肠癌患者临床资料和肿瘤组织的全转录组测序数据。排除CIMP为缺失值的72例后纳入513例进一步分析,其中男性278例,女性235例,平均年龄(67±13)岁。根据CIMP状态分为CIMP+组(n=93)和CIMP-组(n=420),比较两组临床特点差异,绘制Kaplan-Meier生存曲线比较总生存期和无病生存期差异;提取dMMR亚组71例,分为CIMP+组(n=43)和CIMP-组(n=28),K-M曲线分析两组总生存期和无病生存期差异。组间比较采用t检验、χ^(2)检验或者Mann-WhitneyU非参数检验,生存曲线组间差异性检验采用Long-rank检验。结果CIMP+组患者年龄大于CIMP-组[(70.84±12.60)岁比(66.21±13.08)岁,t=3.18,P=0.002];右半结肠肿瘤起源于CIMP+分子通路途径是左半结肠癌起源于CIMP+的9.3倍(OR=9.3,95%CI:5.2~17.9);BRAF突变型结肠癌起源于CIMP+是BRAF野生型结肠癌起源与CIMP+的215.2倍(OR=215.2,95%CI:53.2~1906.7);dMMR结肠癌患者起源于CIMP+是pMMR患者的12.8倍(OR=12.8,95%CI:7.0~23.9)。CIMP+和CIMP-两组在总生存期和无病生存期方面差异无统计学意义(P=0.590、0.220)。在dMMR结肠癌亚组中,CIMP状态与患者总生存期和无病生存期无相关性(P>0.05)。结论CIMP+结肠癌患病人群多为高龄,肿瘤起源有右半结肠,多合并BRAF基因突变,表现为错配修复缺陷dMMR结肠癌。CIMP状态与结肠癌TNM分期及生存预后无相关性。CIMP+所致dMMR结肠癌与MMR基因突变所致dMMR结肠癌,生存预后无显著差异。
文摘目的在散发性左、右半肠癌中分别分析错配修复蛋白功能缺失(deficient mismatch repair,dMMR)与临床病理特征的相关性。方法收集昆明医科大学第一附属医院2014年1月至2019年9月经病理证实为腺癌的1922例患者的临床病理资料,分别在散发性左、右半肠癌中分析dMMR与性别、年龄、体重指数(body mass index,BMI)、民族、血型、术前癌胚抗原(carcino-embryonic antigen,CEA)水平、病理类型、肿瘤分化程度、肿瘤直径、pT分期、pN分期、淋巴结检出数目、远处转移、(union for international cancer control,UICC)UICC分期、脉管侵犯、神经侵犯的关联。结果共有1922例散发性肠癌符合纳入标准,散发性右半肠癌患者占23.99%(461/1922),散发性左半肠癌患者占76.01%(1461/1922)。所有散发性肠癌患者dMMR率为23.47%(451/1922),散发性右半肠癌dMMR率38.83%(179/461);散发性左半肠癌dMMR率18.62%(272/1461)。与既往研究一致的是,所有散发性肠癌的dMMR更多见于年龄<62岁(OR=1.551,P<0.001)、右半肠癌(OR=2.603,P<0.001)、肿瘤直径≥4 cm(OR=1.362,P=0.009)、病理分化程度为中低分化(OR=1.538,P=0.046)、低分化(OR=2.124,P=0.013)及未分化(OR=1.850,P=0.045)、UICC分期Ⅰ~Ⅱ期(OR=1.340,P=0.014)、无神经侵犯者(OR=1.407,P=0.004)。在散发性右半肠癌中,dMMR多见于年龄<62岁(OR=1.888,P=0.001),pT1~T2(OR=3.778,P=<0.001)以及肿瘤直径≥4 cm者(OR=1.856,P=0.012);在散发性左半肠癌中,dMMR多见于年龄<62岁(OR=1.525,P=0.002),肿瘤直径≥4 cm(OR=1.391,P=0.016),无神经侵犯(OR=1.454,P=0.009)。结论不论肠道肿瘤原发部位如何,dMMR均多见于年龄<62岁,肿瘤直径≥4 cm者,而无神经侵犯及pT1~T2分别多见于散发性左半及右半肠癌。
