CN109752546B - Application of serum immunoglobulin G sugar chain modification in early diagnosis of pulmonary vitreous nodule - Google Patents
Application of serum immunoglobulin G sugar chain modification in early diagnosis of pulmonary vitreous nodule Download PDFInfo
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Abstract
The invention relates to the field of biotechnology, in particular to application of serum immunoglobulin G sugar chain modification in early diagnosis of pulmonary vitreous nodules. The invention, through extensive and intensive research, finds that: the combination of IgG high mannose type sugar chains, IgG poly-N-acetylglucosamine type sugar chains, IgG core fucose type sugar chains and IgG alpha 2, 6-sialyl sugar chains is used as a serum biomarker to assist the existing imaging CT examination, so that the sensitivity and specificity of screening high-risk invasive GGN patients can be improved, the diagnosis accuracy of the existing invasive GGN patients with higher malignancy can be improved, and the clinical over-treatment of non-invasive GGN patients is avoided.
Description
Technical Field
The invention relates to the field of biotechnology, in particular to application of serum immunoglobulin G sugar chain modification in early diagnosis of pulmonary vitreous nodules.
Background
Lung cancer is one of the most prevalent malignancies with the second highest incidence and mortality among all cancers (Siegel R L, Miller K D, Jemal A. cancer statistics,2017. CACACACANCER J Clin.2017; 67(1): 7-30.). According to the latest statistics of Chinese tumor patients, lung cancer is also the most common malignant tumor in China and is the leading cause of cancer death (Chen W, Zheng R, Baade PD, et al. cancer statistics in China,2015. CACACACACancer J Clin.2016; 66(2): 115-32.). Most patients are diagnosed with lung cancer already in the middle and late stages of lung cancer, missing the most effective treatment opportunity. The early detection rate of the lung cancer is improved, intervention treatment is carried out in time, and the survival rate of the lung cancer patient can be greatly improved. Early lung cancer often manifests as pulmonary nodules, which are classified into pure Ground-glass nodules (pGGN), mixed Ground-glass nodules (mGGN), and solid nodules (solid nodules) based on differences in nodule density. In recent five years, Lung GGN detection rates have seen a explosive growth trend, predominantly in female patients, and more frequently in Multiple GGN patients (Yang H, Sun Y, Yao F, et al. surgical Therapy for double Multiple Primary surgery cancer. Ann third surgery. 2016; 101(3):1145-52 Zuin A, Andrio LG, Marulli G, et al. being a segmented reaction breast cancer in the segmented Primary Lung cancer cell repair. 2013; 44(2): e 120-5).
According to histopathological classification, GGNs can be classified into benign lung diseases (benign pulmonary diseases, such as local interstitial fibrosis, inflammation, granuloma, lung abscess, and tuberculoid, etc.), Atypical Adenomatous Hyperplasias (AAH), Adenocarcinomas In Situ (AIS), microaneurysmic adenocarcinomas (MIA), and Invasive Adenocarcinomas (IA). The first three are non-invasive GGNs with lower malignancy, the second two are invasive GGNs with higher malignancy, and surgical intervention is required in time. However, the CT imaging technology most widely used in clinical screening of lung cancer, conventional blood index and tumor marker index, etc. can not distinguish the malignancy of GGN (especially GGN less than or equal to 10 mm), and can not accurately judge and predict the growth condition of GGN because the growth condition of GGN has no obvious rule (Cho J, Kim ES, Kim SJ, Lee YJ, Park JS, Cho YJ, et al, Long-Term Follow-up of Small Pulmony group-Glass Nodules Stable stage for 3Years: implants of the present clinical practice of the above patients with good Follow-up Period and Risk Factors for Subsequent of the third clinical practice of the fourth clinical practice of GGN, and the patient with strong color and low subjective Risk of the second clinical practice of the fourth clinical practice of the fourth general of the fourth clinical practice of the fourth of the fifth of the fourth of the third of the fourth of the third of the fourth of the third of the fourth of the fifth of the fourth of the fifth of the fourth of the fifth of the fourth of the fifth of the fourth of the fifth of the fourth of the fifth of the fourth of the fifth of the, park C M, Lee H J.group-glass nodules on chest CT as imaging biomarkers in the management of long adonociceps.American Journal of Roentgenology,2011,196(3): 533-. Therefore, the method finds noninvasive serological indexes which can reflect the pathological malignancy degree of the GGN patients, have high sensitivity, good specificity and simple and convenient operation, assists the existing imaging examination means to screen out high-risk invasive GGN patients to perform surgical intervention as early as possible, is key to improve the early diagnosis rate of lung cancer and the life quality of the lung cancer patients, and has important clinical significance.
