CN105154542B - One group of gene for being used for lung cancer molecule parting and its application - Google Patents
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Abstract
The invention discloses the gene that one group is used for lung cancer molecule parting, including 13 genes such as COMP genes, FXYD3 genes.In addition, the invention also discloses a kind of kit for lung cancer molecule parting and its application.The present invention helps to carry out antidiastole to lung cancer hypotype, after lung cancer sample is obtained, the hypotype of lung cancer by the detection and Conjoint Analysis to said gene group, can be objectively and accurately differentiated, so as to targetedly be treated to patient.
Description
Technical field
The present invention relates to cancer diagnosis and biology field, and the application of diagnostic techniques clinically.Specifically,
The present invention relates to the gene that one group is used for lung cancer molecule parting, by the foundation of lung cancer molecular typing methods and by detecting lung cancer
The expression of specific gene in tissue, differentiates the most important hypotype of lung cancer：Adenocarcinoma of lung and lung squamous cancer.The invention further relates to completion
The kit of the lung cancer molecular typing methods.
Background technology
Lung cancer is to one of malignant tumour of population health and life threat maximum in world wide.Male lung cancer incidence
First of malignant tumour is accounted for the death rate, female lung cancer incidence accounts for the second of malignant tumour, is only second to breast cancer, extremely
The rate of dying holds pride of place.According to《2012 tumour registration annual reports》, the incidence of national tumour registration area lung cancer is 53.57/10 ten thousand,
Chinese population standardized rate is 25.34/10 ten thousand, and male is 1.94 times of women；The death rate of lung cancer is 45.57/10 ten thousand, Nan Xingwei
2.05 times of women.
Lung cancer can be divided into non-small cell lung cancer and Small Cell Lung Cancer.Wherein, non-small cell lung cancer accounts for more than 80%, mainly by
Gland cancer (also known as adenocarcinoma of lung) and squamous carcinoma (also known as squamous cell carcinoma or lung squamous cancer) composition.In the work of current clinical practice, tissue
Pathological examination is pulmonary cancer diagnosis and the goldstandard of classification, and traditional histopathological methods are to pass through the pathological tissues of acquisition
Fix, dewax, dyeing and etc., section is made and observes its morphological feature under the microscope.Detection method step is various, waits
Time is longer, and testing result has certain subjectivity.Particularly when Tumor Differentiation is poor, lack adenocarcinoma of lung and the shape of lung squamous cancer
State feature, parting is with regard to relatively difficult.Therefore there is indefinite this concept of type non-small cell lung cancer of histological type.2009
Year, one research found that in biopsy sample the indefinite type non-small cell lung cancer of histological type accounts for 25%, in cytologic specimen
In account for 40%.Therefore, it is necessary to a kind of adenocarcinoma of lung and the method for lung squamous cancer can be effectively distinguished than more objective.
In addition, lung cancer is the disease of the horizontal upper height heterogeneity of molecule, and the identical tumour of Histological Study, its molecule
Science of heredity change is not the same, so as to result in the difference of lung cancer therapy reaction and prognosis.More and more new chemicotherapy medicines
The appearance requirement of thing and targeted drug is stringent to distinguish adenocarcinoma of lung and lung squamous cancer.Life cycle is notable after using pemetrexed such as adenocarcinoma of lung
Increase, risk of the Lung Squamous Carcinoma Patients using bevacizumab there are massive haemorrhage, albumin paclitaxel with cisplatin treatment late period lung squama
Cancer curative effect is preferable, therefore the inevitable requirement that accurate parting is lung cancer individualized treatment is carried out to it.
In recent years, the understanding to lung cancer has been deepened in the research of tumor markers significantly so as to its further classification, diagnosis
And Index for diagnosis is possibly realized.As carcinomebryonic antigen (CEA) is used for the detection of adenocarcinoma of lung, cytokeratin 19 fragment 21-1
(CYFR21-1) it is used for the detection of lung squamous cancer, nerve specificity olefinic alcohol enzyme (NSE) is used for diagnosis of cellule adenocarcinoma of lung etc., but
The problem of being because of Sensitivity and Specificity, there is higher false positive and false negative, diagnosis efficiency is low.Gene molecule diagnosis tool
There are high sensitivity, high specificity, the clear and definite advantage of background mechanism, applied to various tumours more and more in recent years.Therefore,
Diagnosed using gene molecule, find a kind of differentiation adenocarcinoma of lung and the method for lung squamous cancer, help to realize personalized medicine, to patient
Carrying out precisely treatment has important clinical meaning.
The content of the invention
One of the technical problem to be solved in the present invention is to provide one group of gene for being used for lung cancer molecule parting, establishes lung cancer system
Analysis model is counted, helps to realize individualized treatment.
The second technical problem to be solved by the present invention is to provide the purposes of one group of gene for being used for lung cancer molecule parting.
The third technical problem to be solved by the present invention is to provide a kind of kit for lung cancer molecule parting and application thereof.
The four of the technical problem to be solved in the present invention are to provide one group of gene for being used for lung cancer molecule parting and are used in preparation
Judge the application in the genetic chip of lung cancer hypotype.
