CN108893533A - For predicting or assisting the kit of prediction lung radiation future trouble radiation pneumonitis risk - Google Patents
For predicting or assisting the kit of prediction lung radiation future trouble radiation pneumonitis risk Download PDFInfo
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Abstract
The present invention relates to lung cancer therapy fields, specifically, it provides a kind of for predicting or assisting the kit of prediction lung radiation future trouble radiation pneumonitis risk, it include the system that can evaluate the genotype that patient chest tumour receives the detection genetic biomarker object that whether can cause 2 grades or 2 grades or more of radiation pneumonitis after radiation treatment in the kit, wherein, sharing 31 genetic biomarker objects can be used as testing and evaluation target spot.The kit can accurately and efficiently prejudge out patient chest tumour receives 2 grades or 2 grades or more of radiation pneumonitis whether can be caused after radiation treatment, use simplicity, it is easy to operate, as a result reliably, for the monitoring after Patients Treated by Radiotherapy and treat with very important directive significance.
Description
Technical field
The present invention relates to lung cancer therapy fields, in particular to one kind for predicting or assisting after predicting lung's radiation
Suffer from the kit of radiation pneumonitis risk.
Background technique
Lung cancer is the high-incidence tumour of the first high-incidence women second of male in China, while being also that the lethal number in China is most and swelling
Tumor.Radiation treatment is a kind of important technical of oncotherapy, with advances in technology, the treatment for lung cancer, radiotherapy
Therapeutic effect can compare the effect of operative treatment, while radiotherapy is small to the damage of patient body, patient after treatment
Quality of life is good, and cost needed for mean treatment is also lower than operative treatment.It, can be pre- along with the development of national economy
More medical institutions will be had by, which seeing, can introduce advanced radiotherapy apparatus, while raising of the people to quality of life demand, radiotherapy
Will increasingly important role gradually will be played in the field of oncotherapy.
In the accurate medical field of lung cancer, technology is delineated in the progress of technology, such as advanced therapeutic equipments and advanced image,
Impart Radio-oncologist personalized treatment, the ability of precise radiotherapy.But these accurate medical treatment are all based on clinic
Parameter and anatomic information determine dosage.One ultimate challenge of radiation treatment is the resistance to spoke for how handling tumor hypoxia cell
The susceptibility of penetrating property, that is, tumour to ray itself.Whether patient is for that can cause complication (such as after the radiotherapy of certain dose
Lung, the injury of kidney etc. that radiotherapy causes) etc. these with accurately relevant information of radiating medical be all that can not be conciliate from clinical parameter
It cuts open and obtains in information.So lacking reliable radiological dose biological marker at present.The radioactivity of lung cancer is controlled at present
It treats, maximum limiting factor is induced lung injury.The damage is caused by being damaged caused by surrounding normal tissue as ray,
Including acute radiation pneumonitis and chronic radiation fibrosis of lung.Therefore, clinically solution is badly in need of in the radiotherapy of lung cancer at present
Certainly the problem of is：How to prejudge out whether patient can occur the radiation pneumonitis of high risk sexual 2 grades or 2 grades or more in advance.
In view of this, the present invention is specifically proposed.
Summary of the invention
The first object of the present invention is to provide a kind of for predicting or assisting prediction lung radiation future trouble radiation pneumonitis
The kit of risk receives radiation to alleviate to lack one kind in the prior art and can accurately and efficiently prejudge patient chest tumour
Property treatment after whether can cause 2 grades or 2 grades or more radiation pneumonitis product.
The second object of the present invention is the system for providing the genotype of detection genetic biomarker object in reagent preparation box
In application, the third object of the present invention is to provide the system of the genotype of detection genetic biomarker object and records as follows
Weight coefficient and the carrier of evaluation method are applied in the kit of preparation diagnosis or auxiliary diagnosis radiation pneumonitis, existing to alleviate
There is the technical issues of biomarker and evaluation method for lacking anticipation radiation pneumonitis generation in technology.
In order to realize above-mentioned purpose of the invention, spy uses following technical scheme：
The present invention provides a kind of for predicting or assisting the kit of prediction lung radiation future trouble radiation pneumonitis risk, packet
The system for including the genotype of detection genetic biomarker object, the genetic biomarker object are as follows：
The physical coordinates are with the mankind with reference to genome version 37 for reference.
Further, the kit further includes the carrier for recording following weight coefficient and evaluation method：
The genotype for detecting the above-mentioned genetic biomarker level point of patient is opposed with the mankind with reference to genome version 37
Than original to be assigned a value of 0 when being Wild homozygous；For wild heterozygous or variation heterozygous when, it is original to be assigned a value of 1；For variation
It is original to be assigned a value of 2 when homozygous, the original assignment in each site is multiplied with the weight coefficient in the site as final assignment,
By the final assignment summation in all sites as calculating score value；
If calculating score value is greater than 0.5, which, which is predicted to be, can occur 2 grades or 2 grades or more radiation pneumonitis.
Further, the system of the genotype of the detection genetic biomarker object is by described in the detection of gene sequencing method
Reagent needed for the genotype of genetic biomarker object and/or instrument；
The reagent as detection genetic biomarker object genotype primer or probe and carry out gene sequencing needed for
Other reagents composition wanted.
Further, the system of the genotype of the detection genetic biomarker object is detects institute by biochip technology
Reagent needed for stating the genotype of genetic biomarker object and/or instrument；
Required for probe and progress genechip detection of the reagent as the genotype of detection genetic biomarker object
Other reagents composition.
