Background: Breast cancer patients who are positive for hormone receptor typically exhibit a favorable prognosis. It is controversial whether chemotherapy is necessary for them after surgery. Our study aimed to establ...Background: Breast cancer patients who are positive for hormone receptor typically exhibit a favorable prognosis. It is controversial whether chemotherapy is necessary for them after surgery. Our study aimed to establish a multigene model to predict the relapse of hormone receptor-positive early-stage Chinese breast cancer after surgery and direct individualized application of chemotherapy in breast cancer patients after surgery. Methods: In this study, differentially expressed genes (DEGs) were identified between relapse and nonrelapse breast cancer groups based on RNA sequencing. Gene set enrichment analysis (GSEA) was performed to identify potential relapse-relevant pathways. CIBERSORT and Microenvironment Cell Populations-counter algorithms were used to analyze immune infiltration. The least absolute shrinkage and selection operator (LASSO) regression, log-rank tests, and multiple Cox regression were performed to identify prognostic signatures. A predictive model was developed and validated based on Kaplan-Meier analysis, receiver operating characteristic curve (ROC). Results: A total of 234 out of 487 patients were enrolled in this study, and 1588 DEGs were identified between the relapse and nonrelapse groups. GSEA results showed that immune-related pathways were enriched in the nonrelapse group, whereas cell cycle- and metabolism-relevant pathways were enriched in the relapse group. A predictive model was developed using three genes ( CKMT1B , SMR3B , and OR11M1P ) generated from the LASSO regression. The model stratified breast cancer patients into high- and low-risk subgroups with significantly different prognostic statuses, and our model was independent of other clinical factors. Time-dependent ROC showed high predictive performance of the model. Conclusions: A multigene model was established from RNA-sequencing data to direct risk classification and predict relapse of hormone receptor-positive breast cancer in Chinese patients. Utilization of the model could provide individualized evaluation of chemotherapy after surgery for breast cancer patients.展开更多
Breast cancer is one of the most common malignant tumors in women all over the world.Metastasis represents a major adverse progression of breast cancer,resulting in poor survival duration.Axillary lymph node metastasi...Breast cancer is one of the most common malignant tumors in women all over the world.Metastasis represents a major adverse progression of breast cancer,resulting in poor survival duration.Axillary lymph node metastasis is often the first step of systemic metastasis process of breast cancer.However,themechanismof lymph node metastasis and the genomic signatures of primary breast tumors and lymph node metastasis are still under exploration.Whole exome sequencing was applied to primary breast cancer,axillary metastatic lymph nodes,andwhite blood cells from10Chinesewomen patients in our study.Single nucleotide variants(SNVs)and copynumber variants(CNVs)were compared between primary tumors and lymph nodes for individual patients.There are somatic SNVs(average 5.58±2.56 per megabase)in primary breast cancers and somatic SNVs(average 5.46±2.66 per megabase)in axillary metastatic lymph nodes were identified,which is corresponding to a semblable mutation burden in two malignant sites(P=0.81).No difference was found in CNVs(P=0.33).In primary breast cancer,somatic SNVs(48.12±13.80%)and CNVs(61.72±35.00%)were overlapping with somatic SNVs(49.43±12.30%)and CNVs(72.01±24.31%)in axillary metastatic lymph nodes.Nine genes were screened for significant specificmutations in primary tumors,and 15 genes were significantly mutated in metastatic lymph nodes.Using MutSigCV screening,it was found that HRNR and AHNAK2 are lymph node metastasis-specific genes.In our study,primary breast tumors are directly related to axillary lymph node metastases together and there are most SNVs and CNVs which were overlapping in primary andmetastatic sites.These variants which are overlapping is closely related to themetastatic process of tumor invasion with early genetic variability.This is the first timeto prove the concept of polyclonalmetastaticmodel and in thismodelmore than one clonemigrates establish the metastases to axillary lymph nodes.This study was approved by the institutional review board(IRB)of the Cancer Hospital,Chinese Academy of Medical Sciences,and Peking Union Medical College,China(approval No.NCC2016G-030)on March 3,2016.展开更多
