Colorectal cancer(CRC) is one of the most prevalent malignancies in the world. CRC-associated morbidity and mortality is continuously increasing, in part due to a lack of early detection. The existing screening tools ...Colorectal cancer(CRC) is one of the most prevalent malignancies in the world. CRC-associated morbidity and mortality is continuously increasing, in part due to a lack of early detection. The existing screening tools such as colonoscopy, are invasive and yet high cost, affecting the willingness of patients to participate in screening programs. In recent years, evidence is accumulating that the interaction of aberrant genetic and epigenetic modifications is the cornerstone for the CRC development and progression by alternating the function of tumor suppressor genes, DNA repair genes and oncogenes of colonic cells. Apart from the understanding of the underlying mechanism(s) of carcinogenesis, the aforementioned interaction has also allowed identification of clinical biomarkers, especially epigenetic, for the early detection and prognosis of cancer patients. One of the ways to detect these epigenetic biomarkers is the cell-free circulating DNA(circ DNA), a blood-based cancer diagnostic test, mainly focusing in the molecular alterations found in tumor cells, such as DNA mutations and DNA methylation.In this brief review, we epitomize the current knowledge on the research in circ DNA biomarkers-mainly focusing on DNA methylation-as potential blood-based tests for early detection of colorectal cancer and the challenges for validation and globally implementation of this emergent technology.展开更多
Cancer treatment has entered the era of precision medicine, where knowledge of a patient's genetic profile is used to facilitate early diagnosis, drug selection, prognosis, prediction of drug responsiveness, the o...Cancer treatment has entered the era of precision medicine, where knowledge of a patient's genetic profile is used to facilitate early diagnosis, drug selection, prognosis, prediction of drug responsiveness, the onset of secondary resistance, and relapse. Circulating free DNA (cfDNA) has emerged as an ideal source of genetic information for cancer patients, and numerous studies have explored its validity in various clinical applications. However, clinical implementation of cfDNA-based tests has been slow. In this review, we addressed some of the pre-and post-analytical issues regarding cfDNA tests. First, we summarized the charac-teristics of cfDNA and reviewed the methods used to identify tumor-derived cfDNA from the pool of total cfDNA. Second, we described the procedures used to extract cfDNA, which have a great impact on representativeness and yield. Finally, we discussed our thoughts on the validation of cfDNA-based tests and the reporting of test results amid drastic limitations.展开更多
The histo-pathologic and molecular mechanisms leading to initiation and progression of hepatocellular carcinoma (HCC) are still ill-defined; however, there is increasing evidence that the gradual accumulation of mutat...The histo-pathologic and molecular mechanisms leading to initiation and progression of hepatocellular carcinoma (HCC) are still ill-defined; however, there is increasing evidence that the gradual accumulation of mutations, genetic and epigenetic changes which occur in preneoplastic hepatocytes results in the development of dysplastic foci, nodules, and finally, overt HCC. As well as many other neoplasias, liver cancer is considered an “inflammatory cancer”, arising from a context of inflammation, and characterized by inflammation-related mechanisms that favor tumor cell survival, proliferation, and invasion. Molecular mechanisms that link inflammation and neoplasia have been widely investigated, and it has been well established that inflammatory cells recruited at these sites with ongoing inflammatory activity release chemokines that enhance the production of reactive oxygen species. The latter, in turn, probably have a major pathogenic role in the continuum starting from hepatitis followed by chronic inflammation, and ultimately leading to cancer. The relationship amongst chronic liver injury, free radical production, and development of HCC is explored in the present review, particularly in the light of the complex network that involves oxidative DNA damage, cytokine synthesis, telomere dysfunction, and microRNA regulation.展开更多
Currently the clinical management of breast cancer relies on relatively few prognostic/predictive clinical markers(estrogen receptor, progesterone receptor, HER2), based on primary tumor biology. Circulating biomarker...Currently the clinical management of breast cancer relies on relatively few prognostic/predictive clinical markers(estrogen receptor, progesterone receptor, HER2), based on primary tumor biology. Circulating biomarkers, such as circulating tumor DNA(ctDNA) or circulating tumor cells(CTCs) may enhance our treatment options by focusing on the very cells that are the direct precursors of distant metastatic disease, and probably inherently different than the primary tumor's biology. To shift the current clinical paradigm, assessing tumor biology in real time by molecularly profiling CTCs or ctDNA may serve to discover therapeutic targets, detect minimal residual disease and predict response to treatment. This review serves to elucidate the detection,characterization, and clinical application of CTCs and ctDNA with the goal of precision treatment of breast cancer.展开更多