Glycosylation is an important post-translational modification of proteins and is widely involved in various processes of cellular life activities. Sugar chains have the property of characterizing the signal of the terminal of vital activity, and thus, the microheterogeneity of glycoproteins and sugar chains thereon has become an important window for monitoring the development of diseases. Changes in protein glycosylation are closely related to the immune state of the body, and immune evaluation and immunotherapy have become a new window and a new research hotspot for early diagnosis and disease monitoring of tumors. Studies have shown that inflammatory responses involving the immune system play an important role in the development, progression and metastasis of tumors (Grvennikov S I, Greten F R, Karin M. immunity, inflammation, and cancer. cell,2010,140(6): 883-. Immunoglobulin g (igg) is the most abundant antibody in serum and is a glycoprotein. The Asn297 position of IgG contains at least 2 conserved N-glycosylation sites, and the sugar chain in this position is important for the biological activity and biological function of IgG molecule, e.g., the N-sugar chain in its Fc fragment can exert the effector function of antibody by binding to Fc receptor or complement C1q (Shinkawa T, Nakamura K, Yamane N, Shoji-Hosaka E, Kanda Y, Sakurad M, the expression of the antibody of the mutant peptide of the expression of microorganism or bioscience N-acetyl oligosaccharide of human IgG1 lex-type oligosaccharide peptides of the molecular family of biochemical reactions of the recombinant enzyme of the expression of biological specificity. 2005-biochemical binding of the biological specificity of the biological receptor of the biological antigen J. 73., Zgene of biological receptor of the biological antibody of the biological specificity of the biological receptor of the biological antigen J.3. Z400. Zgene of the biological specificity of the biological antibody of the biological receptor of the biological specificity of the biological receptor of the biological antigen of the biological receptor of the biological antigen J.3. Zn.3. the antibody of the biological receptor of the biological antibody of the biological specificity of the biological receptor of the biological receptor of the biological receptor of the biological receptor of the biological receptor of the biological receptor of the biological of the, and alter the serum half-life of the antibody by binding to the neonatal Fc receptor (FcRn) (roparian DC, Akilesh S.FcRn: the neonatal Fc receptor coms of age. Nature reviews Immunology 2007; 7:715-25.), the asialoglycoprotein receptor (Stockert RJ. the asialoglycoprotein receptor: translation shift between structures, function, and expression. physiological reviews 1995; 75:591-609.) and the mannose receptor (Stahl PD. the neonatal receptor monoclonal expression in Immunology 1992; 4: 49-52.). Aberrant glycosylation modification of IgG is closely associated with the development of many diseases, especially tumors, such as: osteoarthritis (Harre U, Lang SC, Pfeife R, Rombouts Y, Fruhbesser S, Amara K, et al. Glycosylation of immunological G inhibitors differentiation and bone loss. Nature communication 2015; 6:6651.), Ovarian Cancer (Ruhaak LR, et al. protein-Specific Differential Glycosylation of immunological proteins in Serum of protein research; 15:1002-10. haak LR, et al. protein-Specific differentiation of immunological analysis of immunological protein of Serum of protein research; 15:1002-10. yeast LR, et al. protein-Specific differentiation of immunological analysis of physiological protein of Serum of protein research 2016; J. Zybolt, J. Zymology, J. expression of immunological analysis of protein, J.S.S.S. -free controls, biochemical and biological research communications 2016; 469:1140-5.Kyselova Z, et al, Breast cancer Diagnosis and physiology qualitative measures of serum glycerol profiles clinical chemistry 2008; 1166-75, Abd Hamid UM, et al.A. linear to secondary potential markers from a server polypeptides associated with a branched cancer protocol 2008; 1105-18.), liver cancer (Yi C H WHL, Zhou F G, et al, elongated core-fused IgG is a new marker for liver B viruses-related hepatocellular receptors 2015; 2015,4(12): e1011503.), Gastric cancer (Ruhaak LR, Barkauskas DA, Torres J, Cooke CL, Wu LD, Stroble C, et al. the Serum immunological tissue G Glycosylation Signature of Gastric cancer. EuPA open proteins 2015; 1-9.Kodar K, et al, immunoglobulin G Fc N-glycan profiling in substrates with structural cancer by LC-ESI-MS, translation to molecular progression and overview. Glycoconjugate outlet 2012; 57-66.) and lung cancer (Kanoh Y, et al, relationship shift between N-linked oligosaccharide peptides of human serum immunoglobulin G and serum tumor markers with non-small cell lung cancer, anticancer research 2006; 26:4293-7.), and the like. However, the correlation between the glycosylation change of serum IgG and the benign and malignant lung nodules at early stage is not reported.