Prolonged activation of nuclear factor(NF)-кB signaling significantly contributes to the development of colorectal cancer(CRC).New therapeutic opportunities are emerging from targeting this distorted cell signaling t...Prolonged activation of nuclear factor(NF)-кB signaling significantly contributes to the development of colorectal cancer(CRC).New therapeutic opportunities are emerging from targeting this distorted cell signaling transduction.Here,we discovered the critical role of RING finger 138(RNF138)in CRC tumorigenesis through regulating the NF-кB signaling,which is independent of its Ubiquitin-E3 ligase activity involved in DNA damage response.RNF138^(−/−) mice were hyper-susceptible to the switch from colitis to aggressive malignancy,which coincided with sustained aberrant NF-кB signaling in the colonic cells.Furthermore,RNF138 suppresses the activation of NF-кB signaling pathway through preventing the translocation of NIK and IKK-Beta Binding Protein(NIBP)to the cytoplasm,which requires the ubiquitin interaction motif(UIM)domain.More importantly,we uncovered a significant correlation between poor prognosis and the downregulation of RNF138 associated with reinforced NF-кB signaling in clinical settings,raising the possibility of RNF138 dysregulation as an indicator for the therapeutic intervention targeting NF-кB signaling.Using the xenograft models built upon either RNF138-dificient CRC cells or the cells derived from the RNF138-dysregulated CRC patients,we demonstrated that the inhibition of NF-кB signaling effectively hampered tumor growth.Overall,our work defined the pathogenic role of aberrant NF-кB signaling due to RNF138 downregulation in the cascade events from the colitis switch to colonic neoplastic transformation and progression,and also highlights the possibility of targeting the NF-кB signaling in treating specific subtypes of CRC indicated by RNF138-ablation.展开更多
基金supported by the National Key Research and Development Program of China(2019YFE0110000)National Natural Science Foundation of China(82072097)+1 种基金CAMS Innovation Fund for Medical Science(CIFMS)(2020-I2M-C&T-B-069,2021-I2M-1-014)and Beijing Hope Run Special Fund of Cancer Foundation of China(LC2020A18).
文摘Background: Breast cancer patients who are positive for hormone receptor typically exhibit a favorable prognosis. It is controversial whether chemotherapy is necessary for them after surgery. Our study aimed to establish a multigene model to predict the relapse of hormone receptor-positive early-stage Chinese breast cancer after surgery and direct individualized application of chemotherapy in breast cancer patients after surgery. Methods: In this study, differentially expressed genes (DEGs) were identified between relapse and nonrelapse breast cancer groups based on RNA sequencing. Gene set enrichment analysis (GSEA) was performed to identify potential relapse-relevant pathways. CIBERSORT and Microenvironment Cell Populations-counter algorithms were used to analyze immune infiltration. The least absolute shrinkage and selection operator (LASSO) regression, log-rank tests, and multiple Cox regression were performed to identify prognostic signatures. A predictive model was developed and validated based on Kaplan-Meier analysis, receiver operating characteristic curve (ROC). Results: A total of 234 out of 487 patients were enrolled in this study, and 1588 DEGs were identified between the relapse and nonrelapse groups. GSEA results showed that immune-related pathways were enriched in the nonrelapse group, whereas cell cycle- and metabolism-relevant pathways were enriched in the relapse group. A predictive model was developed using three genes ( CKMT1B , SMR3B , and OR11M1P ) generated from the LASSO regression. The model stratified breast cancer patients into high- and low-risk subgroups with significantly different prognostic statuses, and our model was independent of other clinical factors. Time-dependent ROC showed high predictive performance of the model. Conclusions: A multigene model was established from RNA-sequencing data to direct risk classification and predict relapse of hormone receptor-positive breast cancer in Chinese patients. Utilization of the model could provide individualized evaluation of chemotherapy after surgery for breast cancer patients.
基金This research was funded in part by the National Natural Science Foundation of China(81602343 to Xin Wang)the Chinese Academy of Medical Sciences(CAMS)initiative Fund for Medical Sciences,China(2016-I2M-1-001 to Xiang Wang,2017-I2M-3-004 to Xin Wang)+3 种基金the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences,China(2018PT32013,2017PT32001 and 2016ZX310178 to Xin Wang)the Beijing Hope Run Special Fund,China(LC2017B15 to Xin Wang)the Capital’s Funds for Health Improvement and Research,China(2016-4-4026 to Xin Wang)Youth Research Fund of Beijing Tiantan Hospital,China(2017-YQN-09 to Wenyan Wang).
