Background:A central challenge in cancer research is to create models that bridge the gap between the molecular level on which interventions can be designed and the cellular and tissue levels on which the disease phen...Background:A central challenge in cancer research is to create models that bridge the gap between the molecular level on which interventions can be designed and the cellular and tissue levels on which the disease phenotypes are manifested.This study was undertaken to construct such a model from functional annotations and explore its use when integrated with large-scale cancer genomics data.Methods:We created a map that connects genes to cancer hallmarks via signaling pathways.We projected gene mutation and focal copy number data from various cancer types onto this map.We performed statistical analyses to uncover mutually exclusive and co-occurring oncogenic aberrations within this topology.Results:Our analysis showed that although the genetic fingerprint of tumor types could be very different,there were less variations at the level of hallmarks,consistent with the idea that different genetic alterations have similar functional outcomes.Additionally,we showed how the multilevel map could help to clarify the role of infrequently mutated genes,and we demonstrated that mutually exclusive gene mutations were more prevalent in pathways,whereas many co-occurring gene mutations were associated with hallmark characteristics.Conclusions:Overlaying this map with gene mutation and focal copy number data from various cancer types makes it possible to investigate the similarities and differences between tumor samples systematically at the levels of not only genes but also pathways and hallmarks.展开更多
Background: Familial cylindromatosis is a rare genetic disorder, giving rise to neoplasms of the skin appendages. We have recently shown that loss of the cylindromatosis tumour suppressor gene leads to activation of ...Background: Familial cylindromatosis is a rare genetic disorder, giving rise to neoplasms of the skin appendages. We have recently shown that loss of the cylindromatosis tumour suppressor gene leads to activation of NF-κ B, a transcription factor having antiapoptotic activity. This provides a possible explanation for the deregulated growth of cylindromas. In cell-based assays, salicylate can prevent NF-κ B activation caused by loss of the cylindromatosis gene, suggesting that salicylic acid application might be a potential treatment for cylindromatosis. Objectives: To assess the effectiveness of topical application of salicylic acid on familial cylindromas. Methods: Cylindromas in five patients from four different cylindromatosis families were treated with twice daily and then once daily topical salicylic acid. Clinical response was determined by serial tumour measurements. Results: In total 17 cylindromas in five patients were studied: 12 target lesions and five control lesions. The median size of the cylindromas was 1.0 cm (range, 0.6- 2.8 cm). Two of the 12 cylindromas showed a complete remission. Another eight lesions showed some response, but not sufficient to qualify as partial remission. The control lesions remained stable or increased in size. Conclusions: Salicylic acid is a well-tolerated and potential new treatment for cylindromatosis.展开更多
Identification of the driver mutations in cancer has resulted in the development of a new category of molecularly targeted anti-cancer drugs. However, as was the case with conventional chemotherapies, the effectivenes...Identification of the driver mutations in cancer has resulted in the development of a new category of molecularly targeted anti-cancer drugs. However, as was the case with conventional chemotherapies, the effectiveness of these drugs is limited by the emergence of drug-resistant variants. While most cancer therapies are given in combinations that are designed to avoid drug resistance, we discuss here therapeutic approaches that take advantage of the changes in cancer cells that arise upon development of drug resistance. This approach is based on notion that drug resistance comes at a fitness cost to the cancer cell that can be exploited for therapeutic benefit. We discuss the development of sequential drug therapies in which the first therapy is not given with curative intent, but to induce a major new sensitivity that can be targeted with a second drug that selectively targets the acquired vulnerability. This concept of collateral sensitivity has hitherto not been used on a large scale in the clinic and holds great promise for future cancer therapy.展开更多