Although circulating cell-free DNA(cfDNA)methylation has emerged as the mainstream approach in multi-cancer detection blood tests(MCDBTs),the potential of integrating proteins and mutations,to enhance its performance ...Although circulating cell-free DNA(cfDNA)methylation has emerged as the mainstream approach in multi-cancer detection blood tests(MCDBTs),the potential of integrating proteins and mutations,to enhance its performance remains unclear.The PROMISE study(NCT04972201)was conducted to investigate the feasibility of a multi-omics integration strategy in MCDBTs across nine types of cancers in head and neck(excluding nasopharynx),esophagus,lung,stomach,liver,biliary tract,pancreas,colorectum,and ovary.Blood samples were pro-spectively collected from 1,706 participants(840 non-cancer;866 can-cer)and then randomly divided into training and validation sets.The complementarity between various omics were investigated,and specific omics features were carefully selected for further multimodal model construction.The methylation-based classifier outperformed both the mutation-based and protein-based classifiers.As 95.0%of cancer cases detected by the mutation-based classifier were simultaneously identified by the methylation-based classifier,while 14.0%of the protein-positive samples were missed,protein markers may provide complementary value to the methylation-based classifier.Compared with the methyl-ation-based classifier,the multimodal classifier combining methylation and protein features exhibited an improved sensitivity of 75.1%(95%confidence interval[CI],69.3%-80.3%)at the same specificity of 98.8%with the accuracy of top predicted origin(TPO1)of 73.1%(95%CI,66.2%-79.2%).Notably,the TPO1 accuracy reached 100%in liver and ovarian cancers with negative results of the methylation-based classi-fier.Collectively,these data suggest that the integration of protein markers in the multimodal classifier can offer additional benefits to the methylation-based classifier,particularly in identifying liver and ovarian cancers.展开更多
文摘Colorectal cancer(CRC) is one of the most prevalent malignancies in the world. CRC-associated morbidity and mortality is continuously increasing, in part due to a lack of early detection. The existing screening tools such as colonoscopy, are invasive and yet high cost, affecting the willingness of patients to participate in screening programs. In recent years, evidence is accumulating that the interaction of aberrant genetic and epigenetic modifications is the cornerstone for the CRC development and progression by alternating the function of tumor suppressor genes, DNA repair genes and oncogenes of colonic cells. Apart from the understanding of the underlying mechanism(s) of carcinogenesis, the aforementioned interaction has also allowed identification of clinical biomarkers, especially epigenetic, for the early detection and prognosis of cancer patients. One of the ways to detect these epigenetic biomarkers is the cell-free circulating DNA(circ DNA), a blood-based cancer diagnostic test, mainly focusing in the molecular alterations found in tumor cells, such as DNA mutations and DNA methylation.In this brief review, we epitomize the current knowledge on the research in circ DNA biomarkers-mainly focusing on DNA methylation-as potential blood-based tests for early detection of colorectal cancer and the challenges for validation and globally implementation of this emergent technology.
文摘Cancer treatment has entered the era of precision medicine, where knowledge of a patient's genetic profile is used to facilitate early diagnosis, drug selection, prognosis, prediction of drug responsiveness, the onset of secondary resistance, and relapse. Circulating free DNA (cfDNA) has emerged as an ideal source of genetic information for cancer patients, and numerous studies have explored its validity in various clinical applications. However, clinical implementation of cfDNA-based tests has been slow. In this review, we addressed some of the pre-and post-analytical issues regarding cfDNA tests. First, we summarized the charac-teristics of cfDNA and reviewed the methods used to identify tumor-derived cfDNA from the pool of total cfDNA. Second, we described the procedures used to extract cfDNA, which have a great impact on representativeness and yield. Finally, we discussed our thoughts on the validation of cfDNA-based tests and the reporting of test results amid drastic limitations.
