CN114199980B - Lung cancer typing judgment system based on mass spectrum imaging technology - Google Patents
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Abstract
According to the invention, a sample is collected once through a mass spectrum imaging mode and different distribution markers are directionally extracted, so that the direct parting discrimination and diagnosis of benign and malignant lung cancer, small cell cancer, non-small cell cancer, adenocarcinoma, squamous cell cancer and the like can be realized without the help of other traditional pathological diagnosis methods.
Description
Technical Field
The invention relates to a medicine detection system, in particular to a lung cancer typing judgment system based on a mass spectrum imaging technology.
Background
Lung cancer is a heterogeneous disease, one of the most rapidly growing malignant tumors that have the greatest morbidity and mortality, and are the greatest threat to the health and life of the population. According to reports, the incidence and death rate of lung cancer in many countries are obviously increased in recent 50 years, the incidence and death rate of lung cancer in men are the first place of all malignant tumors, the incidence of lung cancer in women is the second place, and the death rate is the second place. The pathological types of lung cancer mainly comprise two major types of non-small cell lung cancer and small cell lung cancer. Non-small cell lung cancer accounts for about 80% -85% of lung cancer, including adenocarcinoma, squamous carcinoma, etc. While small cell lung cancer accounts for about 15% -20% of lung cancer.
The main basis of the existing lung cancer treatment mode selection is pathological typing and stage diagnosis. Pathotyping is generally by histological determination of its subtype: important typing is for example: small cell vs non-small cell, adenocarcinoma vs squamous cell carcinoma, etc. Differentiation between the various morphological subtypes of lung cancer is necessary in guiding patient management, as are the different pathological subtypes, with their corresponding treatment strategies, such as: the small cell undifferentiated lung cancer has high malignancy, is easy to transfer in early stage, is sensitive to radiotherapy and chemotherapy, and is a main treatment means for non-operative treatment of systemic chemotherapy and local radiotherapy. The non-small cell lung cancer mainly comprises squamous carcinoma and adenocarcinoma, the I, II-stage non-small cell lung cancer mainly adopts an operation, and the non-small cell lung cancer can be cured by partially combining postoperative auxiliary chemoradiotherapy. For non-small cell lung cancer, the tumor cells of the adenocarcinoma grow faster, and most of the tumors are transferred in early stages, so that the tumors are more sensitive to chemotherapeutics and have poor reflex treatment effect, and modes such as surgery, chemotherapy, immunization, targeted treatment and the like are often selected. The scale cancer is relatively slow, most of early stage is local invasion, mainly the lymph node metastasis way, and distant metastasis occurs relatively late, so the sensitivity to the radiation therapy of the scale cancer is higher, and the modes of operation, radiation, immunotherapy and the like are generally adopted.
In the current clinical practice, histopathological examination is the gold standard for lung cancer diagnosis and classification, and the traditional histopathological method is to make the obtained pathological tissue into a slice through the steps of fixing, dewaxing, staining and the like, and observe the morphological characteristics of the slice under a microscope. The detection method has the advantages of multiple steps, long waiting time and certain subjectivity of detection results. In particular, when tumors are poorly differentiated, they lack the morphological characteristics of lung adenocarcinoma and lung squamous carcinoma, and they are difficult to type. Thus, the concept of histologically undefined type of non-small cell lung cancer appears.
Lung cancer is a type of disease with high heterogeneity at the molecular level, and is a tumor with the same histomorphology, and the molecular genetic changes are not uniform, so that the difference of the lung cancer treatment response and prognosis is caused. The advent of more and more new chemoradiotherapy and targeted drugs requires strict differentiation between lung adenocarcinoma and lung squamous carcinoma. If the survival time of lung adenocarcinoma after pemetrexed is obviously prolonged, the risk of massive hemorrhage exists when bevacizumab is used by a lung squamous carcinoma patient, and the curative effect of treating advanced lung squamous carcinoma by combining albumin taxol with cisplatin is good, so that accurate typing is a necessary requirement for individualized treatment of lung cancer.
In the prior art, except for carrying out lung cancer typing by histopathological examination, the lung cancer typing is mainly carried out by modes such as biological protein, gene sequencing and the like. Lung cancer typing and diagnosis was performed as expression of at least two tumor marker genes in NCAM splice variants NCAM 120, NCAM140 and/or NCAM 180, cytokeratin (CK), neuroendocrine Specific Protein (NSP) -reticulon (RTN 1), synaptobrevin (synh), chromogranin a (CHGA), thyroid transcription factor 1 (TITF-1), gamma neuron specific enolase (γnse) and heat shock protein-47 (HSP 47) as in CN102084253 a. In CN109954148A, the autofluorescence intensity of normal lung tissues of a subject is excited by using excitation light between 440nm and 700nm for lung cancer typing, and when the autofluorescence intensity of the normal lung tissues of the subject is reduced by any value between 0% and 60%, the subject is judged to be lung adenocarcinoma; a subject is determined to be lung squamous carcinoma when the autofluorescence intensity of normal tissue of the subject's lung decreases by any value between 70% -100%.
