CN113804901B - Serum lipid marker for early noninvasive diagnosis of oral squamous carcinoma and application thereof - Google Patents
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Abstract
The invention discloses a serum lipid marker for noninvasive diagnosis of oral squamous carcinoma in early stage and application thereof. Specifically, the invention discloses a characteristic lipid molecular compound which can be detected by CPSI-MS in situ mass spectrometry, wherein the characteristic lipid molecular compound comprises Arginyl-methionine, glycerophosphocholine and propionyl choline, and the three lipid markers indicate that a subject is an oral squamous cell carcinoma patient or a potential oral squamous cell carcinoma patient when the expression of the three lipid markers is down-regulated. The biomarker provided by the invention can be used for early diagnosis and screening of oral squamous cell carcinoma, and the method is simple, easy to operate and high in accuracy, and provides a new method and thought for early diagnosis and screening of oral squamous cell carcinoma.
Description
Technical Field
The invention belongs to the field of biological medicine, and relates to a serum lipid marker and application thereof in noninvasive diagnosis of oral squamous cell carcinoma in early stage.
Background
Head and neck neoplasms are the eighth most common malignancy worldwide, with over 60 new cases each year worldwide, and oral squamous cell carcinoma (oral squamous cell carcinoma, OSCC) is one of the most common types of head and neck malignancy. Clinically, the currently accepted first-choice treatment method for oral squamous cell carcinoma is surgical treatment, and is assisted by radiotherapy and chemotherapy or biological treatment. Since radiation treatment can cause fibrosis of the tissue in the irradiated area, which affects later surgical procedures, radiation treatment is generally recommended for oral squamous carcinoma at about 6 weeks post-operative, with a commonly used radiation dose of 60cGy. For patients with oral squamous cell carcinoma who have developed regional lymph node metastasis, radiation therapy of their neck can prevent possible metastasis and recurrence. In recent years, chemotherapy has become an important adjunct to the treatment of locally advanced oral squamous cell carcinoma, including: preoperative induction chemotherapy or concurrent radiotherapy and chemotherapy (preoperative or postoperative radiotherapy and chemotherapy). Pre-operative induction chemotherapy or preoperative contemporaneous radiotherapy and chemotherapy almost become a main treatment mode before the operation of huge advanced oral squamous carcinoma, and the purpose of reducing tumor is expected to be achieved through chemotherapy or contemporaneous radiotherapy and chemotherapy, so that conditions are created for the operation. Currently, the most commonly used chemotherapeutic drug is the platinum-based drug (cisplatin), and the recommended chemotherapeutic regimen is TPF (docetaxel+cisplatin+5-Fu). Biological targeted therapies have recently begun to be used in the adjuvant treatment of oral squamous cell carcinoma. Studies show that part of oral squamous cell carcinoma cases highly express the epidermoid growth factor receptor (epidermal growth factor receptor, EGFR), and the researches show that the high expression is an independent predictor of poor prognosis of oral squamous cell carcinoma. The targeting drug cetuximab (monoclonal antibody of EGFR) designed for EGFR is the most common biological therapeutic drug for oral squamous cell carcinoma, and researches report that the drug can improve prognosis of oral squamous cell carcinoma patients. However, some patients with oral squamous carcinoma may develop resistance to cetuximab, thereby affecting the clinical therapeutic effect of the drug.
In recent decades, although the technology and concept of treatment of oral squamous cell carcinoma are continuously improved, the overall treatment effect is not improved significantly. The 5-year survival rate of oral squamous carcinoma patients is not significantly improved, and is still wandering around 60%, and advanced patients are even less than 30%, wherein the main reason is that most patients are already in a late stage of tumor at the time of diagnosis. Literature reports that the postoperative local recurrence rate of oral squamous cell carcinoma is 6.9-22%, and once postoperative recurrence occurs, the survival rate of patients is obviously reduced. Previous studies have shown that 3-year Overall Survival (OS) for postoperative relapsed patients is about 52.6% and only 24-50% for 5 years. Therefore, the realization of early diagnosis and early treatment of oral squamous cell carcinoma has important significance for improving prognosis of oral cancer and reducing economic burden and psychological stress of patients.
