乳腺癌特征性血清多肽组图谱研究
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摘要
血清多肽组谱图(简称血肽图)是指通过质谱技术分析获得的血清中多肽(蛋白质)组的精确质量数的谱图。谱图中以精确质量数标识的多肽(蛋白质)峰，必要时可进一步通过生物质谱分析蛋白质序列，得到疾病标志物。乳腺癌一直是威胁妇女健康的主要癌瘤，占女性恶性肿瘤的1／3。其发病率在全世界范围内仍在上升，而且在我国的发病率己高于发达国家。早期发现可明显提高病人的生存时间，降低病人的死亡率，因此早期诊断显得十分重要，对患者的愈后与生存意义重大。本论文研究开发的金属磁珠体系，可稳定有效地富集血清样品中的多肽组，并利用该磁珠体系和质谱技术检测乳腺癌的血清多肽图，通过专用生物信息学软件分析其特征性标志峰，在此基础上提出多肽图诊断乳腺癌的数据标准，为乳腺癌的早期诊断提供依据。
Breast cancer is the most frequent malignancy among women representing a major health problem in many countries. Despite the major advances in basic research, breast cancer continues to be a leading cause of death. Early detection is a major factor contributing to the 3.2% annual decline in breast cancer death rates over the past 5 years. Unfortunately, currently available breast cancer screening tools such as mammography and breast examination miss up to 40% of early breast cancers and are least effective in detecting cancer in young women, whose tumors are often more aggressive. It has thus been suggested that early cancer diagnosis is probably the most promising way to achieve clinically therapeutic success.
The emergence of mass spectrometry (MS)-based serum peptide spectrum has generated considerable enthusiasm among oncologists as a novel method of tumor diagnosis. MS now permit the display of hundreds of small- to medium-sized peptides with only microliters of serum. Several recent reports have advocated employing the MS approach to determine specific patterns that are indicative ovarian, pancreatic, prostate, bladder, colon, melanoma and breast cancer.In the study of the paper on Lancet in 2002, Petricoin et al apply the serum peptides pattern to diagnose ovary cancer on a early stage successfully by USA FDA/NIH protein plan subsidy. They analyse the peptides pattern of healthy control and the disease group to diagnose ovary cancer. The results revealed that all 50 ovary cancer patients were correctly classified including 18 stage I, 63 of 66 benign ovary tumour patients were correctly classified. The result yielded 100% sensitivity and 95% specificity. The positive predictive value for this sample set was 94%, distinctly better than the detection for traditional CA125 for the same samples. Afterwards, the majority of these studies have used serum peptide pattern to diagnose disease. For instance, Soltys et al of USA Stanford University in 2004 having announced on Cancer Research by the study that the serum peptides technology to be carried out for a diagnose on squamous epithelium cancer. Kazufumi Honda et al of Japan country cancer centre have announced on Cancer Research by making use of low resolution TOF-MS and high resolution Q-TOF-MS to diagnose pancreas cancer in 2005. Villanueva pathological study of the United States early in 2006 at the Sloan-Kettering published by serum peptides technique of bladder cancer, breast and prostate cancer were diagnosed. Nature magazine published by the end of 2006 to comment on the article, article on the development and application of this technology takes a positive attitude. Recently, Lancet magazine also published an article by serum peptide technique for the diagnosis of tuberculosis and was more than 95% sensitivity and specificity of the results. Petricoin et al published on nature magazines that the serum peptide mapping technology to the discovery of tumor markers in the comments. the author says that the serum of the low molecular weight peptides associated with cancer of the group includes a lot of information. The study of serum peptide profiling than traditional biological markers in the diagnosis method has higher sensitivity and specificity. The majority of these studies have been applied to the low resolution of technology. Recently, there have been reports of the application of high-resolution MALDI-TOF-MS research papers published. The more sophisticated forms of the instrument, such as the Fourier Transfer (FT) MS/MS, allow the identification of peptide sequences. These research results obtained, the sample preparation is the key. More recently, affinity bead-based purification was developed and adopted by some investigators. Metal affinity chromatography with a suitable buffer in the mass spectrometry analysis of body fluids as much as possible from the information obtained peptides and proteins. It is overcoming the existing proteomics in the diagnosis of clinical problems encountered in the sample preparation for the use of magnetic bead separation and mass spectrometry analysis directly. Since spherical beads have larger combined surface areas and a higher binding capacity than small-diameter spots. The elution serum biomarkers from the beads could be analysed by MALDI-TOF-MS directly, further in-depth study could be done, such as the series of biomarkers do Electrospray Tandem Mass Spectrometry analysis. Biomarkers and protein chip can be cleared down to further studies are very limited.
