CN111286540B - Use of POLN gene as molecular marker for predicting radiation sensitivity - Google Patents
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Abstract
The invention belongs to the technical field of biological detection, and relates to application of POLN genes as molecular markers for predicting radiation sensitivity. The POLN gene can be used as a molecular marker for predicting radiation sensitivity, and can be used for predicting radiation sensitivity with high efficiency and low cost by judging whether the rs2022302 locus of the POLN gene is mutated or not.
Description
Technical Field
The invention belongs to the technical field of biological detection, and relates to application of POLN genes as molecular markers for predicting radiation sensitivity.
Background
Currently, radiation therapy remains the primary means of modern cancer treatment, with radiation being required by approximately 50% of cancer patients. However, patients who received the same dose of radiation treatment exhibited different radiotoxicities: few people have no obvious toxic effects, most have mild or moderate toxic reactions in clinic, and few people cause serious normal tissue complications and may even be life threatening. Thus, there is a need to find a molecular marker that correlates with radiosensitivity for predicting whether a patient is a radiosensitive (or radioresistant) individual.
The prediction of radiation sensitivity is to be able to tailor the radiation therapy regimen for an individual patient to improve prognosis, so that on the one hand the radiation dose can be reduced to reduce toxicity to sensitive individuals and on the other hand the radiation dose can be increased to allow more radiation resistant patients to be effectively treated. This will maximize tumor control while minimizing damage to the normal tissue of the patient. In addition, about 20 ten thousand radiological staff exist in China, the radiological staff receive professional irradiation for a long time during daily work, and prediction of the radiation sensitivity of the radiological staff is helpful for preventing and reducing professional injuries.
The POLN rs2022302 locus is located on chromosome 4 at 2174006, the allele is A > G, and the gene encoding DNA polymerase A type family member. The encoded protein plays a role in DNA repair and homologous recombination.
A single nucleotide polymorphism marker (SNP) is a "third generation DNA genetic marker", 300 thousands of which exist in the human genome, and is considered as a genetic marker with the best application prospect. SNPs can truly reflect genetic differences and are associated with radiation-induced toxicity in normal tissues.
Disclosure of Invention
The purpose of the invention is to provide the application of POLN gene as a molecular marker for predicting radiation sensitivity, so that the radiation sensitivity can be predicted with high efficiency and low cost by mutating the rs2022302 locus of the POLN gene.
To achieve this object, in a basic embodiment, the present invention provides the use of a POLN gene as a molecular marker for predicting radiation sensitivity, i.e.the use of a POLN gene as a molecular marker for the preparation of a detection kit for predicting radiation sensitivity.
In a preferred embodiment, the invention provides the use of the mutation site of the POLN gene rs2022302 as a molecular marker for predicting radiation sensitivity, i.e. the use of the mutation site of the POLN gene rs2022302 as a molecular marker for preparing a detection kit for predicting radiation sensitivity.
The sequence of the POLN gene is shown as SEQ ID NO.1, the mutation site is the rs2022302 site (mutation from A to G) of the POLN gene, and the sequence of the POLN gene after mutation is shown as SEQ ID NO. 2.
The method has the beneficial effects that the POLN gene can be used as a molecular marker for predicting the radiation sensitivity, and the radiation sensitivity can be predicted through whether the rs2022302 locus of the POLN gene is mutated with high efficiency and low cost.
Detailed Description
The practice of the invention is further illustrated by the following examples, but the embodiments of the invention are not limited to the following examples.
Example 1:
1. preliminary screening of molecular markers for predicting radiation sensitivity using whole exon trap sequencing technology
1) Sample acquisition illumination and chromosome aberration analysis
Collecting peripheral blood of 20-30 years old healthy adult male, and administering 0-2 Gy 60 And (5) Co gamma ray irradiation. Chromosome aberration analysis is carried out on a 2Gy gamma-ray irradiation sample, and the crowd is divided into a sensitive group, a general group and a resistant group. Blood samples were cultured for 52h after irradiation and chromosomes were harvested and pelleted. Each sample was analyzed for 200 metaphase phases.