In order to solve the above technical problems, the present invention adopts the following technical scheme that：
In one aspect of the invention, there is provided one group of gene for being used for lung cancer molecule parting, including following 13 genes：COMP
Gene, FXYD3 genes, GABRP genes, HLA-DQA1 genes, MMP10 genes, NMU genes, NTS genes, RPS4Y1 genes,
SERPINB4 genes, SERPINB5 genes, SPRR2A genes, SPRR3 genes, UPK1B genes.
As currently preferred technical solution, which is used for the gene of tumor cells parting, further includes following 17 bases
Because of (i.e. including 30 genes)：CLCA2 genes, DSG3 genes, FGB genes, HSD17B2 genes, KRT14 genes, KRT17 bases
Cause, KRT5 genes, KRT6A genes, KRT6B genes, MIR205HG genes, MMP12 genes, S100A2 genes, SERPINB3 bases
Cause, SPINK1 genes, SPRR1B genes, TFPI2 genes, TRIM29 genes.
The present invention establishes gene marker by the use in conjunction of genetic test, marker combination and data mining algorithm
Built-up pattern, the main hypotype of lung cancer, i.e. adenocarcinoma of lung and lung squamous cancer is distinguished using polygenes prediction model, mainly including following
Step：
(1) the clinical diagnosis data and gene expression profile data of lung cancer are collected, structure includes more than 20,000 a bases known to the mankind
Because of the lung cancer gene expression profile data storehouse of, 2000 samples；
(2) statistical analysis is carried out to gene expression pattern, filters out 30 genes closely related with lung cancer hypotype, respectively
For：CLCA2 genes, COMP genes, DSG3 genes, FGB genes, FXYD3 genes, GABRP genes, HLA-DQA1 genes,
HSD17B2 genes, KRT14 genes, KRT17 genes, KRT5 genes, KRT6A genes, KRT6B genes, MIR205HG genes,
MMP10 genes, MMP12 genes, NMU genes, NTS genes, RPS4Y1 genes, S100A2 genes, SERPINB3 genes,
SERPINB4 genes, SERPINB5 genes, SPINK1 genes, SPRR1B genes, SPRR2A genes, SPRR3 genes, TFPI2 bases
Cause, TRIM29 genes, UPK1B genes.
(3) above-mentioned 30 gene expression patterns are calculated, lung cancer hypotype is evaluated by Statistic analysis models, calculate life
Thing imitates the similarity score (Similarity Score) of product and lung cancer hypotype.Judge rule according to similarity score is highest
Then, hypotype is judged.
The present invention provides a kind of detection method for being used to judge lung cancer hypotype, comprise the following steps：
(1) biological sample for being derived from patients with lung cancer is contacted with biomarker, the biomarker includes above-mentioned
30 genes；The biological sample is taken from the tumor tissue in vitro of the object, can be fresh sample or formal
Paraffin embedding (FFPE) sample that woods is fixed；
On this basis, lung cancer hypotype judgement is further carried out：
(2) expression pattern and expression of 30 genes in the biological sample, the expression based on 30 genes are detected
Level judges the hypotype classification of the biological sample.Using data analysing method, the biological sample and lung cancer hypotype are calculated
Similarity score (Similarity Score).According to the highest decision rule of similarity score, hypotype is judged.The detection
Including being used for PCR (PCR) from the sample preparation RNA, the RNA, the PCR is reverse transcription PCR (RT-
PCR), optional real-time RT-PCR either genetic chip or high throughput sequencing technologies.
In another aspect of this invention, there is provided one group of gene for being used to judge lung cancer hypotype is being prepared for judging lung cancer Asia
Application in the kit of type.
In another aspect of this invention, there is provided a kind of kit for being used to judge lung cancer hypotype, which includes as follows
Biomarker, the biomarker is selected from above-mentioned one group any one being used in the gene of lung cancer molecule parting or more
Kind.
As currently preferred technical solution, the biomarker is nucleic acid, oligonucleotide chain or PCR primer group.
As currently preferred technical solution, the PCR primer group includes：
COMP genes：Forward primer is as shown in SEQ ID NO.1, and reverse primer is as shown in SEQ ID NO.2；
FXYD3 genes：Forward primer is as shown in SEQ ID NO.3, and reverse primer is as shown in SEQ ID NO.4；
GABRP genes：Forward primer is as shown in SEQ ID NO.5, and reverse primer is as shown in SEQ ID NO.6；
HLA-DQA1 genes：Forward primer is as shown in SEQ ID NO.7, and reverse primer is as shown in SEQ ID NO.8；
MMP10 genes：Forward primer is as shown in SEQ ID NO.9, and reverse primer is as shown in SEQ ID NO.10；
NMU genes：Forward primer is as shown in SEQ ID NO.11, and reverse primer is as shown in SEQ ID NO.12；
NTS genes：Forward primer is as shown in SEQ ID NO.13, and reverse primer is as shown in SEQ ID NO.14；
RPS4Y1 genes：Forward primer is as shown in SEQ ID NO.15, and reverse primer is as shown in SEQ ID NO.16；
SERPINB4 genes：Forward primer is as shown in SEQ ID NO.17, and reverse primer is as shown in SEQ ID NO.18；
SERPINB5 genes：Forward primer is as shown in SEQ ID NO.19, and reverse primer is as shown in SEQ ID NO.20；
SPRR2A genes：Forward primer is as shown in SEQ ID NO.21, and reverse primer is as shown in SEQ ID NO.22；
SPRR3 genes：Forward primer is as shown in SEQ ID NO.23, and reverse primer is as shown in SEQ ID NO.24；
UPK1B genes：Forward primer is as shown in SEQ ID NO.25, and reverse primer is as shown in SEQ ID NO.26.
