Colorectal cancer(CRC) is the second most commonly diagnosed cancer among females and third among males worldwide. It also contributes significantly to cancer-related deaths, despite the continuous progress in diagnos...Colorectal cancer(CRC) is the second most commonly diagnosed cancer among females and third among males worldwide. It also contributes significantly to cancer-related deaths, despite the continuous progress in diagnostic and therapeutic methods. Biomarkers currently play an important role in the detection and treatment of patients with colorectal cancer. Risk stratification for screening might be augmented by finding new biomarkers which alone or as a complement of existing tests might recognize either the predisposition or early stage of the disease. Biomarkers have also the potential to change diagnostic and treatment algorithms by selecting the proper chemotherapeutic drugs across a broad spectrum of patients. There are attempts to personalise chemotherapy based on presence or absence of specific biomarkers. In this review, we update review published last year and describe our understanding of tumour markers and biomarkers role in CRC screening, diagnosis, treatment and follow-up. Goal of future research is to identify those biomarkers that could allow a non-invasive and cost-effective diagnosis, as well as to recognise the best prognostic panel and define the predictive biomarkers for available treatments.展开更多
RAS is one of the most well-known proto-oncogenes. Its gain-of-function mutations occur in approximately 30% of all human cancers. As the most frequently mutated RAS isoform, KRAS is intensively studied in the past ye...RAS is one of the most well-known proto-oncogenes. Its gain-of-function mutations occur in approximately 30% of all human cancers. As the most frequently mutated RAS isoform, KRAS is intensively studied in the past years. Despite its well-recognized importance in cancer malignancy,continuous efforts in the past three decades failed to develop approved therapies for KRAS mutant cancer. KRAS has thus long been considered to be undruggable. Encouragingly, recent studies have aroused renewed interest in the development of KRAS inhibitors either directly towards mutant KRAS or against the crucial steps required for KRAS activation. This review summarizes the most recent progress in the exploration of KRAS-targeted anticancer strategies and hopefully provides useful insights for the field.展开更多
Colorectal cancer(CRC)is one of the most common cancer worldwide and results from the accumulation of mutations and epimutations in colonic mucosa cells ultimately leading to cell proliferation and metastasis.Unfortun...Colorectal cancer(CRC)is one of the most common cancer worldwide and results from the accumulation of mutations and epimutations in colonic mucosa cells ultimately leading to cell proliferation and metastasis.Unfortunately,CRC prognosis is still poor and the search of novel diagnostic and prognostic biomarkers is highly desired to prevent CRC-related deaths.The present article aims to summarize the most recent findings concerning the use of either genetic or epigenetic(mainly related to DNA methylation)biomarkers for CRC diagnosis,prognosis,and response to treatment.Recent large-scale DNA methylation studies suggest that CRC can be divided into several subtypes according to the frequency of DNA methylation and those of mutations in key CRC genes,and that this is reflected by different prognostic outcomes.Increasing evidence suggests that the analysis of DNA methylation in blood or fecal specimens could represent a valuable non-invasive diagnostic tool for CRC.Moreover,a broad spectrum of studies indicates that the inter-individual response to chemotherapeutic treatments depends on both epigenetic modifications and genetic mutations occurring in colorectal cancer cells,thereby opening the way for a personalized medicine.Overall,combining genetic and epigenetic data might represent the most promising tool for a proper diagnostic,prognostic and therapeutic approach.展开更多