Lung squamous cell carcinoma （LUSC） causes approximately 400 000 deaths each year worldwide. The occurrence of LUSC is attributed to exposure to cigarette smoke, which induces the development of numerous genomic abn...Lung squamous cell carcinoma （LUSC） causes approximately 400 000 deaths each year worldwide. The occurrence of LUSC is attributed to exposure to cigarette smoke, which induces the development of numerous genomic abnormalities. However, few studies have investigated the genomic variations that occur only in normal tissues that have been similarly exposed to tobacco smoke as tumor tissues. In this study, we sequenced the whole genomes of three normal lung tissue samples and their paired adjacent squamous cell carcinomas. We then called genomic variations specific to the normal lung tissues through filtering the genomic sequence of the normal lung tissues against that of the paired tumors, the reference human genome, the dbSNP138 common germline variants, and the variations derived from sequencing artifacts. To expand these observations, the whole exome sequences of 478 counterpart normal controls （CNCs） and paired LUSCs of The Cancer Genome Atlas （TCGA） dataset were analyzed. Sixteen genomic variations were called in the three normal lung tissues. These variations were confirmed by Sanger capillary sequencing. A mean of 0.5661 exonic variations/Mb and 7.7887 altered genes per sample were identified in the CNC genome sequences of TCGA. In these CNCs, C：G→T：A transitions, which are the genomic signatures of tobacco carcinogen N-methyl-N-nitro-N-nitrosoguanidine, were the predominant nucleotide changes. Twenty five genes in CNCs had a variation rate that exceeded 2%, including ARSD （18.62%）, MUC4 （8.79%）, and RBMX（7.11%）. CNC variations in CTAGE5 and USP17L7were associated with the poor prognosis of patients with LUSC. Our results uncovered previously unreported genomic variations in CNCs, rather than LUSCs, that may be involved in the develooment of LUSC.展开更多
Over the years, a chasm between biomedical researchers and the patients who may benefit from their discoveries has been opened. On one hand, millions of patients with diseas- es such as cancer are anxiously waiting fo...Over the years, a chasm between biomedical researchers and the patients who may benefit from their discoveries has been opened. On one hand, millions of patients with diseas- es such as cancer are anxiously waiting for new remedies to save their lives. On the other hand, many exciting basic science discoveries do not have opportunities to find practi- cal applications. Recently emerging translational medicine aims to tie basic research to clinical results and optimize both patient care and preventive measures.展开更多
基金supported in part by the National Cancer Institute (U24CA143835 to IS and TAK)the Netherlands Organization for Scientific Research-The Cancer System Biology Center(to LFAW and TB)
文摘Background:A central challenge in cancer research is to create models that bridge the gap between the molecular level on which interventions can be designed and the cellular and tissue levels on which the disease phenotypes are manifested.This study was undertaken to construct such a model from functional annotations and explore its use when integrated with large-scale cancer genomics data.Methods:We created a map that connects genes to cancer hallmarks via signaling pathways.We projected gene mutation and focal copy number data from various cancer types onto this map.We performed statistical analyses to uncover mutually exclusive and co-occurring oncogenic aberrations within this topology.Results:Our analysis showed that although the genetic fingerprint of tumor types could be very different,there were less variations at the level of hallmarks,consistent with the idea that different genetic alterations have similar functional outcomes.Additionally,we showed how the multilevel map could help to clarify the role of infrequently mutated genes,and we demonstrated that mutually exclusive gene mutations were more prevalent in pathways,whereas many co-occurring gene mutations were associated with hallmark characteristics.Conclusions:Overlaying this map with gene mutation and focal copy number data from various cancer types makes it possible to investigate the similarities and differences between tumor samples systematically at the levels of not only genes but also pathways and hallmarks.
文摘Background: Familial cylindromatosis is a rare genetic disorder, giving rise to neoplasms of the skin appendages. We have recently shown that loss of the cylindromatosis tumour suppressor gene leads to activation of NF-κ B, a transcription factor having antiapoptotic activity. This provides a possible explanation for the deregulated growth of cylindromas. In cell-based assays, salicylate can prevent NF-κ B activation caused by loss of the cylindromatosis gene, suggesting that salicylic acid application might be a potential treatment for cylindromatosis. Objectives: To assess the effectiveness of topical application of salicylic acid on familial cylindromas. Methods: Cylindromas in five patients from four different cylindromatosis families were treated with twice daily and then once daily topical salicylic acid. Clinical response was determined by serial tumour measurements. Results: In total 17 cylindromas in five patients were studied: 12 target lesions and five control lesions. The median size of the cylindromas was 1.0 cm (range, 0.6- 2.8 cm). Two of the 12 cylindromas showed a complete remission. Another eight lesions showed some response, but not sufficient to qualify as partial remission. The control lesions remained stable or increased in size. Conclusions: Salicylic acid is a well-tolerated and potential new treatment for cylindromatosis.
