CN114875151B - Application of plasma exosome biomarker in screening or efficacy prediction of gastric cancer newly assisted chemotherapy sensitive population - Google Patents

Application of plasma exosome biomarker in screening or efficacy prediction of gastric cancer newly assisted chemotherapy sensitive population Download PDF

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CN114875151B
CN114875151B CN202210676338.3A CN202210676338A CN114875151B CN 114875151 B CN114875151 B CN 114875151B CN 202210676338 A CN202210676338 A CN 202210676338A CN 114875151 B CN114875151 B CN 114875151B
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季加孚
李子禹
唐小欢
郭婷
高翔宇
邢晓芳
陕飞
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Beijing Cancer Hospital
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Abstract

The invention relates to a plasma exosome mRNA, miRNA and/or lncRNA biomarker and application thereof in screening new auxiliary chemotherapy sensitive population of gastric cancer patients, predicting new auxiliary chemotherapy curative effect and screening gastric cancer therapeutic drugs. The invention determines that the plasma exosome miRNAlet-7i-5p, miR-1307-3p, miR-181a-5p and miR-1843, plasma exosome mRNA LZIC and SRSF6 and plasma exosome lncRNAlncFTH1-211 and lncPTMA-209 are in-vivo key molecular characteristics of response of gastric cancer patients to novel auxiliary chemotherapy for the first time. The biomarker and the combination thereof can be used for effectively screening the sensitive crowd of the new auxiliary chemotherapy of the gastric cancer patient and predicting the curative effect of the new auxiliary chemotherapy by only a small amount of blood samples before treatment, thereby greatly promoting the realization of the optimized treatment strategy of the gastric cancer patient.