Disclosure of Invention
In view of the above-mentioned drawbacks of the prior art, the present invention aims to provide the use of serum immunoglobulin G sugar chain modification in early diagnosis of pulmonary frosting nodules, for solving the problems of the prior art.
To achieve the above and other related objects, the present invention provides, in a first aspect, the use of a combination of an IgG high mannose-type sugar chain, an IgG poly-N-acetylglucosamine-type sugar chain, an IgG core fucose-type sugar chain and an IgG α 2, 6-sialyl sugar chain for the preparation or screening of a diagnostic reagent for pulmonary frosting of nodules.
The IgG high mannose-type sugar chain, IgG poly-N-acetylglucosamine sugar chain, IgG core fucose-type sugar chain and IgG alpha 2, 6-sialyl sugar chain of the present invention are all located on IgG.
Specifically, the method comprises the following steps:
the IgG high-mannose sugar chain of the present invention is located on IgG and is formed by high-mannose modification of IgG.
The IgG poly-N-acetylglucosamine sugar chain of the present invention is located on the IgG and is formed by modifying the IgG with poly-N-acetylglucosamine sugar.
The IgG core fucose-type sugar chain of the present invention is located on IgG and is formed by modifying IgG with core fucose.
The IgG alpha 2, 6-sialyl sugar chain of the present invention is located on IgG and is formed by modification of IgG with alpha 2, 6-sialyl sugar.
Further, the lung milled glass nodule diagnostic reagent is a lung pure milled glass nodule diagnostic reagent.
Further, the lung milled glass nodule diagnostic reagent is an invasive lung pure milled glass nodule diagnostic reagent.
Further, the IgG high mannose-type sugar chain, the IgG poly-N-acetylglucosamine sugar chain, the IgG core fucose-type sugar chain, and the IgG alpha 2, 6-sialylsugar chain are used in combination as a biomarker.
Further, the combination of the IgG high mannose-type sugar chain, the IgG poly N-acetylglucosamine sugar chain, the IgG core fucose-type sugar chain and the IgG alpha 2, 6-sialyl sugar chain serves as a serum biomarker.
Further, the combination of IgG high mannose type sugar chain, IgG poly N-acetylglucosamine type sugar chain, IgG core fucose type sugar chain and IgG alpha 2, 6-sialyl sugar chain is used for preparing or screening diagnostic reagent for lung frosted nodule, including two aspects:
first, the joint use of an IgG high mannose-type sugar chain, an IgG poly-N-acetylglucosamine sugar chain, an IgG core fucose-type sugar chain, and an IgG alpha 2, 6-sialyl sugar chain for the preparation of a diagnostic reagent for a pulmonary milled glass nodule means that the joint use of an IgG high mannose-type sugar chain, an IgG poly-N-acetylglucosamine sugar chain, an IgG core fucose-type sugar chain, and an alpha 2, 6-sialyl sugar chain for the preparation of a diagnostic reagent for a pulmonary milled glass nodule as a diagnostic index for a pulmonary milled glass nodule. In some embodiments, the combination of an IgG high mannose-type sugar chain, an IgG poly N-acetylglucosamine sugar chain, an IgG core fucose-type sugar chain, and an IgG α 2, 6-sialylsugar chain can be used as a standard or a positive control for measuring the content of the IgG high mannose-type sugar chain, the IgG poly N-acetylglucosamine sugar chain, the IgG core fucose-type sugar chain, and the IgG α 2, 6-sialylsugar chain in the serum of a sample. Alternatively, IgG containing a high mannose-type sugar chain, IgG containing a poly-N-acetylglucosamine sugar chain, IgG containing a core fucose-type sugar chain, and IgG containing an α 2, 6-sialylsugar chain may be used in combination as a standard or a positive control.