AIM:To investigate gene mutations and DNA mismatch repair(MMR) protein abnormality in Chinese colorectalcarcinoma(CRC) patients and their correlations with clinicopathologic features.METHODS:Clinical and pathological ...AIM:To investigate gene mutations and DNA mismatch repair(MMR) protein abnormality in Chinese colorectalcarcinoma(CRC) patients and their correlations with clinicopathologic features.METHODS:Clinical and pathological information for 535 patients including 538 tumors was reviewed and recorded.Mutation analyses for exon 2 of KRAS gene and exon 15 of BRAF gene were performed by Sanger sequencing except that in 9 tumors amplification refractory mutation system PCR was used.Expression of MMR proteins including MHL1,MSH2,MSH6 and PMS2 was evaluated by immunohistochemistry.Correlations of KRAS and BRAF mutation status and the expression status of MMR proteins with age,gender,cancer stage,location,and histology were analyzed.Correlations between KRAS or BRAF mutations and MMR protein expression were also explored.RESULTS:The overall frequencies of KRAS and BRAF mutations were 37.9% and 4.4%,respectively.KRAS mutations were more common in patients ≥ 50 years old(39.8% vs 22% in patients < 50 years old,P < 0.05).The frequencies of BRAF mutants were higher in tumors from females(6.6% vs males 2.8%,P < 0.05),located in the right colon(9.6% vs 2.1% in the left colon,1.8% in the rectum,P < 0.01),with mucinous differentiation(9.8% vs 2.8% without mucinous differentiation,P < 0.01),or being poorly differentiated(9.5% vs 3.4% well/moderately differentiated,P < 0.05).MMR deficiency was strongly associated with proximal location(20.5% in the right colon vs 9.2% in the left colon and 5.1% in the rectum,P < 0.001),early cancer stage(15.0% in stages Ⅰ-Ⅱ vs 7.7% in stages Ⅲ-Ⅳ,P < 0.05),and mucinous differentiation(20.2% vs 9.2% without mucin,P < 0.01).A higher frequency of MLH1/PMS2 loss was found in females(9.2% vs 4.4% in males,P < 0.05),and MSH2/MSH6 loss tended to be seen in younger(<50 years old) patients(12.0% vs 4.0% ≥ 50 years old,P < 0.05).MMR deficient tumors were less likely to have KRAS mutations(18.8% vs 41.7% in MMR proficient tumors,P < 0.05) and tumorswith abnormal MLH1/PMS2 tended to harbor BRAF mutations(1展开更多
The roles of concealed microproteins encoded by long noncoding RNAs(lncRNAs)are gradually being exposed,but their functions in tumorigenesis are still largely unclear.Here,we identify and characterize a conserved 99-a...The roles of concealed microproteins encoded by long noncoding RNAs(lncRNAs)are gradually being exposed,but their functions in tumorigenesis are still largely unclear.Here,we identify and characterize a conserved 99-amino acid microprotein named KRASIM that is encoded by the putative lncRNA NCBP2-AS2.KRASIM is differentially expressed in normal hepatocytes and hepatocellular carcinoma(HCC)cells and can suppress HCC cell growth and proliferation.Mechanistically,KRASIM interacts and colocalizes with the KRAS protein in the cytoplasm of human HuH-7 hepatoma cells.More importantly,the overexpression of KRASIM decreases the KRAS protein level,leading to the inhibition of ERK signaling activity in HCC cells.These results demonstrate a novel microprotein repressor of the KRAS pathway for the first time and provide new insights into the regulatory mechanisms of oncogenic signaling and HCC therapy.展开更多
AIM: To investigate efficacy and safety of cetuximab combined with two chemotherapy regimens in patients with unresectable metastatic colorectal cancer (mCRC). METHODS: Randomized patients received cetuximab with 5-fl...AIM: To investigate efficacy and safety of cetuximab combined with two chemotherapy regimens in patients with unresectable metastatic colorectal cancer (mCRC). METHODS: Randomized patients received cetuximab with 5-fluorouracil (5-FU), folinic acid (FA) and oxaliplatin (FOLFOX) 6 (arm A, n = 74) or 5-FU, FA and irinotecan (FOLFIRI) (arm B, n = 77). KRAS mutation status was determined retrospectively in a subset of tumors (n = 117). RESULTS: No significant difference was found between treatment arms A and B in the progression-free survival (PFS) rate at 9 mo, 45% vs 34%; median PFS, 8.6 mo vs 8.3 mo [hazard ratio (HR) = 1.06]; overall response rate (ORR) 43% vs 45% [odds ratio (OR) = 0.93] and median overall survival (OS), 17.4 mo vs 18.9 mo (HR = 0.98). Patients with KRAS wild-type tumors demonstrated improved PFS (HR = 0.55, P = 0.0051), OS, (HR = 0.62, P = 0.0296) and ORR (53% vs 36%) and in arm A, improved PFS (HR = 0.49, P = 0.0196), OS (HR = 0.48, P = 0.0201) and ORR (56%vs 30%), compared with patients with KRAS mutated tumors. In arm B no significant differences were found in efficacy by KRAS mutation status. Treatment in arms A and B was generally well tolerated. CONCLUSION: This study confirms that combinations of cetuximab with FOLFOX6 or FOLFIRI are effective and significantly improve clinical outcome in KRAS wild-type compared with KRAS mutated mCRC.展开更多