Description

Application of plasma exosome biomarker in screening or efficacy prediction of gastric cancer newly assisted chemotherapy sensitive population
Technical Field
The invention relates to the field of tumor molecular biology, in particular to a biomarker related to a gastric cancer neoadjuvant therapy and application thereof.
Background
About 42% of gastric cancer worldwide occurs in our country, of which about 71% is progressive gastric cancer (AGC). In recent years, the therapeutic mode of AGC has gradually changed from single surgery to surgery-based multidisciplinary integrated therapy. Multiple studies have shown that for most AGC with late stages, perioperative treatment patterns can further improve patient survival compared to standard radical therapy combined postoperative adjuvant chemotherapy patterns.
The New Adjuvant Chemotherapy (NACT) is systemic chemotherapy before operation, and aims at shrinking tumor, reducing tumor stage, providing drug sensitive result after operation and eliminating undetected micrometastasis, so as to facilitate subsequent operation and other treatments, and can significantly improve survival of gastric cancer patients in progressive stage. However, more than half of gastric cancer patients have no apparent tumor regression in the postoperative pathological foci, suggesting that this fraction of patients cannot benefit from NACT. Therefore, exploring NACT efficacy predictions and screening for patients who are sensitive to NACT is important to clinical practice.
At present, TNM stage and TRG stage are commonly used clinically to judge the response of the new adjuvant therapy population and the therapy, however, TNM standard cannot identify the sensitive population for the therapy; TRG grading relies on post-operative pathology and does not allow efficacy assessment before and during neoadjuvant therapy. Recent researches show that the molecular typing of the tumor has a certain correlation with the chemotherapy curative effect of gastric cancer patients, such as TCGA and ACRG, wherein MSI-H typed tumor in TCGA typing has poor chemotherapy curative effect; tumor Mutational Burden (TMB) also has a certain hint effect. However, whether treatment would benefit from treatment with these molecular typing guidelines with clinically practical patients remains to be validated; moreover, the molecular spectrum analysis of enough samples obtained by multiple endoscopic biopsies is not only high in damage to patients, but also high in cost, and is difficult to realize in clinic.
In addition, previous studies have mostly screened markers based on patient survival, which is affected by many factors and cannot directly reflect the pathological changes of the tumor caused by treatment. The treatment effect is estimated more directly and reliably by estimating the pathological response of the tumor, but the related biomarkers are fewer at present, so that the development of the exosome biomarkers which have higher accuracy and are more reliable and can be used for screening the sensitive crowd of the gastric cancer neoadjuvant chemotherapy, predicting the curative effect of the gastric cancer neoadjuvant chemotherapy or screening the gastric cancer therapeutic drugs is urgently needed.
Disclosure of Invention
In order to solve the problems, the invention provides a biomarker capable of rapidly and accurately screening a sensitive crowd of a gastric cancer patient for new auxiliary chemotherapy and predicting the curative effect of the gastric cancer patient for new auxiliary chemotherapy, and a composition, a reagent, a kit and application thereof. The technical scheme provided by the invention does not need in vivo biopsy, can realize noninvasive and real-time detection by only a small amount of blood, and has low cost and convenient use; has high AUC value, high sensitivity, high accuracy and high stability; the treatment effect is estimated more directly and reliably by estimating the pathological response of the tumor; can effectively screen the sensitive crowd of the new auxiliary chemotherapy of the gastric cancer patients, forecast the new auxiliary chemotherapy curative effect of the gastric cancer patients or screen the drugs for treating the gastric cancer.
Specifically, the invention provides a biomarker for screening a patient with gastric cancer for new adjuvant chemotherapy sensitive population, predicting the new adjuvant chemotherapy curative effect of the patient with gastric cancer or screening a drug for treating gastric cancer, wherein the biomarker comprises at least one of the following genes: let-7i-5p, miR-1307-3p, miR-181a-5p, miR-1843, LZIC, SRSF6, lncFTH1-211 and lncPTMA-209.
Further, the biomarker is an exosome biomarker;
still further, the biomarker is a plasma exosome biomarker.
In another aspect, the present invention also provides an application of the biomarker of the present invention in preparing a product for screening a patient with gastric cancer for a patient sensitive to neoadjuvant chemotherapy, or in preparing a product for predicting a therapeutic effect of neoadjuvant chemotherapy for a patient with gastric cancer, or in preparing a product for screening a therapeutic agent for gastric cancer, wherein the biomarker comprises at least one of the following genes: let-7i-5p, miR-1307-3p, miR-181a-5p, miR-1843, LZIC, SRSF6, lncFTH1-211 and lncPTMA-209.
Further, the biomarkers include one, two, three, four, five, six, seven, or eight thereof; preferably, the biomarkers include two, three or four thereof.
Further, the biomarker comprises at least let-7i-5p; preferably, the biomarker comprises at least let-7i-5p and LZIC, let-7i-5p and miR-1307-3p, let-7i-5p and lncPTMA209, or let-7i-5p+lncFTH1-211.
Still further, the biomarker is: let-7i-5p+lncFTH1-211, let-7i-5p+LZIC, let-7i-5p+lncPTMA209, let-7i-5p+miR-1307-3p+lncFTH1-211, miR-1843+let-7i-5p+LZIC, let-7i-5p+miR-1307-3p+LZIC, miR-1843+let-7i-5p+lncPTMA209, miR-181 a-5p+5let-7 i-5p+LZIC, miR-181 a-5p+LZIC, let-7i-5p+miR-1307-3p+LZIC or miR-181 a-5p+miR-7 i-5p+miR-1307-3p+LZIC.
Further, the biomarker is an exosome biomarker; still further, the biomarker is a plasma exosome biomarker.
Further, the novel auxiliary chemotherapy refers to the chemotherapy of fluorouracil antitumor drugs combined with platinum antitumor drugs; preferably, the fluorouracil is 5-fluorouracil, capecitabine, tegafur, ulipratin, carmofur or tegafur, and the platinum is cisplatin, carboplatin, nedaplatin, lobaplatin or oxaliplatin; further preferred, the neoadjuvant chemotherapy is an oxaliplatin-tegafur regimen or an oxaliplatin-capecitabine regimen.