Lung cancer is classified into non-small cell lung cancer and small cell lung cancer, and non-small cell cancer is classified into squamous cell cancer, adenocarcinoma, large cell cancer, and the like. CN113484518A discloses a diagnostic biomarker for distinguishing lung diseases, which adopts phenylalanyl phenylalanine as a marker to mainly distinguish lung cancer and tuberculosis. CN106795565a discloses a method for assessing lung cancer status by determining the mRNA expression level of one or more informative-genes associated with lung cancer status in the biological sample and determining the mRNA expression level of one or more genome-associated genes associated with one or more self-reportable features of the subject in the biological sample; and determining a lung cancer risk score based on the determined expression level, which indicates a likelihood that the subject has lung cancer.
The accurate pathological typing of lung cancer plays an extremely important role in effectively treating lung cancer and researching the mechanism of lung cancer pathogenesis and development, and has become one of research hot spots and key points in the related fields in recent years.
The prior clinical field mainly depends on morphological pathological means such as HE staining, immunohistochemistry and the like and combines NGS molecular pathological indexes, and the methods not only need to relate to various instruments, have long time consumption and complex pretreatment, but also very depend on personal experience and judgment of doctors in diagnosis and lack of index standards. In the prior art, the typing of benign and malignant lung cancer, small cell cancer and non-small cell cancer, adenocarcinoma and squamous cell cancer can be distinguished and identified simultaneously by a simple detection mode.
Disclosure of Invention
The invention takes a human lung cancer clinical sample (with benign paracancerous tissue lung cancer sample, small cell lung cancer sample and adenocarcinoma and squamous cell carcinoma sample) as an important research object, and discovers that the microscopic mass spectrometry imaging technology can realize the visual typing of the distributed marker index of the lung cancer.
The invention opens up a brand-new method for judging the benign and malignant lung cancer, small cell cancer and non-small cell cancer, adenocarcinoma and squamous cell cancer by differentiating the distribution of small molecular metabolites based on mass spectrum imaging means besides the traditional pathological means (including HE staining, immunofluorescence and the like). The method is favorable for accurately judging benign and malignant lung cancer and parting from two aspects of accurate small molecular differential markers and visual distribution, thereby realizing a novel method for researching and diagnosing lung cancer outside the traditional morphology and molecular pathology.
According to the invention, a sample is collected once through a mass spectrum imaging mode and different distribution markers are directionally extracted, so that the direct parting discrimination and diagnosis of benign and malignant lung cancer, small cell cancer, non-small cell cancer, adenocarcinoma, squamous cell cancer and the like can be realized without the help of other traditional pathological diagnosis methods.
The patent uses microscopic mass spectrometry imaging technology to carry out experimental study on human lung cancer tissues (small cell carcinoma, adenocarcinoma and squamous cell carcinoma). According to experimental results, 4 distribution markers with extremely strong correlation with pathological typing of small cell cancer and lung small cell cancer (adenocarcinoma, squamous cell cancer) are found, and the typing judgment of benign and malignant lung cancer, small cell cancer, non-small cell cancer, adenocarcinoma and squamous cell cancer of lung cancer tissues can be realized without the help of traditional pathological means by performing one comparison on the 4 distribution markers. The imaging mass spectrum technology provides accurate substance positioning qualitative and quantitative information for carrying out pathological typing research on major diseases such as lung cancer on a molecular level, and can provide more reliable experimental data and basic information for multiple fields such as clinical pathological research and application.
The invention provides a lung cancer benign and malignant parting system, which comprises a matrix sublimation system, an imaging mass spectrometry microscope system and a data processing system; wherein the sample is subjected to a matrix sublimation system; analysis using an imaging mass spectrometry microscope system; the data processing system processes mass spectrum imaging data of the sample; the data processing system comprises an m/z 775.55 analysis system, m/z 775.55 fragments being low expressed in cancer tissue and high expressed in paracancerous or normal tissue; to distinguish lung cancer benign or malignant, or normal tissue from cancer tissue.