Cancer is the leading cause of death worldwide,and its treatment and outcomes have been dramatically revolutionised by targeted therapies.As the most frequently mutated oncogene,Kirsten rat sarcoma viral oncogene homo...Cancer is the leading cause of death worldwide,and its treatment and outcomes have been dramatically revolutionised by targeted therapies.As the most frequently mutated oncogene,Kirsten rat sarcoma viral oncogene homologue(KRAS)has attracted substantial attention.The understanding of KRAS is constantly being updated by numerous studies on KRAS in the initiation and progression of cancer diseases.However,KRAS has been deemed a challenging therapeutic target,even“undruggable”,after drugtargeting efforts over the past four decades.Recently,there have been surprising advances in directly targeted drugs for KRAS,especially in KRAS(G12C)inhibitors,such as AMG510(sotorasib)and MRTX849(adagrasib),which have obtained encouraging results in clinical trials.Excitingly,AMG510 was the first drug-targeting KRAS(G12C)to be approved for clinical use this year.This review summarises the most recent understanding of fundamental aspects of KRAS,the relationship between the KRAS mutations and tumour immune evasion,and new progress in targeting KRAS,particularly KRAS(G12C).Moreover,the possible mechanisms of resistance to KRAS(G12C)inhibitors and possible combination therapies are summarised,with a view to providing the best regimen for individualised treatment with KRAS(G12C)inhibitors and achieving truly precise treatment.展开更多
The KRAS oncogene is mutated in approximately 35%-45% of colorectal cancers, and KRAS mutational status testing has been highlighted in recent years. The most frequent mutations in this gene, point substitutions in co...The KRAS oncogene is mutated in approximately 35%-45% of colorectal cancers, and KRAS mutational status testing has been highlighted in recent years. The most frequent mutations in this gene, point substitutions in codons 12 and 13, were validated as negative predictors of response to anti-epidermal growth factor receptor antibodies. Therefore, determining the KRAS mutational status of tumor samples has become an essential tool for managing patients with colorectal cancers. Currently, a variety of detection methods have been established to analyze the mutation status in the key regions of the KRAS gene; however, several challenges remain related to standardized and uniform testing, including the selection of tumor samples, tumor sample processing and optimal testing methods. Moreover, new testing strategies, in combination with the mutation analysis of BRAF , PIK3CA and loss of PTEN proposed by many researchers and pathologists, should be promoted. In addition, we recommend that microsatellite instability, a prognostic factor, be added to the abovementioned concomitant analysis. This review provides an overview of KRAS biology and the recent advances in KRAS mutation testing. This review also addresses other aspects of status testing for determining the appropriate treatment and offers insight into the potential drawbacks of mutational testing.展开更多
AIM: To investigate the prognostic role of KRAS and BRAF mutations after adjustment for microsatellite instability(MSI) status in Japanese colorectal cancer(CRC) population.METHODS: We assessed KRAS and BRAF mutations...AIM: To investigate the prognostic role of KRAS and BRAF mutations after adjustment for microsatellite instability(MSI) status in Japanese colorectal cancer(CRC) population.METHODS: We assessed KRAS and BRAF mutations and MSI status in 813 Japanese patients with curatively resected, stage Ⅰ-Ⅲ CRC and examined associations of these mutations with disease-free survival(DFS) and overall survival(OS) using uni- and multivariate Cox proportional hazards models.RESULTS: KRAS and BRAF mutations were detected in 312(38%) of 812 and 40(5%) of 811 tumors, respectively. KRAS mutations occurred more frequently in females than in males(P = 0.02), while the presence of BRAF mutations