Second, the diagnostic reagent for pulmonary frosting nodules, in which an IgG high mannose-type sugar chain, an IgG poly-N-acetylglucosamine-type sugar chain, an IgG core fucose-type sugar chain, and an α 2, 6-sialylsugar chain are used in combination, is a diagnostic reagent for pulmonary frosting nodules, in which an IgG high mannose-type sugar chain, an IgG poly-N-acetylglucosamine-type sugar chain, an IgG core fucose-type sugar chain, and an IgG α 2, 6-sialylsugar chain are used in combination as recognition targets for pulmonary frosting nodules, and the reagents are screened for specifically recognizing these four sugar chains.
In some embodiments, based on the IgG high mannose type sugar chain, IgG poly N-acetylglucosamine type sugar chain, IgG core fucose type sugar chain, and IgG alpha 2, 6-sialylsugar type sugar chain, lectins that specifically recognize these four sugar chains, respectively, are screened for use as a lung frosting nodule diagnostic reagent.
The IgG is of human origin.
In a second aspect of the present invention, there is provided use of a reagent that specifically recognizes an IgG high mannose-type sugar chain, an IgG poly N-acetylglucosamine sugar chain, an IgG core fucose-type sugar chain, and an IgG α 2, 6-sialylsugar chain in the preparation of a diagnostic kit for pulmonary frosting of nodules.
Further, the lung milled glass nodule diagnostic reagent is a lung pure milled glass nodule diagnostic reagent.
Further, the lung milled glass nodule diagnostic reagent is an invasive lung pure milled glass nodule diagnostic reagent.
Further, IgG high mannose-type sugar chains, IgG poly-N-acetylglucosamine sugar chains, IgG core fucose-type sugar chains, and IgG α 2, 6-sialyl sugar chains are used in combination as a biomarker.
Further, IgG high mannose-type sugar chains, IgG poly-N-acetylglucosamine sugar chains, IgG core fucose-type sugar chains, and IgG α 2, 6-sialyl sugar chains are used in combination as serum biomarkers.
In some embodiments, based on the IgG high mannose-type sugar chain, IgG poly N-acetylglucosamine sugar chain, IgG core fucose-type sugar chain, and IgG alpha 2, 6-sialylsugar chain, lectins that specifically recognize these four sugar chains, respectively, can be used as a diagnostic reagent for pulmonary vitreous nodule.
Further, the reagent specifically recognizing IgG high mannose type sugar chain may be galanthus agglutinin GNA.
The reagent specifically recognizing IgG poly N-acetylglucosamine sugar chain may be Leptospermum heterophyllum agglutinin LTL.
The reagent specifically recognizing the IgG core fucose-type sugar chain may be pea lectin PSA.
The agent specifically recognizing the α 2, 6-sialyl sugar chain may be elderberry lectin SNA.
The IgG is of human origin.
In a third aspect of the present invention, there is provided a diagnostic kit for pulmonary frosting of nodules, the kit comprising at least a reagent that specifically recognizes an IgG high mannose-type sugar chain, an IgG poly N-acetylglucosamine sugar chain, an IgG core fucose-type sugar chain, and an IgG α 2, 6-sialylsugar chain.
Furthermore, the diagnostic kit for the pulmonary frosted glass nodules is a diagnostic kit for the pulmonary pure frosted glass nodules.
Further, the diagnostic kit for the pulmonary frosted glass nodules is a diagnostic kit for invasive pulmonary pure frosted glass nodules.