Disclosure of Invention
In order to realize the early rapid and noninvasive diagnosis of oral squamous cell carcinoma, the invention aims to provide a group of serum lipid markers which can accurately distinguish oral cancer patients from healthy volunteers, and the early rapid and noninvasive diagnosis of oral squamous cell carcinoma can be realized by utilizing the marker combination.
The invention also aims to provide application of the serum lipid marker in preparation of a kit for noninvasively diagnosing oral squamous cell carcinoma in early stage.
The technical scheme adopted for solving the technical problems is as follows:
serum lipid markers for the noninvasive diagnosis of oral squamous cell carcinoma in early stage, wherein the markers comprise any one or any combination of Arginyl-methionine, glycerophosphorylcholine and propionyl choline, or any combination of two or three of the three.
Further, the marker is a combination of Arginyl-methionine, glycerophosphorylcholine and propioninyl choline.
A kit for the noninvasive diagnosis of oral squamous carcinoma at an early stage, comprising the serum lipid marker of any of the above.
Application of serum lipid markers in preparing a kit for early noninvasive diagnosis of oral squamous cell carcinoma.
Further, the down-regulated expression of the serum lipid marker indicates that the subject is an oral squamous cell carcinoma patient or a potential oral squamous cell carcinoma patient.
Further, downregulation of expression of each of sperminyl-methionine, glycerophosphorylcholine and propionylcholine indicates that the subject is an oral squamous carcinoma patient or a potential oral squamous carcinoma patient.
The invention has the following beneficial effects:
(1) According to the invention, arginyl-methionine, glycerophosphocholine and Propionylcholine are selected as serum molecular marker combinations, so that early diagnosis and early treatment of oral squamous cell carcinoma can be realized, and the treatment effect of oral squamous cell carcinoma patients is improved.
(2) The serum detection kit based on Arginyl-methionine, glycerophosphocholine and Propionylcholine can be developed into the serum detection kit for oral squamous cell carcinoma, can realize early and rapid noninvasive diagnosis of oral squamous cell carcinoma, can meet the detection requirements of most medical institutions, and has wide clinical application prospects.
In summary, the biomarker of the invention can be used for the early diagnosis and screening of oral squamous cell carcinoma, and the method is simple, easy to operate and high in accuracy, thereby providing a new method and thinking for the early diagnosis and screening of oral squamous cell carcinoma.
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FIG. 1 is a schematic diagram of the differentiating ability of Arginyl-methionene to oral squamous carcinoma of the experimental development group and healthy volunteers; (a): oral squamous carcinoma groups and healthy groups were analyzed for ROC curves (auc=0.83); (b) The relative content of Arginyl-metanine in oral squamous carcinoma group and healthy group is analyzed by a histogram (P < 0.05);
FIG. 2 is a schematic representation of the ability of Propionylcholine to differentiate oral squamous cell carcinoma from healthy volunteers in the experimental development group; (a): oral squamous carcinoma groups and healthy groups were analyzed for ROC curves (auc=0.79); (b): histogram analysis of the relative content of Propionylcholine in oral squamous carcinoma group and healthy group (P < 0.05);
FIG. 3 is a schematic diagram of the ability of glycosphocholine to differentiate oral squamous cell carcinoma from healthy volunteers in the experimental development group; (a): oral squamous carcinoma groups and healthy groups were analyzed for ROC curves (auc=0.79); (b): histogram analysis of relative content of glycosphocholine in oral squamous carcinoma group and healthy group (P < 0.05);
FIG. 4 shows the discrimination ability (logistic regression analysis) of three metabolites of Arginyl-methionine, propionylcholine, glycerophosphocholine as a combination for oral squamous carcinoma group (C) and healthy group (H), wherein the experimental development group was used as training set and the validation group was used as test set.