Further, the system of the genotype of the detection genetic biomarker object is by described in the detection of fluorescent PCR method
Reagent needed for the genotype of genetic biomarker object and/or instrument；
The reagent as detection genetic biomarker object genotype probe and carry out fluorescent PCR detection required for
Other reagents composition；
Preferably, the system of the genotype of the detection genetic biomarker object is by described in the detection of superbead chip technology
Reagent needed for the genotype of genetic biomarker object and/or instrument；
The reagent by detection genetic biomarker object genotype probe and carry out superbead chip technology detect institute
Other reagents composition needed；
Preferably, the system of the genotype of the detection genetic biomarker object is to pass through competitive allele-specific
Reagent and/or instrument needed for round pcr detects the genotype of the genetic biomarker object；
The reagent by detection genetic biomarker object genotype primer and competitive ApoE gene
The composition of other reagents required for technology detects.
The present invention provides application of the system of the genotype of detection genetic biomarker object in reagent preparation box, the examination
The function of agent box is that prediction or auxiliary prediction lung radiate future trouble radiation pneumonitis risk；The genetic biomarker object is as follows：
| Site | Chromosome number | Physical coordinates | Genotype |
| RP2-01 | 15 | 96898166 | [A/G] |
| RP2-02 | 2 | 213937020 | [T/G] |
| RP2-03 | 20 | 3009669 | [T/C] |
| RP2-04 | 6 | 83598005 | [T/C] |
| RP2-05 | 16 | 11347858 | [A/G] |
| RP2-06 | 2 | 76871844 | [A/G] |
| RP2-07 | 13 | 101723882 | [T/C] |
| RP2-08 | 8 | 115464957 | [A/G] |
| RP2-09 | 7 | 97234588 | [T/G] |
| RP2-10 | 6 | 32684257 | [A/G] |
| RP2-11 | 12 | 46122002 | [A/G] |
| RP2-12 | 22 | 21410886 | [T/C] |
| RP2-13 | 3 | 172587874 | [A/G] |
| RP2-14 | 1 | 171386073 | [A/G] |
| RP2-15 | 7 | 84365672 | [T/C] |
| RP2-16 | 8 | 27197773 | [A/G] |
| RP2-17 | 1 | 150958836 | [T/C] |
| RP2-18 | 1 | 16452998 | [A/G] |
| RP2-19 | 2 | 213936394 | [A/C] |
| RP2-20 | 15 | 36005740 | [T/C] |
| RP2-21 | 9 | 89594294 | [A/G] |
| RP2-22 | 6 | 161557940 | [A/G] |
| RP2-23 | 15 | 81870629 | [A/G] |
| RP2-24 | 19 | 13155755 | [A/G] |
| RP2-25 | 8 | 139327776 | [T/C] |
| RP2-26 | 13 | 110833090 | [A/G] |
| RP2-27 | 10 | 133960262 | [A/G] |
| RP2-28 | 2 | 167120956 | [A/G] |
| RP2-29 | 8 | 47196063 | [A/G] |
| RP2-30 | 7 | 44224098 | [A/G] |
| RP2-31 | 14 | 97134921 | [A/G] |
；
The physical coordinates are with the mankind with reference to genome version 37 for reference.
Further, the system of the genotype of the detection genetic biomarker object is by described in the detection of gene sequencing method
Reagent needed for the genotype of genetic biomarker object and/or instrument,
The reagent as detection genetic biomarker object genotype primer or probe and carry out gene sequencing needed for
Other reagents composition wanted；
Or, the system of the genotype of the detection genetic biomarker object is to detect the heredity by biochip technology
Reagent needed for the genotype of biomarker and/or instrument,
Required for probe and progress genechip detection of the reagent as the genotype of detection genetic biomarker object
Other reagents composition；
Or, the system of the genotype of the detection genetic biomarker object is to detect the heredity life by fluorescent PCR method
Reagent needed for the genotype of substance markers object and/or instrument,
The reagent as detection genetic biomarker object genotype probe and carry out fluorescent PCR detection required for
Other reagents composition；
Or, the system of the genotype of the detection genetic biomarker object is to detect the heredity by superbead chip technology
Reagent needed for the genotype of biomarker and/or instrument,
The reagent by detection genetic biomarker object genotype probe and carry out superbead chip technology detect institute
Other reagents composition needed；
Or, the system of the genotype of the detection genetic biomarker object is to pass through competitive ApoE gene
Reagent and/or instrument needed for method detects the genotype of the genetic biomarker object,
The reagent by detection genetic biomarker object genotype primer and being at war with property allele specific
Property PCR method detect required for other reagents composition.
The present invention provides the system of the genotype of detection genetic biomarker object and records following weight coefficient and evaluation
The carrier of method is applied in the kit of preparation diagnosis or auxiliary diagnosis radiation pneumonitis：
The genotype for detecting the above-mentioned site of patient compares with reference to genome version 37 with the mankind, is Wild homozygous
When, it is original to be assigned a value of 0；For wild heterozygous or variation heterozygous when, it is original to be assigned a value of 1；When to make a variation homozygous, original tax
Value is 2, and the original assignment in each site is multiplied as final assignment, most by all sites with the weight coefficient in the site
Whole assignment summation is as calculating score value；
If calculating score value is greater than 0.5, which, which is predicted to be, can occur 2 grades or 2 grades or more radiation pneumonitis.