In some embodiments, based on the IgG high mannose-type sugar chain, IgG poly N-acetylglucosamine sugar chain, IgG core fucose-type sugar chain, and IgG alpha 2, 6-sialylsugar chain, lectins that specifically recognize these four sugar chains, respectively, can be used as a diagnostic reagent for pulmonary vitreous nodule.
Further, the reagent specifically recognizing IgG high mannose type sugar chain may be galanthus agglutinin GNA.
The reagent specifically recognizing IgG poly N-acetylglucosamine sugar chain may be Leptospermum heterophyllum agglutinin LTL.
The reagent specifically recognizing the IgG core fucose-type sugar chain may be pea lectin PSA.
The agent specifically recognizing the α 2, 6-sialyl sugar chain may be elderberry lectin SNA.
The IgG is of human origin.
In a fourth aspect of the present invention, there is provided a use of a combination of an IgG high mannose-type sugar chain, an IgG poly-N-acetylglucosamine sugar chain, an IgG core fucose-type sugar chain and an IgG α 2, 6-sialylsugar chain as a biomarker for diagnosing a pulmonary vitreous nodule.
Further, the biomarker is a serum biomarker.
Further, the pulmonary vitreous nodules are pulmonary pure vitreous nodules.
Further, the lung milled glass nodules are invasive lung pure milled glass nodules.
The IgG is of human origin.
In a fifth aspect of the present invention, there is provided a method for diagnosing pulmonary vitreous nodules, comprising the steps of: the levels of IgG high mannose type sugar chains, IgG poly-N-acetylglucosamine type sugar chains, IgG core fucose type sugar chains, and IgG alpha 2, 6-sialyl sugar chains in the serum of the sample were measured.
Further, the method further comprises performing an imaging CT examination on the patient corresponding to the sample serum.
Further, the pulmonary vitreous nodules are pulmonary pure vitreous nodules.
Further, the lung milled glass nodules are invasive lung pure milled glass nodules.
The IgG is of human origin.
Compared with the prior art, the invention has the beneficial effects that:
the invention, through extensive and intensive research, finds that: the combination of IgG high mannose type sugar chains, IgG poly-N-acetylglucosamine type sugar chains, IgG core fucose type sugar chains and IgG alpha 2, 6-sialyl sugar chains is used as a serum biomarker to assist the existing imaging CT examination, so that the sensitivity and specificity of screening high-risk invasive GGN patients can be improved, the diagnosis accuracy of the existing invasive GGN patients with higher malignancy can be improved, and the clinical over-treatment of non-invasive GGN patients is avoided.
Drawings
FIG. 1 is a graph showing the results of detection of serum IgG-enriched silver staining in GGN patients.
FIG. 2 shows the raw scan results and the 45 lectin net signal value distribution of serum IgG sugar chain expression of GGN patients analyzed by the lectin chip.
FIG. 3 shows the distribution of the net signal values of 45 lectins in two batches of chips for serum IgG from a #30 GGN patient.
FIG. 4 shows the results of the clustering analysis of the heteroadhesin probes found under the five normalization methods.
FIG. 5 shows the results of verifying the expression levels of SNA in non-invasive GGN patients and invasive GGN patients by lectin blotting.
FIG. 6 shows the results of ROC curve analysis of the combined diagnostic model and CT values in training set samples for differentiating the malignancy of GGNs.
FIG. 7 shows the results of ROC curve analysis of the combined diagnostic model and CT values in the validation set of samples for differentiating the malignancy of GGNs.
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
Before the present embodiments are further described, it is to be understood that the scope of the invention is not limited to the particular embodiments described below; it is also to be understood that the terminology used in the examples is for the purpose of describing particular embodiments, and is not intended to limit the scope of the present invention; in the description and claims of the present application, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.
When numerical ranges are given in the examples, it is understood that both endpoints of each of the numerical ranges and any value therebetween can be selected unless the invention otherwise indicated. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition to the specific methods, devices, and materials used in the examples, any methods, devices, and materials similar or equivalent to those described in the examples may be used in the practice of the invention in addition to the specific methods, devices, and materials used in the examples, in keeping with the knowledge of one skilled in the art and with the description of the invention.