The invention also provides a small cell carcinoma and non-small cell carcinoma parting system, which comprises a matrix sublimation system, an imaging mass spectrometry microscope system and a data processing system; wherein the sample is subjected to a matrix sublimation system; analysis using an imaging mass spectrometry microscope system; the data processing system processes mass spectrum imaging data of the sample; the data processing system comprises an m/z885.55 analysis system and an m/z 861.55 analysis system; non-small cell carcinoma when both m/z885.55 and m/z 861.55 fragments are highly expressed in cancer tissue and are poorly expressed in paracancerous tissue; small cell carcinoma when m/z885.55 is highly expressed in cancer tissue and m/z 861.55 is highly expressed in paracancerous tissue.
The invention also provides a parting system of adenocarcinoma and squamous cell carcinoma, which comprises a matrix sublimation system, an imaging mass spectrometry microscope system and a data processing system; wherein the sample is subjected to a matrix sublimation system; analysis using an imaging mass spectrometry microscope system; the data processing system processes mass spectrum imaging data of the sample; the data processing system comprises an m/z 673.48 analysis system, which judges according to different distributions of m/z 673.48 fragments, and when the fragments are highly expressed in cancer and beside the cancer, the fragments are adenocarcinoma; when the fragment is highly expressed only beside the cancer, it is squamous cell carcinoma.
The invention also provides a parting system for simultaneously distinguishing benign and malignant lung cancer, small cell cancer from non-small cell cancer, adenocarcinoma and squamous cell cancer, which comprises a matrix sublimation system, an imaging mass spectrometry microscope system and a data processing system; wherein the sample is subjected to a matrix sublimation system; analysis using an imaging mass spectrometry microscope system; the data processing system processes mass spectrum imaging data of the sample; the data processing system includes an m/z 775.55 analysis system, an m/z885.55 analysis system, an m/z 861.55 analysis system, and an m/z 673.48 analysis system;
m/z 775.55 fragments are low expressed in cancer tissue, but high expressed in paracancerous or normal tissue; to distinguish lung cancer benign or malignant, or normal tissue from cancer tissue;
non-small cell carcinoma when both m/z885.55 and m/z 861.55 fragments are highly expressed in cancer tissue and are poorly expressed in paracancerous tissue; small cell carcinoma when m/z885.55 is highly expressed in cancer tissue and m/z 861.55 is highly expressed in paracancerous tissue;
when m/z 673.48 fragments are highly expressed beside cancer, they are adenocarcinomas; when the fragment is highly expressed only beside the cancer, it is squamous cell carcinoma.
A parting system as described above, characterized in that the matrix sublimation system is an iMLayer vapor deposition system (iMLayer Matrix Vapor Deposition System).
A typing system as described above, characterized in that said imaging mass spectrometry microscope is an imaging mass spectrometry microscope immcope TRIO.
A parting system as described above, characterized in that the substrate coating conditions are:
| species of matrix | 9-Aminoacridine (9 AA) |
| Matrix coating mode | Sublimation method (iMLlayer) |
| Sublimation thickness of matrix | 0.9μm |
。
A typing system as described above, characterized by imaging mass spectrometry conditions of:
| analysis mode | Negative ion mode |
| Acquisition range | m/z 500-1000 |
| Laser diameter | 40μm |
| Acquisition interval | 100μm |
。
A typing system as described above, wherein said data processing system uses Imaging MS Solution Postrun Analysis to process the above collected data; images of m/z 775.55, m/z885.55, m/z 861.55, and/or m/z 673.48 patches are directionally extracted, respectively.
The sample in the invention refers to an isolated sample of a detection object, specifically an isolated sample of lung tissue, and can be an isolated sample of lung cancer tissue.
The invention also provides a marker composition for distinguishing benign and malignant lung cancer, small cell cancer from non-small cell cancer, adenocarcinoma and squamous cell cancer, which is characterized by comprising: 1, 2, 3 or 4 of m/z 775.55, m/z885.55, m/z 861.55, and/or m/z 673.48.
The invention also provides application of the marker composition for distinguishing benign and malignant lung cancer, small cell cancer from non-small cell cancer and adenocarcinoma from squamous cell cancer in preparation of medicines, reagents, kits or devices for distinguishing benign and malignant lung cancer, small cell cancer from non-small cell cancer and adenocarcinoma from squamous cell cancer.
The markers comprise one or more of m/z 775.55, m/z885.55, m/z 861.55, and/or m/z 673.48.
Drawings
Fig. 1: a lung cancer distinguishing flow chart;
fig. 2: the center of cancer (in yellow circle) is distinguished from paracancerous by m/z 775.55;
fig. 3: small cell carcinoma and lung small cell carcinoma are distinguished by different distributions of m/z885.55 and m/z 861.55;
fig. 4: adenocarcinoma AC is distinguished from squamous carcinoma SCC by m/z 673.48.