文摘Breast cancer is one of the most common malignant tumors in women all over the world.Metastasis represents a major adverse progression of breast cancer,resulting in poor survival duration.Axillary lymph node metastasis is often the first step of systemic metastasis process of breast cancer.However,themechanismof lymph node metastasis and the genomic signatures of primary breast tumors and lymph node metastasis are still under exploration.Whole exome sequencing was applied to primary breast cancer,axillary metastatic lymph nodes,andwhite blood cells from10Chinesewomen patients in our study.Single nucleotide variants(SNVs)and copynumber variants(CNVs)were compared between primary tumors and lymph nodes for individual patients.There are somatic SNVs(average 5.58±2.56 per megabase)in primary breast cancers and somatic SNVs(average 5.46±2.66 per megabase)in axillary metastatic lymph nodes were identified,which is corresponding to a semblable mutation burden in two malignant sites(P=0.81).No difference was found in CNVs(P=0.33).In primary breast cancer,somatic SNVs(48.12±13.80%)and CNVs(61.72±35.00%)were overlapping with somatic SNVs(49.43±12.30%)and CNVs(72.01±24.31%)in axillary metastatic lymph nodes.Nine genes were screened for significant specificmutations in primary tumors,and 15 genes were significantly mutated in metastatic lymph nodes.Using MutSigCV screening,it was found that HRNR and AHNAK2 are lymph node metastasis-specific genes.In our study,primary breast tumors are directly related to axillary lymph node metastases together and there are most SNVs and CNVs which were overlapping in primary andmetastatic sites.These variants which are overlapping is closely related to themetastatic process of tumor invasion with early genetic variability.This is the first timeto prove the concept of polyclonalmetastaticmodel and in thismodelmore than one clonemigrates establish the metastases to axillary lymph nodes.This study was approved by the institutional review board(IRB)of the Cancer Hospital,Chinese Academy of Medical Sciences,and Peking Union Medical College,China(approval No.NCC2016G-030)on March 3,2016.
基金supported by CAMS Innovation Fund for Medical Sciences(CIFMS,2021-I2M-1-066,2017-I2M-4-002 to H.Z.,2021-I2M-1-019 to W.S.,2021-1-I2M-014 to C.Z.L.)the National Natural Science Foundation of China(81972311,82141127 and 81672461 to H.Z.,81672472,and 31970794 to W.S.,81570780 to C.Z.L.,32000586 to K.L.)+4 种基金the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences(2019PT310026 to H.Z.)Sanming Project of Medicine in Shenzhen(SZSM202011010 to H.Z.)the National Key Research and Development Program of China(2018YFC1003500 to W.S.)the State Key Laboratory Special fund from the Ministry of Science(2060204 to W.S.)the State Key Project on Infection Diseases of China(2017ZX10201021-007-003 to H.Z.).
文摘Prolonged activation of nuclear factor(NF)-кB signaling significantly contributes to the development of colorectal cancer(CRC).New therapeutic opportunities are emerging from targeting this distorted cell signaling transduction.Here,we discovered the critical role of RING finger 138(RNF138)in CRC tumorigenesis through regulating the NF-кB signaling,which is independent of its Ubiquitin-E3 ligase activity involved in DNA damage response.RNF138^(−/−) mice were hyper-susceptible to the switch from colitis to aggressive malignancy,which coincided with sustained aberrant NF-кB signaling in the colonic cells.Furthermore,RNF138 suppresses the activation of NF-кB signaling pathway through preventing the translocation of NIK and IKK-Beta Binding Protein(NIBP)to the cytoplasm,which requires the ubiquitin interaction motif(UIM)domain.More importantly,we uncovered a significant correlation between poor prognosis and the downregulation of RNF138 associated with reinforced NF-кB signaling in clinical settings,raising the possibility of RNF138 dysregulation as an indicator for the therapeutic intervention targeting NF-кB signaling.Using the xenograft models built upon either RNF138-dificient CRC cells or the cells derived from the RNF138-dysregulated CRC patients,we demonstrated that the inhibition of NF-кB signaling effectively hampered tumor growth.Overall,our work defined the pathogenic role of aberrant NF-кB signaling due to RNF138 downregulation in the cascade events from the colitis switch to colonic neoplastic transformation and progression,and also highlights the possibility of targeting the NF-кB signaling in treating specific subtypes of CRC indicated by RNF138-ablation.