was significantly associated with the female gender(P = 0.006), proximal tumor location(P < 0.001), mucinous or poorly differentiated histology(P < 0.001), and MSI-high tumors(P < 0.001). After adjusting for relevant variables, including MSI status, KRAS mutations were associated with poorer DFS(HR = 1.35; 95%CI: 1.03-1.75) and OS(HR = 1.46; 95%CI: 1.09-1.97). BRAF mutations were poor prognostic factors for DFS(HR = 2.20; 95%CI: 1.19-4.06) and OS(HR = 2.30; 95%CI: 1.15-4.71). Neither the BRAF by MSI interaction test nor the KRAS by MSI interaction test yielded statistically significant results for DFS and OS.CONCLUSION: KRAS and BRAF mutations are associated with inferior survival, independent of MSI status, inJapanese patients with curatively resected CRC.展开更多
文摘Colorectal cancer(CRC) is the second most commonly diagnosed cancer among females and third among males worldwide. It also contributes significantly to cancer-related deaths, despite the continuous progress in diagnostic and therapeutic methods. Biomarkers currently play an important role in the detection and treatment of patients with colorectal cancer. Risk stratification for screening might be augmented by finding new biomarkers which alone or as a complement of existing tests might recognize either the predisposition or early stage of the disease. Biomarkers have also the potential to change diagnostic and treatment algorithms by selecting the proper chemotherapeutic drugs across a broad spectrum of patients. There are attempts to personalise chemotherapy based on presence or absence of specific biomarkers. In this review, we update review published last year and describe our understanding of tumour markers and biomarkers role in CRC screening, diagnosis, treatment and follow-up. Goal of future research is to identify those biomarkers that could allow a non-invasive and cost-effective diagnosis, as well as to recognise the best prognostic panel and define the predictive biomarkers for available treatments.
文摘RAS is one of the most well-known proto-oncogenes. Its gain-of-function mutations occur in approximately 30% of all human cancers. As the most frequently mutated RAS isoform, KRAS is intensively studied in the past years. Despite its well-recognized importance in cancer malignancy,continuous efforts in the past three decades failed to develop approved therapies for KRAS mutant cancer. KRAS has thus long been considered to be undruggable. Encouragingly, recent studies have aroused renewed interest in the development of KRAS inhibitors either directly towards mutant KRAS or against the crucial steps required for KRAS activation. This review summarizes the most recent progress in the exploration of KRAS-targeted anticancer strategies and hopefully provides useful insights for the field.
基金Supported by T Istituto Toscano Tumori(ITT)No.Prot.AOOGRT/325424/Q.80.110 16/12/2009,‘‘Correlation among epigenetic,environmental and genetic factors in colorectal carcinoma’’
文摘Colorectal cancer(CRC)is one of the most common cancer worldwide and results from the accumulation of mutations and epimutations in colonic mucosa cells ultimately leading to cell proliferation and metastasis.Unfortunately,CRC prognosis is still poor and the search of novel diagnostic and prognostic biomarkers is highly desired to prevent CRC-related deaths.The present article aims to summarize the most recent findings concerning the use of either genetic or epigenetic(mainly related to DNA methylation)biomarkers for CRC diagnosis,prognosis,and response to treatment.Recent large-scale DNA methylation studies suggest that CRC can be divided into several subtypes according to the frequency of DNA methylation and those of mutations in key CRC genes,and that this is reflected by different prognostic outcomes.Increasing evidence suggests that the analysis of DNA methylation in blood or fecal specimens could represent a valuable non-invasive diagnostic tool for CRC.Moreover,a broad spectrum of studies indicates that the inter-individual response to chemotherapeutic treatments depends on both epigenetic modifications and genetic mutations occurring in colorectal cancer cells,thereby opening the way for a personalized medicine.Overall,combining genetic and epigenetic data might represent the most promising tool for a proper diagnostic,prognostic and therapeutic approach.
