Relationships among KRAS mutation status, expression of RAS pathway signaling molecules, and clinicopathological features and prognosis of patients with colorectal cancer
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摘要
BACKGROUND The RAS/RAF/MEK/ERK and PI3 K/AKT/mTOR signaling pathways all belong to mitogen-activated protein kinase(MAPK) signaling pathways, Mutations in any one of the upstream genes(such as the RAS gene or the BRAF gene) may be transmitted to the protein through transcription or translation, resulting in abnormal activation of the signaling pathway. This study investigated the relationship between the KRAS gene mutation and the clinicopathological features and prognosis of colorectal cancer(CRC), and the effect of KRAS mutations on its associated proteins in CRC, with an aim to clarify the cause of tumor progression and drug resistance caused by mutation of the KRAS gene.AIM To investigate the KRAS gene and RAS pathway signaling molecules in CRC and to analyze their relationship with clinicopathological features and prognosis METHODS Colorectal cancer tissue specimens from 196 patients were analyzed for KRAS mutations using quantitative polymerase chain reaction and for KRAS, BRAF,MEK, and ERK protein expression levels using immunohistochemistry of tumor microarrays. To analyze differences of RAS pathway signaling molecule expression levels in different KRAS gene status, the relationships between these parameters and clinicopathological features, 4-year progression-free survival, and overall survival were analyzed by independent sample t test, Kaplan-Meier plots,and the log-rank test. Predictors of overall and disease-free survival were assessed using a Cox proportional hazards model.RESULTS Of the 196 patients, 62(32%) carried mutations in codon 12(53/62) or codon 13(9/62) in exon 2 of the KRAS gene. KRAS, BRAF, ERK, and MEK protein expression was detected in 71.4%, 78.8%, 64.3%, and 50.8% of CRC tissues,respectively. There were no significant differences between KRAS mutation status and KRAS, BRAF, MEK, or ERK protein levels. Positive expression of KRAS and ERK was associated with poor tumor differentiation, and KRAS expression was also associated with age < 56 years. MEK expression was significantly associated with distant metastasis(P < 0.05). The 4-year progression-free survival rate, but not overall survival rate, was significantly higher in patients with KRAS-negative tumors than in those with KRAS-positive tumors(P < 0.05), whereas BRAF, MEK,and ERK expression was unrelated to survival. Multivariate analysis showed that only the expression of KRAS protein was a risk factor for tumor recurrence(P <0.05). No other clinicopathological factors correlated with KRAS, BRAF, MEK, or ERK expression.CONCLUSION KRAS gene mutations do not affect downstream protein expression in CRC.KRAS protein is associated with poor tumor differentiation, older age, and a risk of tumor recurrence.
BACKGROUND The RAS/RAF/MEK/ERK and PI3 K/AKT/mTOR signaling pathways all belong to mitogen-activated protein kinase(MAPK) signaling pathways, Mutations in any one of the upstream genes(such as the RAS gene or the BRAF gene) may be transmitted to the protein through transcription or translation, resulting in abnormal activation of the signaling pathway. This study investigated the relationship between the KRAS gene mutation and the clinicopathological features and prognosis of colorectal cancer(CRC), and the effect of KRAS mutations on its associated proteins in CRC, with an aim to clarify the cause of tumor progression and drug resistance caused by mutation of the KRAS gene.AIM To investigate the KRAS gene and RAS pathway signaling molecules in CRC and to analyze their relationship with clinicopathological features and prognosis METHODS Colorectal cancer tissue specimens from 196 patients were analyzed for KRAS mutations using quantitative polymerase chain reaction and for KRAS, BRAF,MEK, and ERK protein expression levels using immunohistochemistry of tumor microarrays. To analyze differences of RAS pathway signaling molecule expression levels in different KRAS gene status, the relationships between these parameters and clinicopathological features, 4-year progression-free survival, and overall survival were analyzed by independent sample t test, Kaplan-Meier plots,and the log-rank test. Predictors of overall and disease-free survival were assessed using a Cox proportional hazards model.RESULTS Of the 196 patients, 62(32%) carried mutations in codon 12(53/62) or codon 13(9/62) in exon 2 of the KRAS gene. KRAS, BRAF, ERK, and MEK protein expression was detected in 71.4%, 78.8%, 64.3%, and 50.8% of CRC tissues,respectively. There were no significant differences between KRAS mutation status and KRAS, BRAF, MEK, or ERK protein levels. Positive expression of KRAS and ERK was associated with poor tumor differentiation, and KRAS expression was also associated with age < 56 years. MEK expression was significantly associated with distant metastasis(P < 0.05). The 4-year progression-free survival rate, but not overall survival rate, was significantly higher in patients with KRAS-negative tumors than in those with KRAS-positive tumors(P < 0.05), whereas BRAF, MEK,and ERK expression was unrelated to survival. Multivariate analysis showed that only the expression of KRAS protein was a risk factor for tumor recurrence(P <0.05). No other clinicopathological factors correlated with KRAS, BRAF, MEK, or ERK expression.CONCLUSION KRAS gene mutations do not affect downstream protein expression in CRC.KRAS protein is associated with poor tumor differentiation, older age, and a risk of tumor recurrence.