As currently preferred technical solution, the PCR primer group further includes：
CLCA2 genes：Forward primer is as shown in SEQ ID NO.27, and reverse primer is as shown in SEQ ID NO.28；
DSG3 genes：Forward primer is as shown in SEQ ID NO.29, and reverse primer is as shown in SEQ ID NO.30；
FGB genes：Forward primer is as shown in SEQ ID NO.31, and reverse primer is as shown in SEQ ID NO.32；
HSD17B2 genes：Forward primer is as shown in SEQ ID NO.33, and reverse primer is as shown in SEQ ID NO.34；
KRT14 genes：Forward primer is as shown in SEQ ID NO.35, and reverse primer is as shown in SEQ ID NO.36；
KRT17 genes：Forward primer is as shown in SEQ ID NO.37, and reverse primer is as shown in SEQ ID NO.38；
KRT5 genes：Forward primer is as shown in SEQ ID NO.39, and reverse primer is as shown in SEQ ID NO.40；
KRT6A genes：Forward primer is as shown in SEQ ID NO.41, and reverse primer is as shown in SEQ ID NO.42；
KRT6B genes：Forward primer is as shown in SEQ ID NO.43, and reverse primer is as shown in SEQ ID NO.44；
MIR205HG genes：Forward primer is as shown in SEQ ID NO.45, and reverse primer is as shown in SEQ ID NO.46；
MMP12 genes：Forward primer is as shown in SEQ ID NO.47, and reverse primer is as shown in SEQ ID NO.48；
S100A2 genes：Forward primer is as shown in SEQ ID NO.49, and reverse primer is as shown in SEQ ID NO.50；
SERPINB3 genes：Forward primer is as shown in SEQ ID NO.51, and reverse primer is as shown in SEQ ID NO.52；
SPINK1 genes：Forward primer is as shown in SEQ ID NO.53, and reverse primer is as shown in SEQ ID NO.54；
SPRR1B genes：Forward primer is as shown in SEQ ID NO.55, and reverse primer is as shown in SEQ ID NO.56；
TFPI2 genes：Forward primer is as shown in SEQ ID NO.57, and reverse primer is as shown in SEQ ID NO.58；
TRIM29 genes：Forward primer is as shown in SEQ ID NO.59, and reverse primer is as shown in SEQ ID NO.60.
The application method of mentioned reagent box comprises the following steps:
(1) biological sample comprising tumor tissues is contacted with biomarker；
(2) expression of the marker in the biological sample is measured；
(3) expression pattern of gene in biological sample is detected, and itself and lung cancer gene expression profile data storehouse are compared
It is right.
The expression of kit detection can by real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR), or
Genetic chip, or high throughput sequencing technologies.
The expression of the kit detection is mRNA expressions.
Example only as the above-mentioned subsidy of the present invention, for paraffin embedding tumor tissues, is gathered using real-time quantitative reverse transcription
Polymerase chain reacts (RT-PCR), and the method for distinguishing lung cancer hypotype, comprises the steps of：
(1) paraffin-embedded tissue of tumor tissues is obtained；
(2) expression of 30 genes in the sample is detected with real-time quantitative reverse transcriptase polymerase chain reaction；
(3) expression pattern of 30 genes in the sample is detected, and itself and lung cancer gene expression profile data storehouse are compared
It is right, distinguish lung cancer hypotype.
In another aspect of this invention, there is provided the kit is preparing the purposes in judging the preparation of lung cancer hypotype.
In another aspect of this invention, there is provided one group of gene for being used for lung cancer molecule parting is being prepared for judging lung cancer Asia
Application in the genetic chip of type, the genetic chip include solid phase carrier and probe, the probe and 13 gene sequences to be measured
Row and/or its complementary series are hybridized, and 13 genes to be measured are：COMP genes, FXYD3 genes, GABRP genes, HLA-
DQA1 genes, MMP10 genes, NMU genes, NTS genes, RPS4Y1 genes, SERPINB4 genes, SERPINB5 genes,
SPRR2A genes, SPRR3 genes, UPK1B genes；The probe is sequence shown in SEQ ID No.61~SEQ ID No.73 respectively
Row.
In another aspect of this invention, there is provided one group of gene for being used for lung cancer molecule parting is being prepared for judging lung cancer Asia
Application in the genetic chip of type, the genetic chip include solid phase carrier and probe, the probe and above-mentioned 30 bases to be measured
Because sequence and/or its complementary series are hybridized, the probe is sequence shown in SEQ ID No.61~SEQ ID No.90 respectively
Row.