基金Supported by Grant from the Xinjiang Uygur Autonomous Region Natural Science Fund,No.201233146-14(partly)
文摘AIM:To investigate gene mutations and DNA mismatch repair(MMR) protein abnormality in Chinese colorectalcarcinoma(CRC) patients and their correlations with clinicopathologic features.METHODS:Clinical and pathological information for 535 patients including 538 tumors was reviewed and recorded.Mutation analyses for exon 2 of KRAS gene and exon 15 of BRAF gene were performed by Sanger sequencing except that in 9 tumors amplification refractory mutation system PCR was used.Expression of MMR proteins including MHL1,MSH2,MSH6 and PMS2 was evaluated by immunohistochemistry.Correlations of KRAS and BRAF mutation status and the expression status of MMR proteins with age,gender,cancer stage,location,and histology were analyzed.Correlations between KRAS or BRAF mutations and MMR protein expression were also explored.RESULTS:The overall frequencies of KRAS and BRAF mutations were 37.9% and 4.4%,respectively.KRAS mutations were more common in patients ≥ 50 years old(39.8% vs 22% in patients < 50 years old,P < 0.05).The frequencies of BRAF mutants were higher in tumors from females(6.6% vs males 2.8%,P < 0.05),located in the right colon(9.6% vs 2.1% in the left colon,1.8% in the rectum,P < 0.01),with mucinous differentiation(9.8% vs 2.8% without mucinous differentiation,P < 0.01),or being poorly differentiated(9.5% vs 3.4% well/moderately differentiated,P < 0.05).MMR deficiency was strongly associated with proximal location(20.5% in the right colon vs 9.2% in the left colon and 5.1% in the rectum,P < 0.001),early cancer stage(15.0% in stages Ⅰ-Ⅱ vs 7.7% in stages Ⅲ-Ⅳ,P < 0.05),and mucinous differentiation(20.2% vs 9.2% without mucin,P < 0.01).A higher frequency of MLH1/PMS2 loss was found in females(9.2% vs 4.4% in males,P < 0.05),and MSH2/MSH6 loss tended to be seen in younger(<50 years old) patients(12.0% vs 4.0% ≥ 50 years old,P < 0.05).MMR deficient tumors were less likely to have KRAS mutations(18.8% vs 41.7% in MMR proficient tumors,P < 0.05) and tumorswith abnormal MLH1/PMS2 tended to harbor BRAF mutations(1
基金This work was supported by the National Key Research and Development Program of China(2017YFA0504400)the National Natural Science Foundation of China(31370791,31671349,31770879)+2 种基金Fundamental Research Funds for the Central Universities(14lgjc18)This research was supported in part by the Guangdong Province Key Laboratory of Computational Science(13lgjc05)the Guangdong Province Computational Science Innovative Research Team(14lgjc18).
文摘The roles of concealed microproteins encoded by long noncoding RNAs(lncRNAs)are gradually being exposed,but their functions in tumorigenesis are still largely unclear.Here,we identify and characterize a conserved 99-amino acid microprotein named KRASIM that is encoded by the putative lncRNA NCBP2-AS2.KRASIM is differentially expressed in normal hepatocytes and hepatocellular carcinoma(HCC)cells and can suppress HCC cell growth and proliferation.Mechanistically,KRASIM interacts and colocalizes with the KRAS protein in the cytoplasm of human HuH-7 hepatoma cells.More importantly,the overexpression of KRASIM decreases the KRAS protein level,leading to the inhibition of ERK signaling activity in HCC cells.These results demonstrate a novel microprotein repressor of the KRAS pathway for the first time and provide new insights into the regulatory mechanisms of oncogenic signaling and HCC therapy.
文摘AIM: To investigate efficacy and safety of cetuximab combined with two chemotherapy regimens in patients with unresectable metastatic colorectal cancer (mCRC). METHODS: Randomized patients received cetuximab with 5-fluorouracil (5-FU), folinic acid (FA) and oxaliplatin (FOLFOX) 6 (arm A, n = 74) or 5-FU, FA and irinotecan (FOLFIRI) (arm B, n = 77). KRAS mutation status was determined retrospectively in a subset of tumors (n = 117). RESULTS: No significant difference was found between treatment arms A and B in the progression-free survival (PFS) rate at 9 mo, 45% vs 34%; median PFS, 8.6 mo vs 8.3 mo [hazard ratio (HR) = 1.06]; overall response rate (ORR) 43% vs 45% [odds ratio (OR) = 0.93] and median overall survival (OS), 17.4 mo vs 18.9 mo (HR = 0.98). Patients with KRAS wild-type tumors demonstrated improved PFS (HR = 0.55, P = 0.0051), OS, (HR = 0.62, P = 0.0296) and ORR (53% vs 36%) and in arm A, improved PFS (HR = 0.49, P = 0.0196), OS (HR = 0.48, P = 0.0201) and ORR (56%vs 30%), compared with patients with KRAS mutated tumors. In arm B no significant differences were found in efficacy by KRAS mutation status. Treatment in arms A and B was generally well tolerated. CONCLUSION: This study confirms that combinations of cetuximab with FOLFOX6 or FOLFIRI are effective and significantly improve clinical outcome in KRAS wild-type compared with KRAS mutated mCRC.