BACKGROUND The RAS/RAF/MEK/ERK and PI3 K/AKT/mTOR signaling pathways all belong to mitogen-activated protein kinase(MAPK) signaling pathways, Mutations in any one of the upstream genes(such as the RAS gene or the BRAF gene) may be transmitted to the protein through transcription or translation, resulting in abnormal activation of the signaling pathway. This study investigated the relationship between the KRAS gene mutation and the clinicopathological features and prognosis of colorectal cancer(CRC), and the effect of KRAS mutations on its associated proteins in CRC, with an aim to clarify the cause of tumor progression and drug resistance caused by mutation of the KRAS gene.AIM To investigate the KRAS gene and RAS pathway signaling molecules in CRC and to analyze their relationship with clinicopathological features and prognosis METHODS Colorectal cancer tissue specimens from 196 patients were analyzed for KRAS mutations using quantitative polymerase chain reaction and for KRAS, BRAF,MEK, and ERK protein expression levels using immunohistochemistry of tumor microarrays. To analyze differences of RAS pathway signaling molecule expression levels in different KRAS gene status, the relationships between these parameters and clinicopathological features, 4-year progression-free survival, and overall survival were analyzed by independent sample t test, Kaplan-Meier plots,and the log-rank test. Predictors of overall and disease-free survival were assessed using a Cox proportional hazards model.RESULTS Of the 196 patients, 62(32%) carried mutations in codon 12(53/62) or codon 13(9/62) in exon 2 of the KRAS gene. KRAS, BRAF, ERK, and MEK protein expression was detected in 71.4%, 78.8%, 64.3%, and 50.8% of CRC tissues,respectively. There were no significant differences between KRAS mutation status and KRAS, BRAF, MEK, or ERK protein levels. Positive expression of KRAS and ERK was associated with poor tumor differentiation, and KRAS expression was also associated with age < 56 years. MEK expression was significantly associated with distant metastasis(P < 0.05). The 4-year progression-free survival rate, but not overall survival rate, was significantly higher in patients with KRAS-negative tumors than in those with KRAS-positive tumors(P < 0.05), whereas BRAF, MEK,and ERK expression was unrelated to survival. Multivariate analysis showed that only the expression of KRAS protein was a risk factor for tumor recurrence(P <0.05). No other clinicopathological factors correlated with KRAS, BRAF, MEK, or ERK expression.CONCLUSION KRAS gene mutations do not affect downstream protein expression in CRC.KRAS protein is associated with poor tumor differentiation, older age, and a risk of tumor recurrence.
引文
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18 Bonin S,Groenen PJTA,Halbwedl I,Popper HH.DNA Extraction from Formalin-Fixed ParaffinEmbedded(FFPE)Tissues.In:Guidelines for Molecular Analysis in Archive Tissues.Springer Berlin Heidelberg 2011;[DOI:10.1007/978-3-642-17890-0_7]
19 Kononen J,Bubendorf L,Kallioniemi A,B?rlund M,Schraml P,Leighton S,Torhorst J,Mihatsch MJ,Sauter G,Kallioniemi OP.Tissue microarrays for high-throughput molecular profiling of tumor specimens.Nat Med 1998;4:844-847[PMID:9662379]
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24 Amado RG,Wolf M,Peeters M,Van Cutsem E,Siena S,Freeman DJ,Juan T,Sikorski R,Suggs S,Radinsky R,Patterson SD,Chang DD.Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.J Clin Oncol 2008;26:1626-1634[PMID:18316791 DOI:10.1200/JCO.2007.14.7116]
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29 Sundstr?m M,Edlund K,Lindell M,Glimelius B,Birgisson H,Micke P,Botling J.KRAS analysis in colorectal carcinoma:analytical aspects of Pyrosequencing and allele-specific PCR in clinical practice.BMC Cancer 2010;10:660[PMID:21122130 DOI:10.1186/1471-2407-10-660]