The present invention is used to distinguish adenocarcinoma of lung by detecting 30 and the relevant gene of lung cancer hypotype, structure Statistic analysis models
And lung squamous cancer, so as to help doctor to carry out medication guide, realize precisely medical treatment, to improve the survival rate of patients with lung cancer, improve and suffer from
Person's survival state.Experiment proves that kit of the present invention can accurately distinguish adenocarcinoma of lung and lung squamous cancer, its is applied widely, accurate
Rate is high, helps to realize personalized medicine, and precisely treatment is carried out to patient has important clinical meaning.
Brief description of the drawings
Fig. 1 is the differentiation result schematic diagram of 30 gene pulmonary cancer diagnosis in the embodiment of the present invention 5.
Embodiment
Following embodiments are merely to illustrate the present invention, rather than limit the scope of the invention.Tool is not specified in embodiment
The experimental method of concrete conditions in the establishment of a specific crime, according to the condition proposed by manufacture kit production company or according to conventional laboratory conditions, such as
Sambrook et al., molecular cloning：Laboratory manual (New York：Cold Spring Harbor Laboratory
Press, 1989) condition described in.Unless otherwise defined, all professional and scientific terms used in text and this area are ripe
It is identical to practice meaning known to personnel.In addition, any method similar or impartial to described content and material all can be applied to
In the present invention.The preferred methods and materials described herein are for illustrative purposes only.
Embodiment 1.
Training set sample collection and processing：
The present invention analyzes the patients with lung cancer clinical data and its biological sample data of large sample size, including 391
Example lung gland, 237 lung squamous cancers, amount to the relevant clinical data and gene expression data of 628 patients, build lung cancer gene expression
Modal data storehouse.
The screening of 13 specific genes：
According to the measured value of gene expression abundance, inventor is examined from being sieved more than 20,000 in a gene using statistical analysis technique T
Select 13 genes closely related with tumour original site.These genes having differences property in lung cancer hypotype is expressed, and is had
Statistical significance, is shown in Table 1.
Table 1：13 gene sets
| Gene | Annotation | P values |
| COMP | Cartilage Oligomeric Matrix Protein | <0.001 |
| FXYD3 | FXYD Domain Containing Ion Transport Regulator 3 | <0.001 |
| GABRP | Gamma-Aminobutyric Acid(GABA)A Receptor,Pi | <0.001 |
| HLA-DQA1 | Major Histocompatibility Complex,Class II,DQ Alpha 1 | <0.001 |
| MMP10 | Matrix Metallopeptidase 10 | <0.001 |
| NMU | Neuromedin U | <0.001 |
| NTS | Neurotensin | <0.001 |
| RPS4Y1 | Ribosomal Protein S4,Y-Linked 1 | <0.001 |
| SERPINB4 | Serpin Peptidase Inhibitor,Clade B(Ovalbumin),Member 4 | <0.001 |
| SERPINB5 | Serpin Peptidase Inhibitor,Clade B(Ovalbumin),Member 5 | <0.001 |
| SPRR2A | Small Proline-Rich Protein 2A | <0.001 |
| SPRR3 | Small Proline-Rich Protein 3 | <0.001 |
| UPK1B | Uroplakin 1B | <0.001 |
The structure of 13 gene Statistic analysis models：
Expression pattern based on 13 specific genes in 628 lung cancer samples, inventor use support vector machines
(Support Vector Machines) algorithm, establishes Statistic analysis models and is used to differentiate lung cancer hypotype.It is to be measured for every an example
Sample, model calculate gland cancer and the similarity score of squamous carcinoma samples in the gene expression pattern and database of the sample, and according to
Similarity score maximum principle differentiates the hypotype classification of the sample.Since invention in 1992, algorithm of support vector machine is wide
It is applied to solve all kinds of pattern recognition problems, including finance data analysis, speech recognition and biological data analysis generally.This area
Technical staff can by free analysis software of increasing income, such as：R, Rapidminer and WEKA uses algorithm of support vector machine.
Algorithm of support vector machine is not limited solely to, other known data digging methods can all use, such as Nearest Neighbor with Weighted Voting
The closest value (K-nearest Neighbors) of (Weighted Voting), K-, random forest (Random Forest), phase
Close property coefficient (Correlation Coefficients) etc..
Embodiment 2.
Verification collection test：
In the present embodiment, inventor analyzes the high-flux sequence data for including 1130 lung cancer, wherein there is adenocarcinoma of lung
576, lung squamous cancer 554.The differentiation of hypotype is carried out to each sample by 13 gene Statistic analysis models, and is examined with clinical pathology
Disconnected result compares, accuracy rate 82.7%.Using adenocarcinoma of lung as reference, the susceptibility of prediction is 93.0%, and specificity is
72.0%, it is shown in Table 2.
Table 2：The differentiation result that 13 genetic models are concentrated in 1130 verifications
Embodiment 3.