文摘Identification of the driver mutations in cancer has resulted in the development of a new category of molecularly targeted anti-cancer drugs. However, as was the case with conventional chemotherapies, the effectiveness of these drugs is limited by the emergence of drug-resistant variants. While most cancer therapies are given in combinations that are designed to avoid drug resistance, we discuss here therapeutic approaches that take advantage of the changes in cancer cells that arise upon development of drug resistance. This approach is based on notion that drug resistance comes at a fitness cost to the cancer cell that can be exploited for therapeutic benefit. We discuss the development of sequential drug therapies in which the first therapy is not given with curative intent, but to induce a major new sensitivity that can be targeted with a second drug that selectively targets the acquired vulnerability. This concept of collateral sensitivity has hitherto not been used on a large scale in the clinic and holds great promise for future cancer therapy.
基金This work was supported by the National Natural Science Funds of China for Distinguished Young Scholar （No. 81425025）, the National Key Research and Development Program of China （No. 2016YFC0905500）, the National Natural Science Foundation of China （No. 81672765）, the Strategic Priority Research Program of the Chinese Academy of Sciences （No. XDA 12010307）, and grants from the State Key Laboratory of Membrane Biology. The funders had no role in the design, data collection, and analysis of the study or in the preparation of and the decision to publish the manuscript. The results shown here are partly based on the data generated by The Cancer Genome Atlas, which is managed by the NCI and NHGRI. Information about TCGA can be found at http：//cancergenome.nih. gov. The dbGaP accession number is phs000178.v9.p8.
文摘Lung squamous cell carcinoma （LUSC） causes approximately 400 000 deaths each year worldwide. The occurrence of LUSC is attributed to exposure to cigarette smoke, which induces the development of numerous genomic abnormalities. However, few studies have investigated the genomic variations that occur only in normal tissues that have been similarly exposed to tobacco smoke as tumor tissues. In this study, we sequenced the whole genomes of three normal lung tissue samples and their paired adjacent squamous cell carcinomas. We then called genomic variations specific to the normal lung tissues through filtering the genomic sequence of the normal lung tissues against that of the paired tumors, the reference human genome, the dbSNP138 common germline variants, and the variations derived from sequencing artifacts. To expand these observations, the whole exome sequences of 478 counterpart normal controls （CNCs） and paired LUSCs of The Cancer Genome Atlas （TCGA） dataset were analyzed. Sixteen genomic variations were called in the three normal lung tissues. These variations were confirmed by Sanger capillary sequencing. A mean of 0.5661 exonic variations/Mb and 7.7887 altered genes per sample were identified in the CNC genome sequences of TCGA. In these CNCs, C：G→T：A transitions, which are the genomic signatures of tobacco carcinogen N-methyl-N-nitro-N-nitrosoguanidine, were the predominant nucleotide changes. Twenty five genes in CNCs had a variation rate that exceeded 2%, including ARSD （18.62%）, MUC4 （8.79%）, and RBMX（7.11%）. CNC variations in CTAGE5 and USP17L7were associated with the poor prognosis of patients with LUSC. Our results uncovered previously unreported genomic variations in CNCs, rather than LUSCs, that may be involved in the develooment of LUSC.
文摘Over the years, a chasm between biomedical researchers and the patients who may benefit from their discoveries has been opened. On one hand, millions of patients with diseas- es such as cancer are anxiously waiting for new remedies to save their lives. On the other hand, many exciting basic science discoveries do not have opportunities to find practi- cal applications. Recently emerging translational medicine aims to tie basic research to clinical results and optimize both patient care and preventive measures.