Further, the system of the genotype of the detection genetic biomarker object is by described in the detection of gene sequencing method
Reagent needed for the genotype of genetic biomarker object and/or instrument,
The reagent as detection genetic biomarker object genotype primer or probe and carry out gene sequencing needed for
Other reagents composition wanted；
Or, the system of the genotype of the detection genetic biomarker object is to detect the heredity by biochip technology
Reagent needed for the genotype of biomarker and/or instrument,
Required for probe and progress genechip detection of the reagent as the genotype of detection genetic biomarker object
Other reagents composition；
Or, the system of the genotype of the detection genetic biomarker object is to detect the heredity life by fluorescent PCR method
Reagent needed for the genotype of substance markers object and/or instrument,
The reagent as detection genetic biomarker object genotype probe and carry out fluorescent PCR detection required for
Other reagents composition；
Or, the system of the genotype of the detection genetic biomarker object is to detect the heredity by superbead chip technology
Reagent needed for the genotype of biomarker and/or instrument,
The reagent by detection genetic biomarker object genotype probe and carry out superbead chip technology detect institute
Other reagents composition needed；
Or, the system of the genotype of the detection genetic biomarker object is to pass through competitive ApoE gene
Reagent and/or instrument needed for method detects the genotype of the genetic biomarker object,
The reagent by detection genetic biomarker object genotype primer and being at war with property allele specific
Property PCR method detect required for other reagents composition.
Further, the genetic biomarker object is as follows：
Compared with prior art, beneficial effects of the present invention are：
The present invention provide it is a kind of for predict or assist prediction lung radiation future trouble radiation pneumonitis risk kit, should
It include that can evaluate patient chest tumour receives 2 grades or 2 grades or more of radiation whether can be caused after radiation treatment in kit
Property pneumonia detection genetic biomarker object genotype system, wherein sharing 31 genetic biomarker objects can be used as
Testing and evaluation target spot.The kit can accurately and efficiently prejudge out patient chest tumour receive after radiation treatment whether
It can cause 2 grades or 2 grades or more of radiation pneumonitis, it is easy to operate using simplicity, as a result reliably, for the monitoring after Patients Treated by Radiotherapy
There is very important directive significance with treatment.
Detailed description of the invention
Fig. 1 is to be radiated with genetic biomarker object according to the present invention to 72 patients with lung cancer in the embodiment of the present invention 4
Property treatment before the radiation pneumonitis risk scoring results statistical chart that is prejudged.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.
The present invention provides a kind of for predicting or assisting the kit of prediction lung radiation future trouble radiation pneumonitis risk, packet
The system for including the genotype of detection genetic biomarker object, wherein genetic biomarker object is as follows：
Physical coordinates are with the mankind with reference to genome version 37 for reference.
Include provided by the present invention for the kit for predicting or assisting prediction lung to radiate future trouble radiation pneumonitis risk
Patient chest tumour can be evaluated and receive the detection that whether can cause 2 grades or 2 grades or more of radiation pneumonitis after radiation treatment
The system of the genotype of genetic biomarker object, wherein sharing 31 genetic biomarker objects can be used as testing and evaluation target
Point.The kit can accurately and efficiently prejudge out after patient chest tumour receives radiation treatment whether 2 grades or 2 can be caused
Grade or more radiation pneumonitis, it is easy to operate using simplicity, as a result reliably, for after Patients Treated by Radiotherapy monitoring with treatment have it is non-
Often important directive significance.
Lung's radiation refers to adopting in the treatment of the breast tumors such as lung cancer, breast cancer, the cancer of the esophagus, mediastinal tumor, thymic tumor
Lung is all or part of in radiation open country in radiation treatment, is illuminated.
It should be noted that genetic biomarker object is denoted as the totally 31 monokaryon glycosides of the RP2-01 to RP2-31 in above-mentioned table
Sour polymorphic site.
The meaning of every a line is specially in table：By taking a line where the site RP2-01 as an example, chromosome number represents RP2-01
No. 11 chromosomes that the specific location of human chromosomal number where point, the i.e. site RP2-01 are located at the mankind；Physical coordinates are with people
Class is the specific location referring to the obtained site RP2-01 on No. 11 chromosomes with reference to genome version 37 (GRCh37), i.e.,
sr94950910；What genotype represented is the type of the base being likely to occur in the site RP2-01, and A/G is indicated may in the site
The base type of appearance is A or G.It is AA, AG and GG in the genotype that the site is likely to occur.
In one embodiment of the present invention, mentioned reagent box further includes recording following weight coefficient and evaluation method
Carrier：
The genotype for detecting the above-mentioned genetic biomarker level point of patient refers to genome version 37 with the mankind
(GRCh37) it compares, it is original to be assigned a value of 0 when being Wild homozygous；For wild heterozygous or variation heterozygous when, original tax
Value is 1；It is original to be assigned a value of 2 when to make a variation homozygous, the original assignment in each site is multiplied work with the weight coefficient in the site
For final assignment, the final assignment summation in all sites is used as and calculates score value；
If calculating score value is greater than 0.5, which, which is predicted to be, can occur 2 grades or 2 grades or more radiation pneumonitis.By the meter
For point counting value multiplied by 100%, resulting value is the probability value that 2 grades or 2 grades or more radiation pneumonitis can occur for the patient.
It should be noted that Wild homozygous, wild heterozygous or variation heterozygous, make a variation homozygous three kinds of genotype
Original assignment refers to the initial value before being assessed, and original assignment, that is, initial value is self-defining value, by this initial value with it is right
The weight coefficient answered is multiplied, and resulting score is as final assignment.Mathematically, if in order to show that dry measure number is had in total amount
Some significance levels give different proportionality coefficients respectively, and here it is weightings.The appointment coefficient of weighting is exactly flexible strategy, also known as
Weight, weight.Weight coefficient is the significance level for indicating a certain index item in index item system, indicate other index item not
In the case where change, influence of the variation of this index item to result.