The screening of 30 specific genes：
The T screening criterias examined are relaxed to P values less than 0.01 by inventor, further obtain 17 extra genes.This
A little genes having differences property in adenocarcinoma of lung and lung squamous cancer is expressed, and difference has statistical significance.By 17 genes and embodiment 1
In 13 genes merge, form 30 gene sets, be shown in Table 3.
Table 3：17 gene sets
| Gene | Annotation | P values |
| KRT5 | Keratin 5,Type II | <0.01 |
| S100A2 | S100A2 | <0.01 |
| KRT6A | Keratin 6A,Type II | <0.01 |
| MIR205HG | MIR205Host Gene | <0.01 |
| KRT17 | Keratin 17,Type I | <0.01 |
| CLCA2 | Chloride Channel Accessory 2 | <0.01 |
| SERPINB3 | Serpin Peptidase Inhibitor,Clade B(Ovalbumin),Member 3 | <0.01 |
| MMP12 | Matrix Metallopeptidase 12 | <0.01 |
| DSG3 | Desmoglein 3 | <0.01 |
| KRT6B | Keratin 6B,Type II | <0.01 |
| KRT14 | Keratin 14,Type I | <0.01 |
| SPINK1 | Serine Peptidase Inhibitor,Kazal Type 1 | <0.01 |
| HSD17B2 | Hydroxysteroid(17-Beta)Dehydrogenase 2 | <0.01 |
| SPRR1B | Small Proline-Rich Protein 1B | <0.01 |
| FGB | Fibrinogen Beta Chain | <0.01 |
| TFPI2 | Tissue Factor Pathway Inhibitor 2 | <0.01 |
| TRIM29 | Tripartite Motif Containing 29 | <0.01 |
The structure of 30 gene Statistic analysis models：
Expression pattern based on 30 specific genes in 628 lung cancer samples, inventor use algorithm of support vector machine,
Statistic analysis models are established to be used to differentiate lung cancer hypotype.For every an example sample to be tested, model calculates the gene expression of the sample
Pattern and gland cancer and the similarity score of squamous carcinoma samples in database, and the sample is differentiated according to similarity score maximum principle
Hypotype classification.
Embodiment 4.
Verification collection test：
In the present embodiment, inventor analyzes the high-flux sequence data for including 1130 lung cancer, wherein gland cancer 576,
Squamous carcinoma 554.By 30 gene Statistic analysis models to each sample carry out hypotype differentiation, and with Clinicopathologic Diagnosis result
Compare, accuracy rate 91.5%.Using adenocarcinoma of lung as reference, the susceptibility of prediction is 95.1%, and specificity 87.7%, is shown in Table
4。
Table 4：The differentiation result that 30 genetic models are concentrated in 1130 verifications
Embodiment 5.
In the present embodiment, the paraffin-embedded sample of the cancerous lung tissue after surgery excision is collected, the biological sample is through pathology
Lung cancer is confirmed as in diagnosis, and is known as adenocarcinoma of lung.Experimenter by hand scraping blade mode from formalin fix paraffin embedding
Tissue block on lung carcinoma cell enrichment region collect and extract total serum IgE；Handled with DNase to ensure to remove genomic DNA completely
Pollution；CDNA is obtained after reverse transcription, carries out the real-time quantitative PCR of 30 genes.Real-time quantitative PCR is reacted in ABI companies
Taqman is applied on 7500 type instrumentsTMTechnology is completed.PCR after reaction, according to the expression pattern of 30 genes of sample, unites
Meter analysis model calculates the similarity score of the sample and lung cancer hypotype.
The PCR primer group difference of 30 genes of design is as follows：
COMP genes：Forward primer is as shown in SEQ ID NO.1, and reverse primer is as shown in SEQ ID NO.2；
FXYD3 genes：Forward primer is as shown in SEQ ID NO.3, and reverse primer is as shown in SEQ ID NO.4；
GABRP genes：Forward primer is as shown in SEQ ID NO.5, and reverse primer is as shown in SEQ ID NO.6；
HLA-DQA1 genes：Forward primer is as shown in SEQ ID NO.7, and reverse primer is as shown in SEQ ID NO.8；
MMP10 genes：Forward primer is as shown in SEQ ID NO.9, and reverse primer is as shown in SEQ ID NO.10；
NMU genes：Forward primer is as shown in SEQ ID NO.11, and reverse primer is as shown in SEQ ID NO.12；
NTS genes：Forward primer is as shown in SEQ ID NO.13, and reverse primer is as shown in SEQ ID NO.14；
RPS4Y1 genes：Forward primer is as shown in SEQ ID NO.15, and reverse primer is as shown in SEQ ID NO.16；
SERPINB4 genes：Forward primer is as shown in SEQ ID NO.17, and reverse primer is as shown in SEQ ID NO.18；
SERPINB5 genes：Forward primer is as shown in SEQ ID NO.19, and reverse primer is as shown in SEQ ID NO.20；
SPRR2A genes：Forward primer is as shown in SEQ ID NO.21, and reverse primer is as shown in SEQ ID NO.22；
SPRR3 genes：Forward primer is as shown in SEQ ID NO.23, and reverse primer is as shown in SEQ ID NO.24；
UPK1B genes：Forward primer is as shown in SEQ ID NO.25, and reverse primer is as shown in SEQ ID NO.26.
