Small cell lung cancer(SCLC)is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction models.Here,we analyzed formalin-fixed,paraffin-embedded(FFPE)samples of surgical re...Small cell lung cancer(SCLC)is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction models.Here,we analyzed formalin-fixed,paraffin-embedded(FFPE)samples of surgical resections by proteomic profiling,and stratified SCLC into three proteomic subtypes(S-I,S-II,and S-III)with distinct clinical outcomes and chemotherapy responses.The proteomic subtyping was an independent prognostic factor and performed better than current tumor–node–metastasis or Veterans Administration Lung Study Group staging methods.The subtyping results could be further validated using FFPE biopsy samples from an independent cohort,extending the analysis to both surgical and biopsy samples.The signatures of the S-II subtype in particular suggested potential benefits from immunotherapy.Differentially overexpressed proteins in S-III,the worst prognostic subtype,allowed us to nominate potential therapeutic targets,indicating that patient selection may bring new hope for previously failed clinical trials.Finally,analysis of an independent cohort of SCLC patients who had received immunotherapy validated the prediction that the S-II patients had better progression-free survival and overall survival after first-line immunotherapy.Collectively,our study provides the rationale for future clinical investigations to validate the current findings for more accurate prognosis prediction and precise treatments.展开更多
While precision medicine driven by genome sequencing has revolutionized cancer care,such as lung cancer,its impact on gastric cancer(GC)has been minimal.GC patients are routinely treated with chemotherapy,but only a f...While precision medicine driven by genome sequencing has revolutionized cancer care,such as lung cancer,its impact on gastric cancer(GC)has been minimal.GC patients are routinely treated with chemotherapy,but only a fraction of them receive the clinical benefit.There is an urgent need to develop biomarkers or algorithms to select chemo-sensitive patients or apply targeted therapy.Here,we carried out retrospective analyses of 1,020 formalin-fixed,paraffin-embedded GC surgical resection samples from 5 hospitals and developed a mass spectrometry-based workflow for proteomic subtyping of GC.We identified two proteomic subtypes:the chemo-sensitive group(CSG)and the chemo-insensitive group(CIG)in the discovery set.The 5-year overall survival of CSG was significantly improved in patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only(64.2%vs.49.6%;Cox P-value=0.002),whereas no such improvement was observed in CIG(50.0%vs.58.6%;Cox P-value=0.495).We validated these results in an independent validation set.Further,differential proteome analysis uncovered 9 FDA-approved drugs that may be applicable for targeted therapy of GC.A prospective study is warranted to test these findings for future GC patient care.展开更多
Accumulating evidence confirmed that many dysregulated signaling pathways and aberrant genetic alterations contribute to the oncogenesis and heterogeneity of lymphoid malignancies. Therapeutically targeting dysregulat...Accumulating evidence confirmed that many dysregulated signaling pathways and aberrant genetic alterations contribute to the oncogenesis and heterogeneity of lymphoid malignancies. Therapeutically targeting dysregulating signaling pathways and their hidden oncogenic biomarkers are becoming available, but did not show desired therapeutic effect in current clinical practice. It is meaningful to further understand the underlying mechanisms of the dysregulated signaling pathways and to address the potential utility of pathway-related biomarkers. To precisely identify the dysregulation of signaling pathways and the 'driver' oncogenic biomarkers, as well as to develop reliable and reproducible risk-stratification based on biomarkers will be challenging. Never-theless, pathway-based targeted therapy will raise the hope to improve the outcomes of the patients with lymphoid malignancies, especially with aggressive types, and the efficient utility of pathway-related biomarkers in diagnosis, prognosis, prediction of lymphoid malignancies may also be able to power precision medicine.展开更多
基金supported by the National Key R&D Program of China(Grant Nos.2018YFA0507503,2017YFA0505102,2017YFA0505103,and 2017YFA0505104)the National Natural Science Foundation of China(Grant Nos.82072597,62131009,31770892,31970725,31870828,81874237,and 81974016)+2 种基金the Beijing Municipal Natural Science Foundation(Grant No.7192199)the State Key Laboratory of Proteomics(Grant No.SKLP-K202002)the Kaifeng Science and Technology Development Plan Project(Grant No.1806005),China.