By taking the site RP2-01 as an example, the genotype in the site is detected, is compared with the mankind with reference to genome version 37,
It a) is Wild homozygous, the original of the site RP2-01 is assigned a value of 0, the weight coefficient -0.039615128 of original assignment and the site
It is multiplied, obtains final assignment 0；It b) is wild heterozygous or variation heterozygous, the original of the site RP2-01 is assigned a value of 1, original
Assignment is multiplied with the weight coefficient -0.039615128 in the site, obtains final assignment -0.039615128；C) homozygous for variation
Type, the original of the site RP2-01 are assigned a value of 2, and original assignment is multiplied with the weight coefficient -0.039615128 in the site, obtains
Final assignment -0.079230256.
By taking the site RP2-02 as an example, the genotype in the site is detected, is compared with the mankind with reference to genome version 37,
It a) is Wild homozygous, the original of the site RP2-02 is assigned a value of 0, the weight coefficient 0.000122236 of original assignment and the site
It is multiplied, obtains final assignment 0；It b) is wild heterozygous or variation heterozygous, the original of the site RP2-02 is assigned a value of 1, original
Assignment is multiplied with the weight coefficient 0.000122236 in the site, obtains final assignment 0.000122236；It is c) homozygous to make a variation,
The original of the site RP2-02 is assigned a value of 2, and original assignment is multiplied with the weight coefficient 0.000122236 in the site, is finally assigned
Value 0.000244472.
Other 29 sites also obtain respective final assignment according to the method in the site RP2-01 and the site RP2-02, will
The final assignment of RP2-01 to RP2-31, which is added to obtain, calculates score value.
It is further to note that the meaning of Wild homozygous is that the genotype of two copies in the site and the mankind refer to
Genome version 37 consistent, is all homozygous；The meaning of wild heterozygous and variation heterozygous is two copies in the site
Genotype in have one copy with the mankind refer to genome version 37 genotype it is consistent, another copy is inconsistent；Become
Different homozygous meaning is consistent between the genotype of two copies in the site, but all refers to genome version 37 with the mankind
Number genotype it is inconsistent, for make a variation it is homozygous.When the genotype in the site does not meet Wild homozygous defined above, wild
When heterozygous, variation heterozygous and homozygous variation, the original of the point is assigned a value of 0, i.e., participates in calculating as Wild homozygous and comment
Estimate.In the rare cases, it is possible to base and common variation base type mismatch of the sample in the variation in the site, it is this
In the case of, the original of the site is assigned a value of 0.For example, RP2-01, is A or G in the base that the site is likely to occur, it is possible
Genotype is that AA, AG and GG mutate if there is special circumstances in the site, and the base of generation is T or C, that is, is appointed
A kind of what base of non-A/G, the assignment in the site is 0, and no matter being mutated the genotype of generation is TA, TG, TT, CA, CG and CC
Any situation therein, the assignment in the site are 0.
The recurrence containing two or more independents variable is usually called multiple linear regression, is expressed as：Y=β 0+ β
1x1+ ...+β pxp+e, or y=X β+e is expressed as with the form of matrix.
In above-mentioned formula, y is dependent variable, and β is regression coefficient, and X is independent variable.Its algorithm is solution regression coefficient, so that：
(y-Xβ)2It is minimum.
If there is obvious linear relationship between response variable and predictive variable, least square regression has very little
Bias, especially if least square regression also has lesser variance when observation quantity n is much larger than predictive variable p.But such as
Fruit n and p relatively, are then easy to produce over-fitting；If n<P, least square regression cannot get significant result.In addition,
Many variables in multiple linear regression model may be unrelated with response variable；It is also possible to generate showing for multicollinearity
As：It is obvious related between i.e. multiple predictive variables.These situations can all increase the complexity of model, weaken solution to model and release energy
Power.At this time need to carry out variables choice (feature selecting).
In given data, the sum of independent variable is p ≈ 700000, the number n of dependent variable<100, it is clear that n<<p.
For problem above, invention applies Rob Tibshirani etc. to propose contraction method (shrinkage
Method) multiple linear regression model is established.Contraction method is also known as regularization.Mainly ridge regression (ridge
Regression it) is returned with lasso.By penalizing constraint to least-squares estimation addition, make certain coefficients is estimated as 0.This hair
Bright to apply elastomeric network (elastic net) to handle the above problem, mode has merged ridge regression and lasso returns two kinds
The method of regularization, is expressed as：
Elastic net is much larger than n for p or serious multicollinearity situation has obvious effects on.For
Elastic net, when alpha is close to 1, elastic net is showed very close to lasso, but is eliminated and caused by extreme correlation
Degenerationization or strange performance.In general, elastic net is ridge regression and the good compromise of lasso, when
Alpha changes to 1 from 0, the sparse solution that the sparse solution (the case where coefficient is 0) of objective function also monotonicallys increase up to lasso from 0.
It (is calculating side most fast about lasso at present that coordinate descent, which is about a kind of quick calculation method of lasso,
Method), bare bones are：Each parameter is optimized in the case where keeping other parameters fixed, is recycled, until coefficient
Until stabilization.This, which is calculated, is carried out in the lattice values of lambda.
In one embodiment of the present invention, above-mentioned weight coefficient and evaluation method are obtained by following algorithms：
All polymorphic sites involved in single sample are done into original assignment first, the algorithm of assignment is：By the site
Genotype compare with the mankind with reference to genome version 37 (GRCh37), when the site is Wild homozygous, original tax
Value is 0；It is original to be assigned a value of 1 when the site is wild heterozygous or variation heterozygous；When the site is that variation is homozygous
When, it is original to be assigned a value of 2.