文摘The histo-pathologic and molecular mechanisms leading to initiation and progression of hepatocellular carcinoma (HCC) are still ill-defined; however, there is increasing evidence that the gradual accumulation of mutations, genetic and epigenetic changes which occur in preneoplastic hepatocytes results in the development of dysplastic foci, nodules, and finally, overt HCC. As well as many other neoplasias, liver cancer is considered an “inflammatory cancer”, arising from a context of inflammation, and characterized by inflammation-related mechanisms that favor tumor cell survival, proliferation, and invasion. Molecular mechanisms that link inflammation and neoplasia have been widely investigated, and it has been well established that inflammatory cells recruited at these sites with ongoing inflammatory activity release chemokines that enhance the production of reactive oxygen species. The latter, in turn, probably have a major pathogenic role in the continuum starting from hepatitis followed by chronic inflammation, and ultimately leading to cancer. The relationship amongst chronic liver injury, free radical production, and development of HCC is explored in the present review, particularly in the light of the complex network that involves oxidative DNA damage, cytokine synthesis, telomere dysfunction, and microRNA regulation.
文摘Currently the clinical management of breast cancer relies on relatively few prognostic/predictive clinical markers(estrogen receptor, progesterone receptor, HER2), based on primary tumor biology. Circulating biomarkers, such as circulating tumor DNA(ctDNA) or circulating tumor cells(CTCs) may enhance our treatment options by focusing on the very cells that are the direct precursors of distant metastatic disease, and probably inherently different than the primary tumor's biology. To shift the current clinical paradigm, assessing tumor biology in real time by molecularly profiling CTCs or ctDNA may serve to discover therapeutic targets, detect minimal residual disease and predict response to treatment. This review serves to elucidate the detection,characterization, and clinical application of CTCs and ctDNA with the goal of precision treatment of breast cancer.
基金supported by the Science and Education Cultivation Fund of the National Cancer and Regional Medical Center of Shanxi Provincial Cancer Hospital(TD2023002)CAMS Innovation Fund for Medical Sciences(2024-I2M-ZD-004,to Z.W.)+5 种基金Noncommunicable Chronic Diseases-National Science and Technology Major Project(2024ZD0519700,to J.W.)Beijing Natural Science Foundation(7242114 to Jiachen Xu)National Natural Science Foundation of China of China(82102886 to Jiachen Xu)Beijing Nova Program(20220484119 to Jiachen Xu)Medical Oncology Key Foundation of Cancer Hospital Chinese Academy of Medical Sciences(CICAMS-MOCP2022003,CICAMS-MOY&M202405 to Jiachen Xu)Key Research Program of Department of Science and Technology of Heilongjiang Province(2022ZXJ03C0).
文摘Although circulating cell-free DNA(cfDNA)methylation has emerged as the mainstream approach in multi-cancer detection blood tests(MCDBTs),the potential of integrating proteins and mutations,to enhance its performance remains unclear.The PROMISE study(NCT04972201)was conducted to investigate the feasibility of a multi-omics integration strategy in MCDBTs across nine types of cancers in head and neck(excluding nasopharynx),esophagus,lung,stomach,liver,biliary tract,pancreas,colorectum,and ovary.Blood samples were pro-spectively collected from 1,706 participants(840 non-cancer;866 can-cer)and then randomly divided into training and validation sets.The complementarity between various omics were investigated,and specific omics features were carefully selected for further multimodal model construction.The methylation-based classifier outperformed both the mutation-based and protein-based classifiers.As 95.0%of cancer cases detected by the mutation-based classifier were simultaneously identified by the methylation-based classifier,while 14.0%of the protein-positive samples were missed,protein markers may provide complementary value to the methylation-based classifier.Compared with the methyl-ation-based classifier,the multimodal classifier combining methylation and protein features exhibited an improved sensitivity of 75.1%(95%confidence interval[CI],69.3%-80.3%)at the same specificity of 98.8%with the accuracy of top predicted origin(TPO1)of 73.1%(95%CI,66.2%-79.2%).Notably,the TPO1 accuracy reached 100%in liver and ovarian cancers with negative results of the methylation-based classi-fier.Collectively,these data suggest that the integration of protein markers in the multimodal classifier can offer additional benefits to the methylation-based classifier,particularly in identifying liver and ovarian cancers.