30 Bokemeyer C,Bondarenko I,Makhson A,Hartmann JT,Aparicio J,de Braud F,Donea S,Ludwig H,Schuch G,Stroh C,Loos AH,Zubel A,Koralewski P.Fluorouracil,leucovorin,and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer.J Clin Oncol 2009;27:663-671[PMID:19114683 DOI:10.1200/JCO.2008.20.8397]
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2 Yang L,Zheng R,Wang N,Yuan Y,Liu S,Li H,Zhang S,Zeng H,Chen W.Incidence and mortality of stomach cancer in China,2014.Zhongguo Aizheng Yanjiu 2018;30:291-298
3 Liu S,Yang L,Yuan Y,Li H,Tian J,Lu S,Wang N,Ji J.Cancer incidence in Beijing,2014.Chin JCancer Res 2018;30:13-20[PMID:29545715 DOI:10.21147/j.issn.1000-9604.2018.01.02]
4 Dienstmann R,Elez E,Argiles G,Matos I,Sanz-Garcia E,Ortiz C,Macarulla T,Capdevila J,Alsina M,Sauri T,Verdaguer H,Vilaro M,Ruiz-Pace F,Viaplana C,Garcia A,Landolfi S,Palmer HG,Nuciforo P,Rodon J,Vivancos A,Tabernero J.Analysis of mutant allele fractions in driver genes in colorectal cancerbiological and clinical insights.Mol Oncol 2017;11:1263-1272[PMID:28618197 DOI:10.1002/1878-0261.12099]
5 De Luca A,Maiello MR,D'Alessio A,Pergameno M,Normanno N.The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways:role in cancer pathogenesis and implications for therapeutic approaches.Expert Opin Ther Targets 2012;16 Suppl 2:S17-S27[PMID:22443084 DOI:10.1517/14728222.2011.639361]
6 Malmstr?m ML,S?ftoiu A,Vilmann P,Klausen TW,G?genur I.Endoscopic ultrasound for staging of colonic cancer proximal to the rectum:A systematic review and meta-analysis.Endosc Ultrasound 2016;5:307-314[PMID:27803903]
7 Castro-Pocas FM,Dinis-Ribeiro M,Rocha A,Santos M,Araújo T,Pedroto I.Colon carcinoma staging by endoscopic ultrasonography miniprobes.Endosc Ultrasound 2017;6:245-251[PMID:28663528 DOI:10.4103/2303-9027.190921]
8 Ignee A,Dong Y,Schuessler G,Baum U,Dietrich CF.Endorectal fusion imaging:A description of a new technique.Endosc Ultrasound 2017;6:241-244[PMID:28685744 DOI:10.4103/2303-9027.209868]
9 Wang Y,Zhou Y,Hu Z.The Functions of Circulating Tumor Cells in Early Diagnosis and Surveillance During Cancer Advancement.J Transl Int Med 2017;5:135-138[PMID:29085785 DOI:10.1515/jtim-2017-0029]
10 Wu D,Li JN,Qian JM.Endoscopic Diagnosis and Treatment of Precancerous Colorectal Lesions in Patients with Inflammatory Bowel Disease:How Does the Latest SCENIC International Consensus Intersect with Our Clinical Practice?J Transl Int Med 2017;5:4-7[PMID:28680833 DOI:10.1515/jtim-2017-0008]
11 Okasha HH,Naguib M,El Nady M,Ezzat R,Al-Gemeie E,Al-Nabawy W,Aref W,Abdel-Moaty A,Essam K,Hamdy A.Role of endoscopic ultrasound and endoscopic-ultrasound-guided fine-needle aspiration in endoscopic biopsy negative gastrointestinal lesions.Endosc Ultrasound 2017;6:156-161[PMID:28621291 DOI:10.4103/2303-9027.201086]
12 Ersan V,Kutlu R,Erdem C,Karagul S,Kayaalp C.Colorectal Stenting for Obstruction due to Retrorectal Tumor in a Patient Unsuitable for Surgery.J Transl Int Med 2017;5:186-188[PMID:29164050 DOI:10.1515/jtim-2017-0026]
13 Ciardiello F,Tortora G.EGFR antagonists in cancer treatment.N Engl J Med 2008;358:1160-1174[PMID:18337605 DOI:10.1056/NEJMra0707704]
14 Qing H,Gong W,Che Y,Wang X,Peng L,Liang Y,Wang W,Deng Q,Zhang H,Jiang B.PAK1-dependent MAPK pathway activation is required for colorectal cancer cell proliferation.Tumour Biol2012;33:985-994[PMID:22252525 DOI:10.1007/s13277-012-0327-1]
15 Levidou G,Saetta AA,Gigelou F,Karlou M,Papanastasiou P,Stamatelli A,Kavantzas N,Michalopoulos NV,Agrogiannis G,Patsouris E,Korkolopoulou P.ERK/pERK expression and B-raf mutations in colon adenocarcinomas:correlation with clinicopathological characteristics.World J Surg Oncol 2012;10:47[PMID:22376079 DOI:10.1186/1477-7819-10-47]