The original assignment has arbitrariness, which does not represent any biological significance, but the overall principle of assignment is former
Beginning assignment can be by Wild homozygous, wild heterozygous or variation heterozygous and homozygous distinguish that make a variation.Then will own
Sample all carry out aforesaid operations, finally obtain the matrix of P × N rank, the polymorphic position that wherein P is counted by each sample
The total number of point, N are overall sample size.The matrix will be used as an input file.By the lung radiation injury of all samples
Scorching grade establishes second matrix file, which is 1 × N rank, and wherein N is overall sample size.By above-mentioned two square
Battle array file is brought into GLMNET R program bag respectively as independent variable and dependent variable carries out operation, and the final result of operation is back
Return coefficient table, i.e., the weight coefficient in each site.
The radioactive damage that can establish the lung based on mononucleotide polymorphism site information by the algorithm is pre-
The multiple linear regression mathematical model of survey.
In conjunction with the algorithm above, it should be appreciated that in the only numerous weight coefficient tables and evaluation method of above-mentioned offer
One kind, those skilled in the art are according to the available a variety of weight coefficient tables of screening technique of the algorithm and corresponding evaluation side
Method.
For example, evaluation method provided by the invention：
The genotype for detecting patient's genetic biomarker level point refers to genome version 37 (GRCh37) with the mankind
It compares, it is original to be assigned a value of 0 when being Wild homozygous；For wild heterozygous or variation heterozygous when, it is original to be assigned a value of 1；For
It is original to be assigned a value of 2 when making a variation homozygous, the original assignment in each site is multiplied with the weight coefficient in the site and is assigned as final
Value, by the final assignment summation in all sites as calculating score value；If calculating score value is greater than 0.5, which is predicted to be
2 grades or 2 grades or more radiation pneumonitis can occur.
According to above-mentioned algorithm, original that can be homozygous to wild-type homozygous type, wild heterozygous or variation heterozygous, variation
Beginning assignment is changed, as long as three original assignment are different, which does not represent any biological significance, original assignment
The overall principle be can by wild-type homozygous type, wild heterozygous or variation heterozygous, variation it is homozygous distinguish, with reach into
One step calculates the purpose of weight coefficient.It is not limited to that Wild homozygous provided by the invention is original to be assigned a value of 0；Wild heterozygosis
Heterozygous is original is assigned a value of 1 for type or variation；Make a variation it is homozygous it is original be assigned a value of 2, a kind of this calculation.According to three mutually not
Identical original assignment can bring operation into and obtain corresponding weight coefficient table, that is, can produce corresponding evaluation method.
In one embodiment of the present invention, the system for detecting the genotype of genetic biomarker object is to pass through gene sequencing
Reagent and/or instrument needed for method detects the genotype of genetic biomarker object；
Reagent as detection genetic biomarker object genotype primer or probe and carry out gene sequencing required for
Other reagents composition.The genotype type detection to 31 mononucleotide polymorphism sites in blood sample of patient may be implemented in the kit
The sample handled well is directly used for gene sequencing instrument and obtains genotype data by preceding sample treatment, using contain weight system
Several and evaluation method carrier, which immediately arrives at after the patient receives radiation treatment, occurs 2 grades or 2 grades or more radiation pneumonitis
Value-at-risk.
Mode, such as Single base extension PCR sequencing PCR can be sequenced for any one in 1 generation, 2 generations or 3 generations in gene sequencing,
As long as the range of sequencing covers 31 mononucleotide polymorphism sites provided by the invention.The detection genetic biomarker object
The substance of genotype is involved when detecting 31 mononucleotide polymorphism site genotype including the use of gene sequencing to be owned
Instrument is used in other reagents such as specificity amplification primer or specific probe and/or detection.
In one embodiment of the present invention, the system for detecting the genotype of genetic biomarker object is to pass through genetic chip
Reagent and/or instrument needed for technology detects the genotype of the genetic biomarker object；
Reagent as detection genetic biomarker object genotype probe and carry out genechip detection required for its
He forms reagent.Before the genotype type detection to 31 mononucleotide polymorphism sites in blood sample of patient may be implemented in the kit
Sample treatment, the sample handled well is directly used for gene chip tester device and obtains genotype data, using containing weight
Coefficient and the carrier of evaluation method, which immediately arrive at after the patient receives radiation treatment, occurs 2 grades or 2 grades or more radiation pneumonitis
Value-at-risk.
The range in the site of genechip detection covers 31 mononucleotide polymorphism sites provided by the invention.The inspection
The substance of the genotype of genetic biomarker object is surveyed including the use of 31 mononucleotide polymorphism site genes of genechip detection
Instrument is used in involved all specific probes and other reagents and/or detection when type.
In one embodiment of the present invention, the system for detecting the genotype of genetic biomarker object is to pass through fluorescent PCR
Reagent and/or instrument needed for method detects the genotype of the genetic biomarker object；
Reagent by detection genetic biomarker object genotype probe and carry out fluorescent PCR detection required for other
Reagent composition.Before the genotype type detection to 31 mononucleotide polymorphism sites in blood sample of patient may be implemented in the kit
The sample handled well is directly used for fluorescent PCR instrument and obtains genotype data by sample treatment, using containing weight coefficient and
The carrier of evaluation method immediately arrives at the patient and receives the risk that 2 grades or 2 grades or more radiation pneumonitis occur after radiation treatment
Value.
Fluorescent PCR method for example can be with but not to be limited to TaqMan probe method and high-resolution solubility curve analytic approach.Fluorescence
The range in the site of PCR detection covers 31 mononucleotide polymorphism sites provided by the invention.The detection genetic organism mark
It is involved when remembering the substance of the genotype of object including the use of fluorescent PCR 31 mononucleotide polymorphism site genotype of detection
Instrument is used in all specific probes and other reagents and/or detection.