FIG. 5 is a schematic of PLS-DA analysis based on three different metabolites of Arginyl-methionine, propionylcholine, glycerophosphocholine, which significantly separated oral squamous carcinoma group (Cancer) and healthy volunteers, C: oral squamous carcinoma group (Cancer), H: healthy group (Health).
Detailed Description
The invention is further described below with reference to the drawings and examples.
1. Embodiment one: the experimental development group preliminarily determines serum lipid metabolism markers for early diagnosis of oral squamous cell carcinoma.
In this example, a total of 556 serum samples were included for the study, with 315 early oral squamous carcinoma cases and 241 healthy volunteers (Table 1), all of the group-entered cases signed informed consent.
Table 1 early oral cancer and clinical case data of healthy volunteers taken into study (n=556)
All cases were studied in an experimental development group and a validation group, wherein the experimental development group included 84 cases of early oral squamous cell carcinoma and 100 healthy volunteers; the validation group included 231 cases of early oral squamous carcinoma and 141 healthy volunteers.
Note that: method for extracting serum samples: whole blood of a primary oral squamous carcinoma patient or a healthy volunteer is collected before operation, put into a coagulation promoting tube, centrifuged for 5min at 3000 rpm, and after centrifugation, 10ul of serum on the upper layer is sucked by a pipetting gun for CPSI-MS analysis, and if not used for a while, the whole blood can be stored in a refrigerator at-80 ℃ for a long time.
Note that: conductive polymer spray ionization mass spectrometry (CPSI-MS) is an advanced in-situ mass spectrometry technology, and can analyze lipid molecules in a sample with high flux in an environment with normal pressure and open. Compared with traditional paper spray ionization, the technology has the following advantages: the sample consumption is less (more than or equal to 100 nL); (2) polar, water-soluble metabolites and drug molecules; (3) the operation is quick and simple (4) qualitative and semi-quantitative; (5) sensitivity is high. The characteristics enable the technology to meet the requirements of timely detection (Point of Care Test, POCT) of clinical samples.
The experiment was first carried out with serum samples of 184 cases (84 oral squamous carcinoma cases, 100 healthy volunteers) as an experimental development group. And (3) performing high-throughput lipid metabolism spectrum analysis on 184 oral squamous cell carcinoma and serum samples of a healthy group by using a CPSI-MS technology, and screening differentially expressed metabolites. A total of 511 m/z ions were obtained using the MetaboAnalyst database. Comparing the oral squamous carcinoma group with the healthy group by using student's t to preliminarily screen 161 differential metabolites (p < 0.05); next, 58 biomarkers were determined from the 161 differential metabolites using further ROC curves (p < 0.05 and AUC > 0.70, see in particular table 2) that significantly differentiated the oral squamous carcinoma group from the healthy group.
Table 2 biomarkers for oral squamous carcinoma group and healthy group determined by experimental development group
2. Embodiment two: the validation group further validates the oral squamous carcinoma early diagnosis candidate marker.
The 58 candidate markers determined in the experimental development group were validated using a validation set 372 serum samples (231 early oral squamous carcinoma cases, 141 healthy volunteers), where 6 metabolites were again detected with statistical differences and ROC curve analysis was able to significantly differentiate between the cancer and healthy groups (t test, p < 0.05 and AUC > 0.70).
Of these 3 metabolites, arginyl-methionine (Arginyl-methionine), glycerophosphorylcholine (glycerophosphoryl), propionylcholine (propionyl choline) were identified for metabolite structure and name by secondary mass spectrometry, and were statistically different (p < 0.05 and AUC > 0.70 see specifically table 3).
Group clustering analysis of the above metabolites using PLS-DA revealed that the same type of group of cases clustered together well (as shown in FIG. 5), i.e., the above metabolites significantly differentiated oral squamous cell carcinoma groups from healthy volunteers.