文摘Small cell lung cancer(SCLC)is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction models.Here,we analyzed formalin-fixed,paraffin-embedded(FFPE)samples of surgical resections by proteomic profiling,and stratified SCLC into three proteomic subtypes(S-I,S-II,and S-III)with distinct clinical outcomes and chemotherapy responses.The proteomic subtyping was an independent prognostic factor and performed better than current tumor–node–metastasis or Veterans Administration Lung Study Group staging methods.The subtyping results could be further validated using FFPE biopsy samples from an independent cohort,extending the analysis to both surgical and biopsy samples.The signatures of the S-II subtype in particular suggested potential benefits from immunotherapy.Differentially overexpressed proteins in S-III,the worst prognostic subtype,allowed us to nominate potential therapeutic targets,indicating that patient selection may bring new hope for previously failed clinical trials.Finally,analysis of an independent cohort of SCLC patients who had received immunotherapy validated the prediction that the S-II patients had better progression-free survival and overall survival after first-line immunotherapy.Collectively,our study provides the rationale for future clinical investigations to validate the current findings for more accurate prognosis prediction and precise treatments.
基金supported by the National Key Research and Development Program of China(2017YFC1308900,2017YFC0908404,2018YFA0507503,2017YFA0505103)Beijing Municipal Government Key Research and Development Program(Z181100001918020,Z161100002616036)+4 种基金the National Natural Science Foundation of China(31870828,81972790,81672319)the Guangdong Provincial Key R&D Programmes(2019B020229002)the Science and Technology Program of Guangzhou(201902020009)the National Key Basic Research Program of China(2014CBA02002)the National Key Technology Support Program(2015BAI13B07).
文摘While precision medicine driven by genome sequencing has revolutionized cancer care,such as lung cancer,its impact on gastric cancer(GC)has been minimal.GC patients are routinely treated with chemotherapy,but only a fraction of them receive the clinical benefit.There is an urgent need to develop biomarkers or algorithms to select chemo-sensitive patients or apply targeted therapy.Here,we carried out retrospective analyses of 1,020 formalin-fixed,paraffin-embedded GC surgical resection samples from 5 hospitals and developed a mass spectrometry-based workflow for proteomic subtyping of GC.We identified two proteomic subtypes:the chemo-sensitive group(CSG)and the chemo-insensitive group(CIG)in the discovery set.The 5-year overall survival of CSG was significantly improved in patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only(64.2%vs.49.6%;Cox P-value=0.002),whereas no such improvement was observed in CIG(50.0%vs.58.6%;Cox P-value=0.495).We validated these results in an independent validation set.Further,differential proteome analysis uncovered 9 FDA-approved drugs that may be applicable for targeted therapy of GC.A prospective study is warranted to test these findings for future GC patient care.
文摘Accumulating evidence confirmed that many dysregulated signaling pathways and aberrant genetic alterations contribute to the oncogenesis and heterogeneity of lymphoid malignancies. Therapeutically targeting dysregulating signaling pathways and their hidden oncogenic biomarkers are becoming available, but did not show desired therapeutic effect in current clinical practice. It is meaningful to further understand the underlying mechanisms of the dysregulated signaling pathways and to address the potential utility of pathway-related biomarkers. To precisely identify the dysregulation of signaling pathways and the 'driver' oncogenic biomarkers, as well as to develop reliable and reproducible risk-stratification based on biomarkers will be challenging. Never-theless, pathway-based targeted therapy will raise the hope to improve the outcomes of the patients with lymphoid malignancies, especially with aggressive types, and the efficient utility of pathway-related biomarkers in diagnosis, prognosis, prediction of lymphoid malignancies may also be able to power precision medicine.