In one embodiment of the present invention, the system for detecting the genotype of genetic biomarker object is to pass through superbead chip
Reagent and/or instrument needed for technology detects the genotype of the genetic biomarker object；
Reagent as detection genetic biomarker object genotype probe and carry out the detection of superbead chip technology required for
Other reagents composition.The genotype type inspection to 31 mononucleotide polymorphism sites in blood sample of patient may be implemented in the kit
The sample handled well is directly used for superbead chip instrument and obtains genotype data by the sample treatment before survey, using containing weight
Coefficient and the carrier of evaluation method, which immediately arrive at after the patient receives radiation treatment, occurs 2 grades or 2 grades or more radiation pneumonitis
Value-at-risk.
Superbead chip technology for example can be, but not be limited to Illumina BeadXpress.The detection of superbead chip technology
The range in site covers 31 mononucleotide polymorphism sites provided by the invention.The gene of the detection genetic biomarker object
Involved all specificity when the substance of type is including the use of fluorescent PCR 31 mononucleotide polymorphism site genotype of detection
Instrument is used in probe and other reagents and/or detection.
In one embodiment of the present invention, the system for detecting the genotype of genetic biomarker object is to pass through competitiveness etc.
Reagent and/or instrument needed for position gene specific PCR method detects the genotype of the genetic biomarker object；
Reagent by detection genetic biomarker object genotype probe and being at war with property ApoE gene
The composition of other reagents required for detecting.The kit may be implemented to 31 mononucleotide polymorphism sites in blood sample of patient
Genotype type detection before sample treatment, the sample handled well is directly used for fluorescent PCR instrument and obtains genotype data, benefit
It is immediately arrived at after the patient receives radiation treatment with the carrier containing weight coefficient and evaluation method and occurs 2 grades or 2 grades or more
The value-at-risk of radiation pneumonitis.
The range in the site of competitive ApoE gene detection covers 31 monokaryon glycosides provided by the invention
Sour polymorphic site.The substance of the genotype of the detection genetic biomarker object detects 31 monokaryon glycosides including the use of fluorescent PCR
Instrument is used in involved all specific probes and other reagents and/or detection when sour polymorphic site genotype.
The present invention provides application of the system of the genotype of detection genetic biomarker object in reagent preparation box, reagent again
The function of box is that prediction or auxiliary prediction lung radiate future trouble radiation pneumonitis risk；Genetic biomarker object is as follows：
Physical coordinates are with the mankind with reference to genome version 37 for reference.
In one embodiment of the present invention, the system for detecting the genotype of genetic biomarker object is to pass through gene sequencing
Reagent and/or instrument needed for method detects the genotype of the genetic biomarker object,
Reagent as detection genetic biomarker object genotype primer or probe and carry out gene sequencing required for
Other reagents composition；
Or, the system of the genotype of detection genetic biomarker object is to detect the genetic organism by biochip technology
Reagent needed for the genotype of marker and/or instrument,
Reagent as detection genetic biomarker object genotype probe and carry out genechip detection required for its
He forms reagent；
Or, the system of the genotype of detection genetic biomarker object is to detect the genetic organism mark by fluorescent PCR method
Reagent and/or instrument needed for remembering the genotype of object,
Reagent by detection genetic biomarker object genotype probe and carry out fluorescent PCR detection required for other
Reagent composition；
Or, the system of the genotype of detection genetic biomarker object is to detect the genetic organism by superbead chip technology
Reagent needed for the genotype of marker and/or instrument.Reagent by detection genetic biomarker object genotype probe and
Carry out other reagents composition required for superbead chip technology detects；
Or, the system of the genotype of detection genetic biomarker object is to be examined by competitive ApoE gene method
Reagent and/or instrument needed for surveying the genotype of the genetic biomarker object.Reagent by detection genetic biomarker object base
Other reagents required for probe and being at war with property ApoE gene method detection because of type form.
The present invention finally provide detection genetic biomarker object genotype system and record following weight coefficient and
The carrier of evaluation method is applied in the kit of preparation diagnosis or auxiliary diagnosis radiation pneumonitis：
The genotype for detecting the above-mentioned site of patient compares with reference to genome version 37 with the mankind, is Wild homozygous
When, it is original to be assigned a value of 0；For wild heterozygous or variation heterozygous when, it is original to be assigned a value of 1；When to make a variation homozygous, original tax
Value is 2, and the original assignment in each site is multiplied as final assignment, most by all sites with the weight coefficient in the site
Whole assignment summation is as calculating score value；
If calculating score value is greater than 0.5, which, which is predicted to be, can occur 2 grades or 2 grades or more radiation pneumonitis.
In one embodiment of the present invention, the system for detecting the genotype of genetic biomarker object is to pass through gene sequencing
Reagent and/or instrument needed for method detects the genotype of genetic biomarker object,
Reagent as detection genetic biomarker object genotype primer or probe and carry out gene sequencing required for
Other reagents composition；
Or, the system of the genotype of detection genetic biomarker object is to detect genetic biomarker by biochip technology
Reagent needed for the genotype of object and/or instrument,
Reagent as detection genetic biomarker object genotype probe and carry out genechip detection required for its
He forms reagent；
Or, the system of the genotype of detection genetic biomarker object is to detect the genetic organism mark by fluorescent PCR method
Reagent and/or instrument needed for remembering the genotype of object,
Reagent by detection genetic biomarker object genotype probe and carry out fluorescent PCR detection required for other
Reagent composition.
Or, the system of the genotype of detection genetic biomarker object is to detect the genetic organism by superbead chip technology
Reagent needed for the genotype of marker and/or instrument.Reagent by detection genetic biomarker object genotype probe and
Carry out other reagents composition required for superbead chip technology detects.