16 Zhao SL,Hong J,Xie ZQ,Tang JT,Su WY,Du W,Chen YX,Lu R,Sun DF,Fang JY.TRAPPC4-ERK2interaction activates ERK1/2,modulates its nuclear localization and regulates proliferation and apoptosis of colorectal cancer cells.PLoS One 2011;6:e23262[PMID:21826244 DOI:10.1371/journal.pone.0023262]
17 Su N,Peng L,Xia B,Zhao Y,Xu A,Wang J,Wang X,Jiang B.Lyn is involved in CD24-induced ERK1/2activation in colorectal cancer.Mol Cancer 2012;11:43[PMID:22731636 DOI:10.1186/1476-4598-11-43]
18 Bonin S,Groenen PJTA,Halbwedl I,Popper HH.DNA Extraction from Formalin-Fixed ParaffinEmbedded(FFPE)Tissues.In:Guidelines for Molecular Analysis in Archive Tissues.Springer Berlin Heidelberg 2011;[DOI:10.1007/978-3-642-17890-0_7]
19 Kononen J,Bubendorf L,Kallioniemi A,B?rlund M,Schraml P,Leighton S,Torhorst J,Mihatsch MJ,Sauter G,Kallioniemi OP.Tissue microarrays for high-throughput molecular profiling of tumor specimens.Nat Med 1998;4:844-847[PMID:9662379]
20 Battifora H.The multitumor(sausage)tissue block:novel method for immunohistochemical antibody testing.Lab Invest 1986;55:244-248[PMID:3525985]
21 Budwit-Novotny DA,McCarty KS,Cox EB,Soper JT,Mutch DG,Creasman WT,Flowers JL,McCarty KS.Immunohistochemical analyses of estrogen receptor in endometrial adenocarcinoma using a monoclonal antibody.Cancer Res 1986;46:5419-5425[PMID:3756890]
22 Brink M,de Goeij AF,Weijenberg MP,Roemen GM,Lentjes MH,Pachen MM,Smits KM,de Bru?ne AP,Goldbohm RA,van den Brandt PA.K-ras oncogene mutations in sporadic colorectal cancer in The Netherlands Cohort Study.Carcinogenesis 2003;24:703-710[PMID:12727799]
23 Karapetis CS,Khambata-Ford S,Jonker DJ,O'Callaghan CJ,Tu D,Tebbutt NC,Simes RJ,Chalchal H,Shapiro JD,Robitaille S,Price TJ,Shepherd L,Au HJ,Langer C,Moore MJ,Zalcberg JR.K-ras mutations and benefit from cetuximab in advanced colorectal cancer.N Engl J Med 2008;359:1757-1765[PMID:18946061 DOI:10.1056/NEJMoa0804385]
24 Amado RG,Wolf M,Peeters M,Van Cutsem E,Siena S,Freeman DJ,Juan T,Sikorski R,Suggs S,Radinsky R,Patterson SD,Chang DD.Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.J Clin Oncol 2008;26:1626-1634[PMID:18316791 DOI:10.1200/JCO.2007.14.7116]
25 Bos JL.ras oncogenes in human cancer:a review.Cancer Res 1989;49:4682-4689[PMID:2547513]
26 Schubbert S,Shannon K,Bollag G.Hyperactive Ras in developmental disorders and cancer.Nat Rev Cancer 2007;7:295-308[PMID:17384584 DOI:10.1038/nrc2109]
27 Tanioka H,Asano M,Yoshida R,Waki N,Uno F,Ishizaki M,Yamashita K,Morishita Y,Nagasaka T.Cetuximab retreatment in patients with metastatic colorectal cancer who exhibited a clinical benefit in response to prior cetuximab:A retrospective study.Oncol Lett 2018;16:3674-3680[PMID:30127977DOI:10.3892/ol.2018.9127]
28 Pu XX,Deng YH,Xu F,Xiao J,Guo HQ,Huang H,Tian Y,He YJ,Lin TY.[Effect of KRAS mutation on efficacy of Cetuximab combined with chemotherapy in advanced colorectal cancer patients].Zhonghua Wei Chang Wai Ke Za Zhi 2009;12:594-597[PMID:19921572]
29 Sundstr?m M,Edlund K,Lindell M,Glimelius B,Birgisson H,Micke P,Botling J.KRAS analysis in colorectal carcinoma:analytical aspects of Pyrosequencing and allele-specific PCR in clinical practice.BMC Cancer 2010;10:660[PMID:21122130 DOI:10.1186/1471-2407-10-660]
30 Bokemeyer C,Bondarenko I,Makhson A,Hartmann JT,Aparicio J,de Braud F,Donea S,Ludwig H,Schuch G,Stroh C,Loos AH,Zubel A,Koralewski P.Fluorouracil,leucovorin,and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer.J Clin Oncol 2009;27:663-671[PMID:19114683 DOI:10.1200/JCO.2008.20.8397]
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