Unless otherwise indicated, the experimental methods, detection methods, and preparation methods disclosed herein all employ techniques conventional in the art of molecular biology, biochemistry, chromatin structure and analysis, analytical chemistry, cell culture, recombinant DNA technology, and related arts. These techniques are well described in the literature, and may be found in particular in the study of the MOLECULAR CLONING, Sambrook et al: a LABORATORY MANUAL, Second edition, Cold Spring Harbor LABORATORY Press, 1989and Third edition, 2001; ausubel et al, Current PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, 1987and periodic updates; the series METHODS IN ENZYMOLOGY, Academic Press, San Diego; wolffe, CHROMATIN STRUCTURE AND FUNCTION, Third edition, Academic Press, San Diego, 1998; (iii) METHODS IN ENZYMOLOGY, Vol.304, Chromatin (P.M.Wassarman and A.P.Wolffe, eds.), Academic Press, San Diego, 1999; and METHODS IN MOLECULAR BIOLOGY, Vol.119, chromatography Protocols (P.B.Becker, ed.) Humana Press, Totowa, 1999, etc.
First, search for lectin Probe
Example 1: collection of serum samples of patients with pulmonary vitreous nodules of different pathological types
In the present invention, 102 serum samples of patients with pure-glass nodules (GGN) were used, and the samples were collected at 2015.01-2016.11 in Hospital, Shanghai, and the types of pathologies were clearly diagnosed by histopathological examination, including 6 benign cases (benign), 2 AAH cases, 31 AIS cases, 42 MIA cases, and 21 IA cases. Clinical information for all patients is shown in Table 1
As shown.
TABLE 1102 clinical information for patients with pure pulmonary vitreous nodules
Remarking: benign, benign disease patients; AAH, atypical adenomatous hyperplasia; AIS, in situ adenocarcinoma; MIA, micro-invasive adenocarcinoma; IA, invasive adenocarcinoma
Example 2: lectin chip-based serum IgG sugar chain spectrum detection and differential lectin probe screening
1. Enrichment and purification of serum IgG
According to the characteristic that Protein G can be efficiently and specifically bound with IgG, IgG is enriched and purified from the patient serum by using commercially available Protein G magnetic beads (BioRad company, USA) (the specific operation process refers to a user manual), the Protein of eluent is quantified by a micro BCA method, and the purity of the enriched product is identified by a silver staining method. The typical effect of IgG enrichment in serum of GGN patients is shown in FIG. 1. FIG. 1: the serum IgG enriched silver staining detection result of the GGN patient represents a picture.
2. Labeling of IgG with Cy3 fluorescent dye
mu.L of the diluted IgG eluate was taken and added to an EP tube containing 10. mu.g of Cy3 fluorescent dye (Cy 3-succinimidyl ester, GE Healthcare Co., UK), mixed, and then reacted at room temperature for 1 hour with exclusion of light. Then, 80. mu.L of Probing buffer (Glyco Technica, Japan) was added to adjust the total volume of all samples to 100. mu.L, and after mixing, the mixture was reacted at room temperature for 2 hours in the dark to block the free Cy3 fluorescent reagent.
3. Detection of sugar chain profile of IgG Using lectin chip
We performed sugar chain expression profiling on IgG samples labeled with Cy3 fluorescent reagent using a commercially available lectin chip LecChip (glyco technical, japan) (refer to the user manual for specific procedures), and scanned using a chip scanner glyco position Reader 1200 (glyco technical, japan). After data transformation, background correction and data combination, the net signals of 45 lectins on the chip were obtained. The net signal values of 45 lectins were analyzed by histogram and found: the positive signals are mainly found in some lectins that specifically recognize N-sugar chains, such as PSA, LCA, RCA120 and ConA, etc. In addition, the LCA signal specifically recognizing core fucose is particularly strong, and the average value is the highest among 45 kinds of lectins, which indicates that the content of IgG containing core glycosylation modification in human serum is very high, which is consistent with the report.