Or, the system of the genotype of detection genetic biomarker object is to be examined by competitive ApoE gene method
Reagent and/or instrument needed for surveying the genotype of the genetic biomarker object.Reagent by detection genetic biomarker object base
Other reagents required for probe and being at war with property ApoE gene method detection because of type form.
In one embodiment of the present invention, genetic biomarker object is as follows：
The technical solution provided to facilitate the understanding of the present invention, below with reference to embodiment to technical solution provided by the invention
It is further described.Actual conditions are not specified in embodiment, carry out according to conventional conditions or manufacturer's recommended conditions.Institute
Production firm is not specified with reagent or instrument, being can be by the conventional products of commercially available acquisition.
The acquisition of 1 clinical sample of embodiment
For clinical blood samples sources in Beijing hospital, sample above obtains my informed consent, and 72 of acquisition
Patients with lung cancer of the sample standard deviation before radiotherapy.Blood collection collects the venous blood of 1ml, blood refrigerating according to clinical routine
It is stored in conventional EDTA anticoagulant tube, the holding time is no more than one week.
The identification of 2 sample genotype of embodiment
The blood sample of acquisition DNA extraction kit is extracted into genomic DNA.
It is sequenced using 72 part genomic DNAs of the gene sequencing method to 72 sample extractions in embodiment 1, obtains this
The genotype of 31 mononucleotide polymorphism sites provided is provided.
The calculating of 3 risk score value of embodiment
The genotype in 31 sites that sample is detected in example 2 and the mankind refer to genome version 37
(GRCh37) it compares, when the result that the site compares is that two copies are all consistent, the original of the site is assigned a value of 0；When this
When the result that site compares is that a copy is consistent, the original of the site is assigned a value of 1；It is copied when the result that the site compares is two
When the equal anomaly of shellfish, the original of the site is assigned a value of 2.Then by the weight coefficient of the original assignment in each site and the site
(see the table below) is multiplied, and institute's value is the calculating score value in the site.The calculating score value in 31 sites of one sample is added, is obtained
To summation be the corresponding value-at-risk of the sample.When sum value is greater than 0.5, it is determined as that the patient can occur 2 grades or 2 grades
Above radiation pneumonitis.By the value-at-risk multiplied by 100%, as 2 grades or 2 grades or more radiation pneumonitis occur for the patient
Risk probability.
4 result of embodiment statistics
The risk score value that 72 samples suffer from radiation pneumonitis will be counted in embodiment 3, it is as a result as shown in Figure 1, pre-
Sentence and shares the postoperative radiation pneumonitis that can suffer from 2 grades or 2 grades or more of 17 patients with lung cancer out.
Postoperative practical follow-up then has been done to this 72 patients, whether radiation pneumonitis is suffered to patient and grade is adjusted
It looks into, as a result as shown in the table：
From in above table it can be seen that in 72 patients 17 obtained 2 grades or 2 grades or more of radiation pneumonitis, and suffer from
The sample number of person and the result that the present invention prejudges are also consistent, illustrate that 31 mononucleotide polymorphism sites provided by the invention can
Using the genetic biomarker object as prediction or auxiliary prediction lung radiation future trouble radiation pneumonitis risk, examination provided by the invention
Agent box can effectively prejudge the risk of radiation pneumonitis.
Although illustrate and describing the present invention with specific embodiment, it will be appreciated that without departing substantially from of the invention
Many other change and modification can be made in the case where spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (10)
1. a kind of for predicting or assisting the kit of prediction lung radiation future trouble radiation pneumonitis risk, which is characterized in that packet
The system for including the genotype of detection genetic biomarker object, the genetic biomarker object are as follows：
The physical coordinates are with the mankind with reference to genome version 37 for reference.
2. kit according to claim 1, which is characterized in that the kit further includes recording following weight coefficient
With the carrier of evaluation method：
The genotype for detecting the above-mentioned genetic biomarker level point of patient compares with reference to genome version 37 with the mankind, is
It is original to be assigned a value of 0 when Wild homozygous；For wild heterozygous or variation heterozygous when, it is original to be assigned a value of 1；It is homozygous for variation
It is original to be assigned a value of 2 when type, the original assignment in each site is multiplied with the weight coefficient in the site as final assignment, by institute
The final assignment summation in some sites is as calculating score value；
If calculating score value is greater than 0.5, which, which is predicted to be, can occur 2 grades or 2 grades or more radiation pneumonitis.
3. kit according to claim 1, which is characterized in that the genotype of the detection genetic biomarker object is
System is reagent and/or instrument needed for detecting the genotype of the genetic biomarker object by gene sequencing method；
The reagent as detection genetic biomarker object genotype primer or probe and carry out gene sequencing required for
Other reagents composition.
4. kit according to claim 1, which is characterized in that the genotype of the detection genetic biomarker object is
System is reagent and/or instrument needed for detecting the genotype of the genetic biomarker object by biochip technology；
The reagent as detection genetic biomarker object genotype probe and carry out genechip detection required for its
He forms reagent.
5. kit according to claim 1, which is characterized in that the genotype of the detection genetic biomarker object is
System is reagent and/or instrument needed for detecting the genotype of the genetic biomarker object by fluorescent PCR method；
The reagent by detection genetic biomarker object genotype probe and carry out fluorescent PCR detection required for other
Reagent composition；
Preferably, the system of the genotype of the detection genetic biomarker object is by by described in the detection of superbead chip technology
Reagent needed for the genotype of genetic biomarker object and/or instrument；
The reagent as detection genetic biomarker object genotype probe and carry out the detection of superbead chip technology required for
Other reagents composition；
Preferably, the system of the genotype of the detection genetic biomarker object is to pass through competitive ApoE gene
Reagent and/or instrument needed for method detects the genotype of the genetic biomarker object；
The reagent by detection genetic biomarker object genotype probe and being at war with property ApoE gene
The composition of other reagents required for method detects.