This new approach has received some criticisms, since independent studies have failed to find the same patterns, and no pattern has yet been validated in an independent laboratory. To overcome these problems, potential sources of systematic bias will have to be carefully considered and avoided. Age and gender are sources of bias that may affect the patterns being evaluated for diagnostic and prognostic purposes. Serum peptide profiles are affected by variations in gene expression and post-transcriptional events. Recently, Tempst reported the serum peptidomes of 200 healthy men and women, over 40 years of age, had no significant age and gender-related serum pattern variation. Since the breast and rectal cancer patients and controls in our study were predominantly 40 years or older, age and gender are unlikely to bias the cancer serum profile patterns. Our results suggested that age and gender-related variations should be considered when studies involve cancer patients younger than 30 years old.
Other sources of bias and variation include blood collection tubes, clotting times and temperature, the number of freeze-thaw cycles, batch to-batch variation of the magnetic beads, MALDI sample crystallization, laser irradiation, MS detection, and data analysis methods. These sources have been studied previously and were all addressed in our study. Quality control was performed to ensure consistent peptide extraction and MS detection conditions. The high sensitivity and reproducibility of the magnetic-bead-based platform for serum profiling, described recently by Villanueva et al., were also achieved in our study where the beads prepared in our lab showed negligible differences between batches.
Identitifying peptides in disease patterns can potentially lead to insights concerning their sources and relationships to the underlying pathology. Although advances in MS now make it possible to identify small- to medium-sized peptides in serum using only microliters of samples, there remains a significant bottleneck in the technology for its application in clinical proteomics. Direct MS/MS identification of peptides using MALDI TOF/TOF is not yet possible due to the presence of multiple peptides and the complexity of the tryptic-digested serum samples. Although off line nanoLC-MALDI could solve this problem, we think that the best method to identify peptides in complex mixtures is FT-MS where the exact mass of the peptide of interest is obtained. By using FT-MS and enrichment strategies in our experiments to identify the low-molecular-weight region of the proteome, we identified 14 peptides. Some of them were reported in breast cancer or other solid tumors. In this issue, we first used in the research and development of a body fluids (blood, urine, gastric) from the MS exclusive representative of protein and peptide nano beads and metal chelate system.
We provide evidence here that MALDI-TOF MS-based serum peptide profiling is sufficiently robust to reflect not only cancer-specific but also cancer type-specific information. In this study, we discovered a serum peptide pattern that could distinguish breast cancer from non-cancer controls with准确88.9% sensitivity and 83.3% specificity. Furthermore, we identified 14 sequence signature peptides by FT-MS/MS. This finding indicates that serum peptide profiling reflects the pathological state of breast cancer. These ions were fractionated using a novel magnetic-bead-based platform with high sensitivity and reproducibility. To our knowledge, this is the first report of that has used serum patterns as a potential tool to identify breast cancer. These studies are also the innovative points of the paper.
Breast cancer is the most frequent malignancy among women representing a major health problem in many countries. Despite the major advances in basic research, breast cancer continues to be a leading cause of death. Early detection is a major factor contributing to the 3.2% annual decline in breast cancer death rates over the past 5 years. Unfortunately, currently available breast cancer screening tools such as mammography and breast examination miss up to 40% of early breast cancers and are least effective in detecting cancer in young women, whose tumors are often more aggressive. It has thus been suggested that early cancer diagnosis is probably the most promising way to achieve clinically therapeutic success.