4. Screening lectin probes that significantly distinguish non-infiltrating from infiltrating GGN patients
Since surgical excision is now routinely performed clinically on invasive GGN patients in the MIA and IA stages, and further follow-up observations are routinely made on non-invasive GGN patients in the benign, AAH and AIS stages, we divided 102 GGN patients into two groups of non-invasive (benign/AAH/AIS) and invasive (MIA/IA) and further screened lectin probes useful for differentiating the two groups of GGN patients in this study. In this study we normalized the net signals of 45 lectins using maximum normalization and specific lectin normalization, respectively, and used for subsequent statistical analysis. FIG. 2: original scan results (B) and 45 lectin net signal value distributions (C) were analyzed for serum IgG sugar chain expression in GGN patients using lectin chips (A). As can be seen from fig. 2, the LCA signal intensity value is the largest among the 45 lectins, so that the signal intensity values of all other lectins (44 lectins) in each sample are normalized to the maximum value by LCA normalization. In addition, since two batches of chips were used in the experiment, and serum IgG from GGN patient #30 was used as an internal reference in the two batches of experiments, PSA, RCA120, NPA and UDA, which were stable in detection in the two batches of chips, were selected for specific lectin normalization from their net signal value distributions of 45 lectins in the two batches of chips (fig. 3). FIG. 3: serum IgG from GGN patient #30 distributed the net signal values of 45 lectins in both batches of chips.
In the specific data processing process, because two batches of chips are used for detection in the research, in order to reduce the difference caused by chip detection among different batches, the lectin net signal value of the chips among different batches is normalized by taking the serum IgG sugar chain expression data of a #30 GGN patient as an internal reference. On this basis, the Relative signal values (Relative intensities) of 45 lectins were obtained for all samples using five normalization methods, Max (LCA) -normalization, PSA-normalization, RCA 120-normalization, NPA-normalization and UDA-normalization, respectively.
Differential agglutinin detected by 45 agglutinin samples of 102 samples found under five normalization methods were subjected to statistics and clustering analysis, and agglutinin probes for distinguishing two groups of GGN patients with non-wettability (benign/AAH/AIS) and wettability (MIA/IA) which can be found under different methods include SNA and TJA-I for identifying sialic acid modification, GNA for identifying high mannose type, VVA for identifying O-sugar and STL and LTL for identifying poly-GlcNAc (Table 2 and FIG. 4). The foregoing analyses suggested that sialylation, high mannose glycosylation, and poly-GlcNAc glycosylation modifications were all reduced on serum IgG from patients infiltrated with GGN. FIG. 4: color represents p-value expression between two groups of GGN patients with non-wettability (benign/AAH/AIS) and wettability (MIA/IA), while green represents smaller p-value and red represents larger p-value, according to the differential lectin clustering analysis found under the five normalysis methods.
TABLE 2 analysis of the p-values of the lectins found under the five normalization methods
II, verifying expression of specific sugar chains identified by differential lectin probes in serum IgG of GGN patients at different pathological stages by lectin blotting
Example 3: lectin blotting verification of expression of specific sugar chains identified by the differential lectin probes in serum IgG of GGN patients at different pathological stages
Furthermore, in order to verify the reliability of the differential lectin probes screened by the lectin chip, we performed expression verification on the differential lectin probes SNA searched for and used for distinguishing two groups of GGN patients by using a lectin blotting method. Since the LCA signal of each sample in the study is strongest, the SNA signal value of the same sample is divided by the corresponding gray quantitative value of the LCA of the sample to be regarded as the relative content of the SNA-specific recognition sugar chain on the serum IgG protein of the patient. By comparing the differences between the two groups using the nonparametric assay, it was found that the amount of SNA-specific recognition sugar chains was significantly reduced in serum IgG from patients with invasive growth GGN (p 0.013, fig. 5), as compared to those from patients with non-invasive growth GGN, and the trend was consistent with the lectin chip experiment results. FIG. 5: expression of SNAs in non-invasive and invasive GGN patients was performed using lectin blotting.