2) Extraction of genomic DNA from peripheral blood
Genomic DNA of the 0Gy irradiated sample was extracted. The whole blood genome DNA is extracted by adopting a Beijing heel biochemical technology limited blood genome DNA extraction kit according to the specification of the product, and the specific steps are shown in the specification. The quantitative detection A260/280 of the sampling nucleic acid is between 1.70 and 1.90, the quality meets the experimental requirements, and the subsequent experiments can be carried out.
3) Whole exon trap sequencing
The sequencing data is first data filtered to remove low quality data and to obtain Clean Reads. Sequencing is required to achieve the clean Reads rate of >90%, the clean base rate of >20G, the clean base rate of >90%, and the Q20 of >98%, and the experimental sample meets the requirements.
4) Bioinformatic analysis
Clear Reads were aligned with the reference genome and screened for differential SNP sites. Reference genome version: GRCh37 (hg 19), ftp:// ftp.1000 genes.ebi.ac.uk/vol 1/ftp/technical/reference/human_g1k_v37.fasta.gz. POLN rs2022302 locus was screened using bioinformatic analysis, as shown in Table 1.
TABLE 1 preliminary screening of sites for predicting radiation sensitivity
| SNP locus | Gene | SNP site position | Alleles of |
| rs2022302 | POLN | chr4：2174006 | A/G |
2. Experiment verification of primary screening site by matrix-assisted laser desorption ionization mass spectrometry technology
1) The kit for extracting the blood genome DNA of Beijing Tianhe Biochemical technology Co., ltd (non-centrifugal column type; catalog number: DP 319) and the whole blood genomic (blood derived from healthy male volunteers aged 20-30 years) DNA extraction was performed according to the product instructions.
2) A specific reaction system (5. Mu.l reaction system comprising 0.95. Mu. l H) was employed with the amplification primer pair of SEQ ID NO.3 and SEQ ID NO.4 2 O、0.625μl PCR Buffer(10×)、0.325μl MgCl 2 (25 mM), 1. Mu.l dNTP (2.5 mM), 1. Mu.l primer, 0.1. Mu.l HotstarTaq (5U/. Mu.L)) were subjected to PCR reaction by the following procedure: 94 ℃ for 15min; [94 ℃,20sec,56 ℃,30sec ]]45 cycles; 72℃for 4min. The reaction product was stored at 4 ℃.
3) Using SAP reaction solution (2. Mu.l SAP reaction solution includes 1.53. Mu.l H) 2 O, 0.17. Mu.l SAP Buffer (10X), 0.3. Mu.l SAP enzyme (1U/. Mu.L)) the reaction product of step 2) was treated by the following procedure: 37 ℃ for 40min;85 ℃ for 5min. The treated product was stored at 4 ℃.
4) Carrying out an extension reaction on the treated product of the step 3) by adopting an extension primer of SEQ ID NO.5,
2 μl of the reaction system includes 0.755 μ l H 2 O, 0.2. Mu.l iPerex Buffer (10X), 0.2. Mu. l iPlex Termination mix, 0.041. Mu.l iPerex enzyme, 0.804. Mu.l primer.
The reaction procedure is: 94 ℃ for 30s; [94 ℃,5s, (52 ℃,5s,80 ℃,5 s) 5 cycles ]40 cycles; 72℃for 3min. The extension product was stored at 4 ℃.
5) Purifying the extension product of step 4). 6mg of resin was uniformly covered with 384 well plates and left to stand for 20min. Centrifuging the 384-well plate containing the extension product of the step 4) at 1000rpm for 1min, adding 25 mu L of deionized water into each well, inverting the mixture on a resin plate, reversely fastening the resin plate on the 384-well plate, knocking to enable the resin to fall into the 384-well plate, and sealing the membrane. Turning over the 384-well plate for 20 minutes with the long axis of the 384-well plate as the axis, centrifuging at 3500rpm for 5 minutes, and then standing by.
6) Detecting the genotype of the genetic locus: the samples processed in step 5) were transferred to MassARRAY SpectroCHIP chip (SAMSUNG, massArray TM Nanodispenser) and tested in a mass spectrometer (sequence om, massARRAY compact System) with the results shown in table 2.