CLCA2 genes：Forward primer is as shown in SEQ ID NO.27, and reverse primer is as shown in SEQ ID NO.28；
DSG3 genes：Forward primer is as shown in SEQ ID NO.29, and reverse primer is as shown in SEQ ID NO.30；
FGB genes：Forward primer is as shown in SEQ ID NO.31, and reverse primer is as shown in SEQ ID NO.32；
HSD17B2 genes：Forward primer is as shown in SEQ ID NO.33, and reverse primer is as shown in SEQ ID NO.34；
KRT14 genes：Forward primer is as shown in SEQ ID NO.35, and reverse primer is as shown in SEQ ID NO.36；
KRT17 genes：Forward primer is as shown in SEQ ID NO.37, and reverse primer is as shown in SEQ ID NO.38；
KRT5 genes：Forward primer is as shown in SEQ ID NO.39, and reverse primer is as shown in SEQ ID NO.40；
KRT6A genes：Forward primer is as shown in SEQ ID NO.41, and reverse primer is as shown in SEQ ID NO.42；
KRT6B genes：Forward primer is as shown in SEQ ID NO.43, and reverse primer is as shown in SEQ ID NO.44；
MIR205HG genes：Forward primer is as shown in SEQ ID NO.45, and reverse primer is as shown in SEQ ID NO.46；
MMP12 genes：Forward primer is as shown in SEQ ID NO.47, and reverse primer is as shown in SEQ ID NO.48；
S100A2 genes：Forward primer is as shown in SEQ ID NO.49, and reverse primer is as shown in SEQ ID NO.50；
SERPINB3 genes：Forward primer is as shown in SEQ ID NO.51, and reverse primer is as shown in SEQ ID NO.52；
SPINK1 genes：Forward primer is as shown in SEQ ID NO.53, and reverse primer is as shown in SEQ ID NO.54；
SPRR1B genes：Forward primer is as shown in SEQ ID NO.55, and reverse primer is as shown in SEQ ID NO.56；
TFPI2 genes：Forward primer is as shown in SEQ ID NO.57, and reverse primer is as shown in SEQ ID NO.58；
TRIM29 genes：Forward primer is as shown in SEQ ID NO.59, and reverse primer is as shown in SEQ ID NO.60.
The results are shown in Figure 1, and the similarity score of gland cancer and squamous carcinoma is respectively 91.7% and 8.3%.Due to the phase of gland cancer
It is higher than squamous carcinoma like degree fraction, therefore the sample is judged as adenocarcinoma of lung, is consistent with Clinicopathologic Diagnosis result.
Embodiment 6.
In the present embodiment, inventor carries out gene chip experiment, wherein gland cancer 125, squamous carcinoma 80 to 205 lung cancer samples
Example.Genetic chip is by the DNA fragmentation of a large amount of particular sequences or few core former times acid fragment by microelectric technique and micro-processing technology
Be fixed on by matrix high density on the carriers such as glass, silicon chip, after sample to be tested is marked with fluorescence molecule, with big DNA on chip or
Few core former times acid fragment hybridization, by a kind of detection method that lots of genes information is obtained after fluorescent scanning and computer analysis.Its
Outstanding feature, can in that can carry out quick, accurate, high-throughout detection and analysis to the nucleic acid sequence information in micro-example
To obtain the gene expression abundance of thousands of a genes at the same time collection of illustrative plates is associated with expression pattern.
Experimenter by hand scraping blade mode from formalin fix paraffin embedding tissue block on lung carcinoma cell enrichment
Collect and extract total serum IgE in area；Handled with DNase to ensure to remove the pollution of genomic DNA completely；Obtained after reverse transcription
cDNA；CDNA is mixed with genetic chip, hybridization reaction；The gene expression abundance of gene is detected by scanning fluorescence signal.Gene core
Piece after reaction, extracts the expression pattern of 30 genes of sample, and Statistic analysis models calculate the sample and tumors subtypes
Similarity score.
By 30 gene Statistic analysis models to each sample carry out hypotype differentiation, and with Clinicopathologic Diagnosis result phase
Compare, accuracy rate 95.6%.Using adenocarcinoma of lung as reference, the susceptibility of prediction is 94.4%, and specificity 97.5%, is shown in Table 5.