6. detecting application of the system of the genotype of genetic biomarker object in reagent preparation box, which is characterized in that the examination
The function of agent box is that prediction or auxiliary prediction lung radiate future trouble radiation pneumonitis risk；The genetic biomarker object is as follows：
The physical coordinates are with the mankind with reference to genome version 37 for reference.
7. application according to claim 6, which is characterized in that the system of the genotype of the detection genetic biomarker object
Reagent and/or instrument needed for genotype to detect the genetic biomarker object by gene sequencing method,
The reagent as detection genetic biomarker object genotype primer or probe and carry out gene sequencing required for
Other reagents composition；
Or, the system of the genotype of the detection genetic biomarker object is to detect the genetic organism by biochip technology
Reagent needed for the genotype of marker and/or instrument,
The reagent as detection genetic biomarker object genotype probe and carry out genechip detection required for its
He forms reagent；
Or, the system of the genotype of the detection genetic biomarker object is to detect the genetic organism mark by fluorescent PCR method
Reagent and/or instrument needed for remembering the genotype of object,
The reagent by detection genetic biomarker object genotype probe and carry out fluorescent PCR detection required for other
Reagent composition；
Or, the system of the genotype of the detection genetic biomarker object is to detect the genetic organism by superbead chip technology
Reagent needed for the genotype of marker and/or instrument,
The reagent as detection genetic biomarker object genotype probe and carry out the detection of superbead chip technology required for
Other reagents composition；
Or, the system of the genotype of the detection genetic biomarker object is to be examined by competitive ApoE gene method
Reagent and/or instrument needed for surveying the genotype of the genetic biomarker object,
The reagent by detection genetic biomarker object genotype primer and being at war with property ApoE gene
The composition of other reagents required for method detects.
8. detecting the system of the genotype of genetic biomarker object and recording following weight coefficient and the carrier of evaluation method exists
It is applied in the kit of preparation diagnosis or auxiliary diagnosis radiation pneumonitis：
The genotype for detecting the above-mentioned site of patient is compared with the mankind with reference to genome version 37, former when being Wild homozygous
Beginning is assigned a value of 0；For wild heterozygous or variation heterozygous when, it is original to be assigned a value of 1；It is original to be assigned a value of when to make a variation homozygous
2, the original assignment in each site is multiplied with the weight coefficient in the site as final assignment, by the final tax in all sites
Value summation is as calculating score value；
If calculating score value is greater than 0.5, which, which is predicted to be, can occur 2 grades or 2 grades or more radiation pneumonitis.
9. application according to claim 8, which is characterized in that the system of the genotype of the detection genetic biomarker object
Reagent and/or instrument needed for genotype to detect the genetic biomarker object by gene sequencing method,
The reagent as detection genetic biomarker object genotype primer or probe and carry out gene sequencing required for
Other reagents composition；
Or, the system of the genotype of the detection genetic biomarker object is to detect the genetic organism by biochip technology
Reagent needed for the genotype of marker and/or instrument,
The reagent as detection genetic biomarker object genotype probe and carry out genechip detection required for its
He forms reagent；
Or, the system of the genotype of the detection genetic biomarker object is to detect the genetic organism mark by fluorescent PCR method
Reagent and/or instrument needed for remembering the genotype of object,
The reagent by detection genetic biomarker object genotype probe and carry out fluorescent PCR detection required for other
Reagent composition；
Or, the system of the genotype of the detection genetic biomarker object is to detect the genetic organism by superbead chip technology
Reagent needed for the genotype of marker and/or instrument,
The reagent as detection genetic biomarker object genotype probe and carry out the detection of superbead chip technology required for
Other reagents composition；
Or, the system of the genotype of the detection genetic biomarker object is to be examined by competitive ApoE gene method
Reagent and/or instrument needed for surveying the genotype of the genetic biomarker object,
The reagent by detection genetic biomarker object genotype primer and being at war with property ApoE gene
The composition of other reagents required for method detects.
10. application according to claim 8 or claim 9, which is characterized in that the genetic biomarker object is as follows：
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| CN112858693A (en) * | 2021-02-01 | 2021-05-28 | 安乐励思科技(苏州)有限公司 | Biomolecule detection method |
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| US20060115827A1 (en) * | 2004-07-01 | 2006-06-01 | University Of Southern California | Genetic markers for predicting disease and treatment outcome |
| CN101473042A (en) * | 2006-05-31 | 2009-07-01 | 健康研究股份有限公司 | Method for predicting susceptibility to radiation pneumonitis |
| WO2013170215A1 (en) * | 2012-05-11 | 2013-11-14 | Fred Hutchinson Cancer Research Center | Methods for predicting and detecting cancer risk |
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| US20060115827A1 (en) * | 2004-07-01 | 2006-06-01 | University Of Southern California | Genetic markers for predicting disease and treatment outcome |
| CN101473042A (en) * | 2006-05-31 | 2009-07-01 | 健康研究股份有限公司 | Method for predicting susceptibility to radiation pneumonitis |
| WO2013170215A1 (en) * | 2012-05-11 | 2013-11-14 | Fred Hutchinson Cancer Research Center | Methods for predicting and detecting cancer risk |
| CN106319057A (en) * | 2016-08-31 | 2017-01-11 | 青岛市中心医院 | Method for early monitoring radioactive pneumonia fibrosis caused by tumor radiotherapy |
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