Table 3 metabolic markers co-determined in experimental and validated groups (t test, p < 0.05 and AUC > 0.70)
Table:Differential metabolites detected in Development group and validation group by CPSI-MS untargeted analysis
The structure identification of the target differential metabolite obtained by the statistical analysis is mainly realized by the following method and flow
And (3) performing identification:
1) Further matching and deducing possible molecular structures thereof through on-line database retrieval;
2) According to the accurate mass number and isotope abundance ratio of molecular ion peaks, the possible molecular formula of the metabolite is presumed, and the [ M+H ] + or [ M-H ] -ion peak of the metabolite is mainly obtained aiming at the primary high-resolution mass spectrum;
3) For differential metabolite ions that can be purchased for the standard, LC-MS/MS analysis is further performed on the standard for the target metabolite and compared with the cleavage results of the secondary mass spectrum to confirm the structural name of the metabolite.
3. Embodiment III: the ability of serum lipid metabolism marker combinations to identify oral squamous carcinoma cases and healthy volunteers.
ROC curve analysis was performed on the above 3 markers Arginyl-methionine, glycerophosphorylcholine, and Propionylcholine, respectively, and the results showed that although a single marker could also distinguish early oral squamous carcinoma cases from healthy volunteers in the experimental development group (as shown in fig. 1a, 2a, and 3 a), the distinguishing ability was not optimal (AUC: 0.79-0.83). Further analysis found that the 3 metabolites were lower in the oral squamous carcinoma group than in healthy volunteers (as shown in fig. 1b, 2b and 3 b), indicating that the evolution from healthy to cancer required a significant consumption of these 3 metabolites, providing energy and raw materials for tumor growth.
Furthermore, when the 3 markers are used as a combination for Logistic Regression regression modeling, the Binomial Models of glmnet are used for modeling the first batch of samples (184 cases) and the second batch of samples are used for verification (372 cases), so that early oral squamous carcinoma cases and healthy volunteers (figure 4) can be accurately distinguished, the early oral squamous carcinoma diagnosis effect is optimal, and the accurate diagnosis of the early oral squamous carcinoma is achieved.
The foregoing is merely a preferred embodiment of the present invention and is not intended to limit the scope of the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the scope of the claims of the present invention.
Claims (4)
1. The kit for the noninvasive early diagnosis of oral squamous cell carcinoma is characterized by comprising three serum lipid markers of Arginyl-methionine, glycerophosphohomoline and propionyl choline.
2. The application of the serum lipid marker in preparing a kit for the early noninvasive diagnosis of oral squamous cell carcinoma is characterized in that the serum lipid marker consists of Arginyl-methionine, glycerophosphorylcholine and propionyl choline.
3. The use of claim 2, wherein the down-regulated expression of the serum lipid marker indicates that the subject is an oral squamous carcinoma patient or a potential oral squamous carcinoma patient.
4. The use of claim 2 or 3, wherein the down-regulated expression of each of Arginyl-methionine, glycerophosphorylcholine and propiophenylcholine indicates that the subject is a human or potential human subject.
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| CN108531597A (en) * | 2018-05-03 | 2018-09-14 | 上海交通大学医学院附属第九人民医院 | A kind of detection kit for oral squamous cell carcinomas early diagnosis |
| CN110716044A (en) * | 2019-10-23 | 2020-01-21 | 郑州大学 | Serum protein marker, kit and detection method for early screening and diagnosis of esophageal squamous carcinoma |
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| US20100210023A1 (en) * | 2008-09-22 | 2010-08-19 | The Regents Of The University Of California | Salivary metabolic biomarkers for human oral cancer detection |
| WO2011113047A2 (en) * | 2010-03-12 | 2011-09-15 | The Johns Hopkins University | Compositions and methods for characterizing breast cancer |
| AU2012347557A1 (en) * | 2011-12-09 | 2014-07-03 | Metabolon, Inc. | Biomarkers for kidney cancer and methods using the same |
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| CN110716044A (en) * | 2019-10-23 | 2020-01-21 | 郑州大学 | Serum protein marker, kit and detection method for early screening and diagnosis of esophageal squamous carcinoma |
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| Exploring the effect of dentition, dental decay and familiality on oral health using metabolomics;Foxman等;Infection, Genetics and Evolution;第22卷;201-207 * |
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