Detailed Description
The invention is further illustrated by the following examples.
Example 1
1. Sample preparation and loading: the clinical samples were frozen and then prepared into slices by a frozen microtome. After sublimation of the matrix of the prepared sections by an iMLayer vapor deposition system (iMLayer Matrix Vapor Deposition System), the sections were analyzed using an imaging mass spectrometry microscope iMScope TRIO as shown in fig. 1:
substrate coating conditions
| Species of matrix | 9-Aminoacridine (9 AA) |
| Matrix coating mode | Sublimation method (iMLlayer) |
| Sublimation thickness of matrix | 0.9μm |
Imaging mass spectrometry conditions
| Analysis mode | Negative ion mode |
| Acquisition range | m/z 500-1000 |
| Laser diameter | 40μm |
| Acquisition interval | 100μm |
2. Software processing and calculation: the above collected data was processed using Imaging MS Solution Postrun Analysis. Images of fragments such as m/z 775.55, m/z885.55, m/z 861.55, m/z 673.48 are extracted directionally, respectively. Recognition and judgment are carried out according to the flow of FIG. 1
3. Sample verification:
1) Cancer and paracancerous: the distribution region discrimination was performed based on m/z 775.55, and the fragments were highly expressed in the paracancerous tissue and lowly expressed in the cancerous tissue, as shown in FIG. 2;
2) Small cell carcinoma SCLC versus non-small cell carcinoma NSCLC: discrimination was made according to the different distributions of m/z885.55, m/z 861.55, which were non-small cell carcinomas when both were highly expressed in cancer tissue and lowly expressed in paracancerous tissue; when m/z885.55 is highly expressed in cancer tissue and m/z 861.55 is highly expressed in paracancerous tissue, it is a small cell carcinoma, as shown in FIG. 3:
3) Adenocarcinoma AC and squamous cell carcinoma SCC: discrimination is performed according to different distributions of m/z 673.48, and when the fragment is highly expressed beside cancer, the fragment is adenocarcinoma; when the fragment is highly expressed only beside the cancer, it is squamous cell carcinoma. As shown in fig. 4.
The above description is a general description of the invention. Variations in form and value may be substituted for the purpose of illustration and not limitation, as the terms are used herein, depending on the circumstances or actual requirements. Various changes and modifications to the present invention may be made by one skilled in the art, and such equivalents are intended to fall within the scope of the present application as defined in the appended claims.
Claims (6)
1. A typing system for simultaneously distinguishing benign and malignant lung cancer, small cell cancer from non-small cell cancer, adenocarcinoma from squamous cell cancer, comprising a matrix sublimation system, an imaging mass spectrometry microscope system, and a data processing system; wherein the sample is subjected to a matrix sublimation system; analysis using an imaging mass spectrometry microscope system; the data processing system processes mass spectrum imaging data of the sample; the data processing system includes an m/z 775.55 analysis system, an m/z885.55 analysis system, an m/z 861.55 analysis system, and an m/z 673.48 analysis system;
m/z 775.55 fragments are low expressed in cancer tissue, but high expressed in paracancerous or normal tissue; to distinguish lung cancer benign or malignant, or normal tissue from cancer tissue;
non-small cell carcinoma when both m/z885.55 and m/z 861.55 fragments are highly expressed in cancer tissue and are poorly expressed in paracancerous tissue; small cell carcinoma when m/z885.55 is highly expressed in cancer tissue and m/z 861.55 is highly expressed in paracancerous tissue;
when m/z 673.48 fragments are highly expressed in cancer and paracancerous tissues, they are adenocarcinomas; squamous cell carcinoma is the case when the fragment is highly expressed only in the paracancerous tissue.
2. The parting system of claim 1, wherein the matrix sublimation system is an iMLayer vapor deposition system (iMLayer Matrix Vapor Deposition System).
3. The parting system of claim 1, wherein the imaging mass microscope is an imaging mass microscope immscope TRIO.
4. The parting system of claim 1, wherein the substrate coating conditions are:
。
5. The parting system of claim 1, wherein the imaging mass spectrometry conditions are:
。
6. The parting system as in claim 1, wherein said data processing system processes the collected data using Imaging MS Solution Postrun Analysis; images of m/z 775.55, m/z885.55, m/z 861.55, and/or m/z 673.48 patches, respectively, are directionally extracted.
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| CN202111317988.0A CN114199980B (en) | 2021-11-08 | 2021-11-08 | Lung cancer typing judgment system based on mass spectrum imaging technology |
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| CN202111317988.0A CN114199980B (en) | 2021-11-08 | 2021-11-08 | Lung cancer typing judgment system based on mass spectrum imaging technology |
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