Table 5：The differentiation result that 30 genetic models are concentrated in 205 verifications
The probe sequence difference of 30 genes is as shown in table 6 below in genetic chip：
Table 6
| Sequence number | Gene | Probe |
| 1 | COMP | SEQ ID NO.61 |
| 2 | FXYD3 | SEQ ID NO.62 |
| 3 | GABRP | SEQ ID NO.63 |
| 4 | HLA-DQA1 | SEQ ID NO.64 |
| 5 | MMP10 | SEQ ID NO.65 |
| 6 | NMU | SEQ ID NO.66 |
| 7 | NTS | SEQ ID NO.67 |
| 8 | RPS4Y1 | SEQ ID NO.68 |
| 9 | SERPINB4 | SEQ ID NO.69 |
| 10 | SERPINB5 | SEQ ID NO.70 |
| 11 | SPRR2A | SEQ ID NO.71 |
| 12 | SPRR3 | SEQ ID NO.72 |
| 13 | UPK1B | SEQ ID NO.73 |
| 14 | CLCA2 | SEQ ID NO.74 |
| 15 | DSG3 | SEQ ID NO.75 |
| 16 | FGB | SEQ ID NO.76 |
| 17 | HSD17B2 | SEQ ID NO.77 |
| 18 | KRT14 | SEQ ID NO.78 |
| 19 | KRT17 | SEQ ID NO.79 |
| 20 | KRT5 | SEQ ID NO.80 |
| 21 | KRT6A | SEQ ID NO.81 |
| 22 | KRT6B | SEQ ID NO.82 |
| 23 | MIR205HG | SEQ ID NO.83 |
| 24 | MMP12 | SEQ ID NO.84 |
| 25 | S100A2 | SEQ ID NO.85 |
| 26 | SERPINB3 | SEQ ID NO.86 |
| 27 | SPINK1 | SEQ ID NO.87 |
| 28 | SPRR1B | SEQ ID NO.88 |
| 29 | TFPI2 | SEQ ID NO.89 |
| 30 | TRIM29 | SEQ ID NO.90 |
Embodiment described above only expresses embodiments of the present invention, its description is more specific and detailed, but can not
Therefore it is interpreted as the limitation to the scope of the claims of the present invention.It should be pointed out that for those of ordinary skill in the art,
Without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the protection model of the present invention
Enclose.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
Claims (13)
1. one group of gene for being used for lung cancer molecule parting, it is characterised in that including following 13 genes：COMP genes, FXYD3 bases
Cause, GABRP genes, HLA-DQA1 genes, MMP10 genes, NMU genes, NTS genes, RPS4Y1 genes, SERPINB4 genes,
SERPINB5 genes, SPRR2A genes, SPRR3 genes, UPK1B genes.
2. the one group as claimed in claim 1 gene for being used for lung cancer molecule parting, it is characterised in that further include following 17 bases
Cause：CLCA2 genes, DSG3 genes, FGB genes, HSD17B2 genes, KRT14 genes, KRT17 genes, KRT5 genes, KRT6A
Gene, KRT6B genes, MIR205HG genes, MMP12 genes, S100A2 genes, SERPINB3 genes, SPINK1 genes,
SPRR1B genes, TFPI2 genes, TRIM29 genes.
3. gene as claimed in claim 1 or 2, it is characterised in that the lung cancer molecule parting is lung to distinguish lung cancer hypotype
Gland cancer and lung squamous cancer.
4. as one group of gene for being used for lung cancer molecule parting of claim 1-2 any one of them is being prepared for lung cancer molecule point
Application in the kit of type.
5. a kind of kit for lung cancer molecule parting, it is characterised in that the kit detects following biomarker, described
Biomarker is selected from one group of gene for being used for lung cancer molecule parting of claim 1-2 any one of them.
6. kit as claimed in claim 5, it is characterised in that the kit includes the core for detecting the biomarker
Acid.
7. kit as claimed in claim 5, it is characterised in that the kit includes the widow for detecting the biomarker
Nucleic acid chains.
8. kit as claimed in claim 5, it is characterised in that the kit, which includes, detects the biomarker
PCR primer group.
9. kit as claimed in claim 8, it is characterised in that the PCR primer group includes：
COMP genes：Forward primer is as shown in SEQ ID NO.1, and reverse primer is as shown in SEQ ID NO.2；
FXYD3 genes：Forward primer is as shown in SEQ ID NO.3, and reverse primer is as shown in SEQ ID NO.4；
GABRP genes：Forward primer is as shown in SEQ ID NO.5, and reverse primer is as shown in SEQ ID NO.6；
HLA-DQA1 genes：Forward primer is as shown in SEQ ID NO.7, and reverse primer is as shown in SEQ ID NO.8；
MMP10 genes：Forward primer is as shown in SEQ ID NO.9, and reverse primer is as shown in SEQ ID NO.10；
NMU genes：Forward primer is as shown in SEQ ID NO.11, and reverse primer is as shown in SEQ ID NO.12；
NTS genes：Forward primer is as shown in SEQ ID NO.13, and reverse primer is as shown in SEQ ID NO.14；
RPS4Y1 genes：Forward primer is as shown in SEQ ID NO.15, and reverse primer is as shown in SEQ ID NO.16；
SERPINB4 genes：Forward primer is as shown in SEQ ID NO.17, and reverse primer is as shown in SEQ ID NO.18；
SERPINB5 genes：Forward primer is as shown in SEQ ID NO.19, and reverse primer is as shown in SEQ ID NO.20；
SPRR2A genes：Forward primer is as shown in SEQ ID NO.21, and reverse primer is as shown in SEQ ID NO.22；
SPRR3 genes：Forward primer is as shown in SEQ ID NO.23, and reverse primer is as shown in SEQ ID NO.24；
UPK1B genes：Forward primer is as shown in SEQ ID NO.25, and reverse primer is as shown in SEQ ID NO.26.