The emergence of mass spectrometry (MS)-based serum peptide spectrum has generated considerable enthusiasm among oncologists as a novel method of tumor diagnosis. MS now permit the display of hundreds of small- to medium-sized peptides with only microliters of serum. Several recent reports have advocated employing the MS approach to determine specific patterns that are indicative ovarian, pancreatic, prostate, bladder, colon, melanoma and breast cancer.In the study of the paper on Lancet in 2002, Petricoin et al apply the serum peptides pattern to diagnose ovary cancer on a early stage successfully by USA FDA/NIH protein plan subsidy. They analyse the peptides pattern of healthy control and the disease group to diagnose ovary cancer. The results revealed that all 50 ovary cancer patients were correctly classified including 18 stage I, 63 of 66 benign ovary tumour patients were correctly classified. The result yielded 100% sensitivity and 95% specificity. The positive predictive value for this sample set was 94%, distinctly better than the detection for traditional CA125 for the same samples. Afterwards, the majority of these studies have used serum peptide pattern to diagnose disease. For instance, Soltys et al of USA Stanford University in 2004 having announced on Cancer Research by the study that the serum peptides technology to be carried out for a diagnose on squamous epithelium cancer. Kazufumi Honda et al of Japan country cancer centre have announced on Cancer Research by making use of low resolution TOF-MS and high resolution Q-TOF-MS to diagnose pancreas cancer in 2005. Villanueva pathological study of the United States early in 2006 at the Sloan-Kettering published by serum peptides technique of bladder cancer, breast and prostate cancer were diagnosed. Nature magazine published by the end of 2006 to comment on the article, article on the development and application of this technology takes a positive attitude. Recently, Lancet magazine also published an article by serum peptide technique for the diagnosis of tuberculosis and was more than 95% sensitivity and specificity of the results. Petricoin et al published on nature magazines that the serum peptide mapping technology to the discovery of tumor markers in the comments. the author says that the serum of the low molecular weight peptides associated with cancer of the group includes a lot of information. The study of serum peptide profiling than traditional biological markers in the diagnosis method has higher sensitivity and specificity. The majority of these studies have been applied to the low resolution of technology. Recently, there have been reports of the application of high-resolution MALDI-TOF-MS research papers published. The more sophisticated forms of the instrument, such as the Fourier Transfer (FT) MS/MS, allow the identification of peptide sequences. These research results obtained, the sample preparation is the key. More recently, affinity bead-based purification was developed and adopted by some investigators. Metal affinity chromatography with a suitable buffer in the mass spectrometry analysis of body fluids as much as possible from the information obtained peptides and proteins. It is overcoming the existing proteomics in the diagnosis of clinical problems encountered in the sample preparation for the use of magnetic bead separation and mass spectrometry analysis directly. Since spherical beads have larger combined surface areas and a higher binding capacity than small-diameter spots. The elution serum biomarkers from the beads could be analysed by MALDI-TOF-MS directly, further in-depth study could be done, such as the series of biomarkers do Electrospray Tandem Mass Spectrometry analysis. Biomarkers and protein chip can be cleared down to further studies are very limited.
This new approach has received some criticisms, since independent studies have failed to find the same patterns, and no pattern has yet been validated in an independent laboratory. To overcome these problems, potential sources of systematic bias will have to be carefully considered and avoided. Age and gender are sources of bias that may affect the patterns being evaluated for diagnostic and prognostic purposes. Serum peptide profiles are affected by variations in gene expression and post-transcriptional events. Recently, Tempst reported the serum peptidomes of 200 healthy men and women, over 40 years of age, had no significant age and gender-related serum pattern variation. Since the breast and rectal cancer patients and controls in our study were predominantly 40 years or older, age and gender are unlikely to bias the cancer serum profile patterns. Our results suggested that age and gender-related variations should be considered when studies involve cancer patients younger than 30 years old.
Other sources of bias and variation include blood collection tubes, clotting times and temperature, the number of freeze-thaw cycles, batch to-batch variation of the magnetic beads, MALDI sample crystallization, laser irradiation, MS detection, and data analysis methods. These sources have been studied previously and were all addressed in our study. Quality control was performed to ensure consistent peptide extraction and MS detection conditions. The high sensitivity and reproducibility of the magnetic-bead-based platform for serum profiling, described recently by Villanueva et al., were also achieved in our study where the beads prepared in our lab showed negligible differences between batches.
Identitifying peptides in disease patterns can potentially lead to insights concerning their sources and relationships to the underlying pathology. Although advances in MS now make it possible to identify small- to medium-sized peptides in serum using only microliters of samples, there remains a significant bottleneck in the technology for its application in clinical proteomics. Direct MS/MS identification of peptides using MALDI TOF/TOF is not yet possible due to the presence of multiple peptides and the complexity of the tryptic-digested serum samples. Although off line nanoLC-MALDI could solve this problem, we think that the best method to identify peptides in complex mixtures is FT-MS where the exact mass of the peptide of interest is obtained. By using FT-MS and enrichment strategies in our experiments to identify the low-molecular-weight region of the proteome, we identified 14 peptides. Some of them were reported in breast cancer or other solid tumors. In this issue, we first used in the research and development of a body fluids (blood, urine, gastric) from the MS exclusive representative of protein and peptide nano beads and metal chelate system.
We provide evidence here that MALDI-TOF MS-based serum peptide profiling is sufficiently robust to reflect not only cancer-specific but also cancer type-specific information. In this study, we discovered a serum peptide pattern that could distinguish breast cancer from non-cancer controls with准确88.9% sensitivity and 83.3% specificity. Furthermore, we identified 14 sequence signature peptides by FT-MS/MS. This finding indicates that serum peptide profiling reflects the pathological state of breast cancer. These ions were fractionated using a novel magnetic-bead-based platform with high sensitivity and reproducibility. To our knowledge, this is the first report of that has used serum patterns as a potential tool to identify breast cancer. These studies are also the innovative points of the paper.
引文
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