Thirdly, establishing and verifying the combined diagnosis model of agglutinin probe and CT value
Example 4: establishment of lectin probe detection and CT value combined diagnosis model in training group
At present, clinical CT is a main means for early screening of lung cancer, but the malignancy of GGNs with different pathological degrees cannot be distinguished only by CT images, in order to evaluate the clinical application potential of differential lectin probes found by lectin chips in the diagnosis of invasive GGNs through auxiliary CT examination, 102 samples are randomly divided into a training group (68 samples in total, 4 samples of benign, 1 sample of AAH, 20 samples of AIS, 28 samples of MIA and 15 samples of IA) and a verification group (34 samples in total, 2 samples of benign, 1 sample of AAH, 11 samples of AIS, 14 samples of MIA and 6 samples of IA) according to a ratio of 2:1, and gender, age and nodule size are uniformly distributed in the two groups as far as possible. And establishing a combined diagnosis model of the relative signal value and the CT value of the lectin probe in the training set by a regression analysis method. And evaluating the clinical application potential of the joint diagnosis model in diagnosing the invasive GGN by performing ROC curve analysis on the joint diagnosis model. The results show that the model is significantly better than the individual indices CT values in the training set of experimental samples (joint diagnostic model: AUC 0.783; CT: AUC 0.664; p 0.037) (fig. 6) for distinguishing patients with non-invasive GGN from those with invasive GGN. FIG. 6: and combining the diagnostic model and the CT value to analyze the ROC curve for distinguishing the malignancy degree of the GGN in the training group samples. The red line represents the ROC curve for the combined index and the blue line represents the ROC plot for the CT value.
The combined diagnostic model (2.158-1.503 GNA-1.664 LTL + 0.561P 3A-1.738 NA +0.001
CT value
Example 5: evaluation of the potential of the Joint diagnostic model for clinical application in diagnosing invasive GGN patients in a validation set
In order to further verify the clinical application value of the joint diagnosis model in diagnosing invasive GGN patients, ROC curve analysis is carried out on the joint diagnosis model in a verification group sample, and the result shows that the effect of the model on distinguishing non-invasive GGN patients from invasive GGN patients is still better than the CT value of an individual index in the verification group sample (the joint diagnosis model: AUC is 0.842; CT value: AUC is 0.722; and p is 0.146) (figure 7). FIG. 7: and combining the diagnosis model and the CT value to analyze the ROC curve for distinguishing the malignancy degree of the GGN in the verification group samples. The red line represents the ROC curve for the combined index and the blue line represents the ROC plot for the CT value. The lectin probe of the serum IgG differential sugar chain screened by the lectin chip technology can be used together with the current clinical CT examination, improves the diagnosis accuracy of the invasive GGN patients, and has certain clinical value.
The invention, through extensive and intensive research, discovers for the first time: four lectin probes (Galanthus nivalis agglutinin GNA/Lotus winged agglutinin LTL/pea agglutinin PSA/Sambucus williamsii agglutinin SNA), the expression of the specific recognition sugar chains in serum IgG of invasive GGN patients is remarkably reduced, and the low expression indicates that the patients need to perform surgical intervention in time.
That is: the lectin probe SNA specifically recognizes an IgG alpha 2, 6-sialylated glycoform, the expression level of which is significantly reduced in serum IgG of patients with invasive GGN compared to non-invasive GGN. The lectin probe GNA specifically recognizes a high mannose type, whose expression level is significantly reduced in serum IgG of patients with invasive GGN, compared to non-invasive GGN. The lectin probe LTL specifically recognizes poly-N-acetylglucosamine glycoforms (poly-GlcNAc), whose expression levels are significantly reduced in serum IgG of patients with invasive GGN compared to non-invasive GGN. The lectin probe PSA specifically recognizes the core fucose type, and the expression level of this glycoform is significantly reduced in serum IgG of patients with invasive GGN, compared to non-invasive GGN.
Furthermore, it was found that a diagnostic model combining the relative net signal and CT values of the four lectin probes (Galanthus galantha lectin GNA/Lotus winged Lotus japonicus lectin LTL/pea lectin PSA/Sambucus nigra lectin SNA) can be used to determine the more malignant invasive GGNs. The diagnostic model better distinguishes patients with invasive GGNs from patients with non-invasive GGNs relative to single CT values.
According to the invention, by establishing the combined diagnosis model of the 4 differential lectin probes and the clinical CT detection value, the diagnosis accuracy of the invasive GGN patient with higher malignancy degree at present can be improved, and the over-treatment of the non-invasive GGN patient in clinic is avoided.
In conclusion, the present invention effectively overcomes various disadvantages of the prior art and has high industrial utilization value.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
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