Table 2 experiment verifies the results
3. Crowd verification for experimental verification sites by matrix-assisted laser desorption ionization mass spectrometry technology
1) Sample acquisition illumination and chromosome aberration analysis
Collecting peripheral blood of 20-30 years old healthy adult male, and administering 0-2 Gy 60 And (5) Co gamma ray irradiation. Chromosome aberration analysis is carried out on a 2Gy gamma-ray irradiation sample, and the crowd is divided into a sensitive group, a general group and a resistant group. After culturing for 52h, the chromosomes were harvested and pelleted. Each sample was analyzed for 200 metaphase phases.
2) Extraction of genomic DNA from peripheral blood
Extracting genome DNA of the 0Gy irradiated sample from the susceptible group and the non-susceptible group. The whole blood genome DNA is extracted by adopting a Beijing heel biochemical technology limited blood genome DNA extraction kit according to the specification of the product, and the specific steps are shown in the specification. The quantitative detection A260/280 of the sampling nucleic acid is between 1.70 and 1.90, the quality meets the experimental requirements, and the subsequent experiments can be carried out.
3) Mass spectrometry detection
And (3) carrying out crowd verification on the sample, and further verifying the site.
4) Statistical analysis
The POLN gene rs2022302 locus was tested using Hardy-Weinberg equilibrium test, with P >0.05, demonstrating that the samples are population representative, and the results are shown in Table 3.
Correlation of POLN gene rs2022302 locus with radiation sensitivity under different genetic models was analyzed by logistic regression. Under the co-dominant model, AG genotypes differed significantly from the normal group in the sensitive group (p=0.010, or=13.980, 95% ci= 2.090-93.360); the differences between the sensitive group and the general group under the dominant model were significant (p=0.010, or=8.030, 95% ci=1.620-39.880), and the results are shown in table 4.
TABLE 3 Hardy-Weinberg equilibrium test results
TABLE 4 logistic regression analysis results
| Genotype of the type | P | OR | 95％CI |
| AA | - | 1 | - |
| AG | 0.010 | 13.980 | 2.090-93.360 |
| GG | 0.970 | 0.920 | 0.020-39.810 |
| TT VS CT+CC | 0.010 | 8.030 | 1.620-39.880 |
Thus, the POLN gene rs2022302 locus was screened as a molecular marker for predicting radiation sensitivity. The AG genotype is the genotype for predicting radiation sensitivity and can be used as an index for personnel to predict radiation sensitivity.
It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof. The foregoing examples or embodiments are merely illustrative of the invention, which may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The described embodiments are, therefore, to be considered in all respects as illustrative and not restrictive. The scope of the invention should be indicated by the appended claims, and any changes that are equivalent to the intent and scope of the claims are intended to be encompassed within the scope of the invention.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB201609977D0 (en) * | 2016-06-08 | 2016-07-20 | Cancer Rec Tech Ltd | Chemosensitivity predictive biomarkers |
| CN111378752A (en) * | 2020-03-24 | 2020-07-07 | 中国辐射防护研究院 | POLN gene mutation site detection kit and application thereof |
| EP3778924A1 (en) * | 2019-08-16 | 2021-02-17 | Siemens Healthcare GmbH | Molecular predictors of patient response to radiotherapy treatment |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB201609977D0 (en) * | 2016-06-08 | 2016-07-20 | Cancer Rec Tech Ltd | Chemosensitivity predictive biomarkers |
| EP3778924A1 (en) * | 2019-08-16 | 2021-02-17 | Siemens Healthcare GmbH | Molecular predictors of patient response to radiotherapy treatment |
| CN111378752A (en) * | 2020-03-24 | 2020-07-07 | 中国辐射防护研究院 | POLN gene mutation site detection kit and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| George-Lucian Moldovan.DNA Polymerase POLN Participates in Cross-Link Repair and Homologous Recombination.《MOLECULAR AND CELLULAR BIOLOGY》.2010,第30卷(第4期),第 1088–1096页. * |
| NCBI.Homo sapiens DNA polymerase nu (POLN), RefSeqGene on chromosome 4.《NCBI》.2019,第1-2页. * |
| 陈荣.射线DNA损伤修复酶基因多态性与福建地区 急性白血病的相关性：病例对照研究.《临床血液杂志》.2020,第33卷(第5期),第320-326页. * |
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