基金This work was supported by grants from the National Natural Science Foundation of China(NO.82073882)Natural Science Research Team Foundation of Guangdong Province,China(NO.2016A030312014).
文摘Cancer is the leading cause of death worldwide,and its treatment and outcomes have been dramatically revolutionised by targeted therapies.As the most frequently mutated oncogene,Kirsten rat sarcoma viral oncogene homologue(KRAS)has attracted substantial attention.The understanding of KRAS is constantly being updated by numerous studies on KRAS in the initiation and progression of cancer diseases.However,KRAS has been deemed a challenging therapeutic target,even“undruggable”,after drugtargeting efforts over the past four decades.Recently,there have been surprising advances in directly targeted drugs for KRAS,especially in KRAS(G12C)inhibitors,such as AMG510(sotorasib)and MRTX849(adagrasib),which have obtained encouraging results in clinical trials.Excitingly,AMG510 was the first drug-targeting KRAS(G12C)to be approved for clinical use this year.This review summarises the most recent understanding of fundamental aspects of KRAS,the relationship between the KRAS mutations and tumour immune evasion,and new progress in targeting KRAS,particularly KRAS(G12C).Moreover,the possible mechanisms of resistance to KRAS(G12C)inhibitors and possible combination therapies are summarised,with a view to providing the best regimen for individualised treatment with KRAS(G12C)inhibitors and achieving truly precise treatment.
基金Supported by Science and Technology Commission of Shanghai Municipality, No. 10DJ1400501
文摘The KRAS oncogene is mutated in approximately 35%-45% of colorectal cancers, and KRAS mutational status testing has been highlighted in recent years. The most frequent mutations in this gene, point substitutions in codons 12 and 13, were validated as negative predictors of response to anti-epidermal growth factor receptor antibodies. Therefore, determining the KRAS mutational status of tumor samples has become an essential tool for managing patients with colorectal cancers. Currently, a variety of detection methods have been established to analyze the mutation status in the key regions of the KRAS gene; however, several challenges remain related to standardized and uniform testing, including the selection of tumor samples, tumor sample processing and optimal testing methods. Moreover, new testing strategies, in combination with the mutation analysis of BRAF , PIK3CA and loss of PTEN proposed by many researchers and pathologists, should be promoted. In addition, we recommend that microsatellite instability, a prognostic factor, be added to the abovementioned concomitant analysis. This review provides an overview of KRAS biology and the recent advances in KRAS mutation testing. This review also addresses other aspects of status testing for determining the appropriate treatment and offers insight into the potential drawbacks of mutational testing.
基金Supported by Japanese Ministry of Health,Labor and Welfare
文摘AIM: To investigate the prognostic role of KRAS and BRAF mutations after adjustment for microsatellite instability(MSI) status in Japanese colorectal cancer(CRC) population.METHODS: We assessed KRAS and BRAF mutations and MSI status in 813 Japanese patients with curatively resected, stage Ⅰ-Ⅲ CRC and examined associations of these mutations with disease-free survival(DFS) and overall survival(OS) using uni- and multivariate Cox proportional hazards models.RESULTS: KRAS and BRAF mutations were detected in 312(38%) of 812 and 40(5%) of 811 tumors, respectively. KRAS mutations occurred more frequently in females than in males(P = 0.02), while the presence of BRAF mutations was significantly associated with the female gender(P = 0.006), proximal tumor location(P < 0.001), mucinous or poorly differentiated histology(P < 0.001), and MSI-high tumors(P < 0.001). After adjusting for relevant variables, including MSI status, KRAS mutations were associated with poorer DFS(HR = 1.35; 95%CI: 1.03-1.75) and OS(HR = 1.46; 95%CI: 1.09-1.97). BRAF mutations were poor prognostic factors for DFS(HR = 2.20; 95%CI: 1.19-4.06) and OS(HR = 2.30; 95%CI: 1.15-4.71). Neither the BRAF by MSI interaction test nor the KRAS by MSI interaction test yielded statistically significant results for DFS and OS.CONCLUSION: KRAS and BRAF mutations are associated with inferior survival, independent of MSI status, inJapanese patients with curatively resected CRC.