10. kit as claimed in claim 8, it is characterised in that the PCR primer group further includes：
CLCA2 genes：Forward primer is as shown in SEQ ID NO.27, and reverse primer is as shown in SEQ ID NO.28；
DSG3 genes：Forward primer is as shown in SEQ ID NO.29, and reverse primer is as shown in SEQ ID NO.30；
FGB genes：Forward primer is as shown in SEQ ID NO.31, and reverse primer is as shown in SEQ ID NO.32；
HSD17B2 genes：Forward primer is as shown in SEQ ID NO.33, and reverse primer is as shown in SEQ ID NO.34；
KRT14 genes：Forward primer is as shown in SEQ ID NO.35, and reverse primer is as shown in SEQ ID NO.36；
KRT17 genes：Forward primer is as shown in SEQ ID NO.37, and reverse primer is as shown in SEQ ID NO.38；
KRT5 genes：Forward primer is as shown in SEQ ID NO.39, and reverse primer is as shown in SEQ ID NO.40；
KRT6A genes：Forward primer is as shown in SEQ ID NO.41, and reverse primer is as shown in SEQ ID NO.42；
KRT6B genes：Forward primer is as shown in SEQ ID NO.43, and reverse primer is as shown in SEQ ID NO.44；
MIR205HG genes：Forward primer is as shown in SEQ ID NO.45, and reverse primer is as shown in SEQ ID NO.46；
MMP12 genes：Forward primer is as shown in SEQ ID NO.47, and reverse primer is as shown in SEQ ID NO.48；
S100A2 genes：Forward primer is as shown in SEQ ID NO.49, and reverse primer is as shown in SEQ ID NO.50；
SERPINB3 genes：Forward primer is as shown in SEQ ID NO.51, and reverse primer is as shown in SEQ ID NO.52；
SPINK1 genes：Forward primer is as shown in SEQ ID NO.53, and reverse primer is as shown in SEQ ID NO.54；
SPRR1B genes：Forward primer is as shown in SEQ ID NO.55, and reverse primer is as shown in SEQ ID NO.56；
TFPI2 genes：Forward primer is as shown in SEQ ID NO.57, and reverse primer is as shown in SEQ ID NO.58；
TRIM29 genes：Forward primer is as shown in SEQ ID NO.59, and reverse primer is as shown in SEQ ID NO.60.
11. kit as claimed in claim 5 is preparing the purposes in judging the preparation of lung cancer hypotype.
12. the one group as claimed in claim 1 gene for being used for lung cancer molecule parting is preparing the base for judging lung cancer hypotype
Because of the application in chip, the genetic chip includes solid phase carrier and probe, it is characterised in that the probe and 13 bases to be measured
Because sequence and/or its complementary series are hybridized, the probe is sequence shown in SEQ ID NO.61~SEQ ID NO.73 respectively
Row.
13. the one group as claimed in claim 2 gene for being used for lung cancer molecule parting is preparing the base for judging lung cancer hypotype
Because of the application in chip, the genetic chip includes solid phase carrier and probe, it is characterised in that the probe and 30 bases to be measured
Because sequence and/or its complementary series are hybridized, the probe is sequence shown in SEQ ID NO.61~SEQ ID NO.90 respectively
Row.
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| CN109852697A (en) * | 2019-03-28 | 2019-06-07 | 中国科学院上海生命科学研究院 | The molecular target of adenosquamous carcinoma diagnosis and its application |
| CN110379465A (en) * | 2019-07-19 | 2019-10-25 | 元码基因科技（北京）股份有限公司 | Based on RNA target to sequencing and machine learning cancerous tissue source tracing method |
| CN112301125A (en) * | 2019-07-30 | 2021-02-02 | 立森印迹诊断技术（无锡）有限公司 | Tumor marker and application thereof |
| CN110400601A (en) * | 2019-08-23 | 2019-11-01 | 元码基因科技(无锡)有限公司 | Based on RNA target to sequencing and machine learning cancer subtypes classifying method and device |
| CN110760577A (en) * | 2019-11-21 | 2020-02-07 | 深圳市龙华区人民医院 | Application of KRT6A gene methylation in asthenospermia diagnostic agent and kit |
| CN112375826B (en) * | 2020-12-03 | 2021-08-27 | 远见生物科技（上海）有限公司 | Circular RNA composition marker for identifying non-small cell lung cancer subtype and application thereof |
| CN114032308B (en) * | 2021-11-19 | 2022-11-29 | 上海生物芯片有限公司 | Use of a combination of FAM83A, KPNA2, KRT6A and LDHA as a biomarker for lung adenocarcinoma |
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Application publication date: 20151216 Assignee: Hangzhou able Gene Technology Co., Ltd. Assignor: HANGZHOU YUANQING BIOTECHNOLOGY CO., LTD. Contract record no.: 2018330000034 Denomination of invention: Group of genes for lung cancer molecular subtyping and application thereof License type: Exclusive License Record date: 20180416 |