Preferably, the product comprises oxaliplatin and tegafur, or capecitabine and capecitabine.
Further, gastric cancer refers to advanced gastric cancer.
Further, the product comprises reagents for detecting the expression level of a biomarker; preferably, the reagent is a reagent comprising fluorescent quantitative PCR; further optionally, detection primers and/or probes are included.
Further, the product comprises an exosome extraction reagent; preferably, the product comprises a plasma exosome extraction reagent; more preferably, the product comprises a plasma exosome RNA extraction reagent.
Further, the product is a reagent, a kit or a gene chip.
In another aspect, the invention also provides a biomarker composition comprising two or more of the following genes: let-7i-5p, miR-1307-3p, miR-181a-5p, miR-1843, LZIC, SRSF6, lncFTH1-211 and lncPTMA-209.
Further, the biomarker composition includes two, three, four, five, six, seven or eight; preferably, the biomarkers comprise two, three or four.
Further, at least includes let-7i-5p and LZIC, let-7i-5p and miR-1307-3p, let-7i-5p and lncPTMA209 or let-7i-5p and lncFTH1-211.
Further, the composition of the biomarkers is: let-7i-5p+lncFTH1-211, let-7i-5p+LZIC, let-7i-5p+lncPTMA209, let-7i-5p+miR-1307-3p+lncFTH1-211, miR-1843+let-7i-5p+LZIC, let-7i-5p+miR-1307-3p+LZIC, miR-1843+let-7i-5p+lncPTMA209, miR-181 a-5p+5let-7 i-5p+LZIC, miR-181 a-5p+LZIC, let-7i-5p+miR-1307-3p+LZIC or miR-181 a-5p+miR-7 i-5p+miR-1307-3p+LZIC.
Further, the biomarker is used for screening a patient with gastric cancer for newly assisted chemotherapy sensitive population, predicting the newly assisted chemotherapy curative effect of the patient with gastric cancer or screening a drug for treating gastric cancer.
Further, the gastric cancer is a progressive gastric cancer.
Further, the biomarker is an exosome biomarker.
Still further, the biomarker is a plasma exosome biomarker.
In another aspect, the invention also provides a reagent for detecting the expression level of the biomarker of the invention and compositions thereof in a biological sample.
Further, the reagent comprises a fluorescent quantitative PCR detection reagent; preferably, the detection reagent comprises a detection primer and/or a probe.
Further, the reagent further comprises an exosome extraction reagent; preferably, the plasma exosome extraction reagent is comprised; further preferred, comprises a plasma exosome RNA extraction reagent.
Further, the reagent is used for screening new auxiliary chemotherapy sensitive groups of gastric cancer patients, predicting new auxiliary chemotherapy curative effects of gastric cancer patients or screening gastric cancer treatment medicines.
In another aspect, the invention also provides a kit comprising the detection reagent of the invention.
Furthermore, the kit is used for screening new auxiliary chemotherapy sensitive groups of gastric cancer patients, predicting new auxiliary chemotherapy curative effects of gastric cancer patients or screening gastric cancer treatment medicines.
In another aspect, the invention also provides a gene chip comprising probes for detecting the expression level of a biomarker or a composition of biomarkers of the invention.
Furthermore, the gene chip is used for screening new auxiliary chemotherapy sensitive groups of gastric cancer patients, predicting new auxiliary chemotherapy curative effects of gastric cancer patients or screening gastric cancer treatment medicines.
On the other hand, the invention also provides application of the biomarker, the biomarker composition, the detection reagent, the detection kit or the gene chip in preparing products for screening new auxiliary chemotherapy sensitive groups of gastric cancer patients, predicting new auxiliary chemotherapy curative effect products of gastric cancer patients or screening gastric cancer treatment drug products.
Further, the gastric cancer is a progressive gastric cancer.
Further, the novel auxiliary chemotherapy refers to the chemotherapy of fluorouracil antitumor drugs combined with platinum antitumor drugs; preferably, the fluorouracil is 5-fluorouracil, capecitabine, tegafur, ulipradine, carmofur or tegafur, and the platinum is cisplatin, carboplatin, nedaplatin, lobaplatin or oxaliplatin.
Still further, the neoadjuvant chemotherapy refers to an oxaliplatin-tegafur regimen or an oxaliplatin-capecitabine regimen.
Further, the biomarker is an exosome biomarker; still further, the biomarker is a plasma exosome biomarker.
Further, the product also comprises an exosome extraction reagent, preferably comprises a plasma exosome extraction reagent, and further preferably comprises a plasma exosome RNA extraction reagent.
Further, the primer and/or probe sequences described in the preceding aspects are selected from the following table:
Figure BDA0003696715760000041
Figure BDA0003696715760000051
on the other hand, the invention also provides a method for screening a sensitive population of the gastric cancer patient for the new adjuvant chemotherapy, extracting plasma exosome RNA of the population to be tested, measuring the expression level of the biomarker or the composition thereof, and screening the sensitive population for the new adjuvant chemotherapy by analyzing the expression level.
On the other hand, the invention also provides a method for predicting the curative effect of the novel adjuvant chemotherapy on the gastric cancer patient, extracting the plasma exosome RNA of the gastric cancer patient to be detected, measuring the expression level of the biomarker or the composition thereof in the biological sample, and predicting the curative effect by analyzing the expression level.
On the other hand, the invention also provides a screening method of gastric cancer therapeutic drugs, wherein drugs to be screened are added into gastric cancer cells, after culturing, the expression level of the biomarker or the composition thereof is measured, and the expression level of the biomarker or the composition thereof in the gastric cancer cells before and after the drug is added is compared, so that the drugs with changed expression level are potential drugs for treating gastric cancer.
Compared with the prior art, the invention at least has the following beneficial technical effects:
1. the invention discovers that the plasma exosome biomarkers let-7i-5p, miR-1307-3p, miR-181a-5p, miR-1843, LZIC, SRSF6, lncFTH1-211 and lncPTMA-209 are key molecules for the response of a gastric cancer patient to new auxiliary chemotherapy for the first time, have high AUC value, high sensitivity, high accuracy and high stability, and can effectively screen sensitive people of the new auxiliary chemotherapy for gastric cancer, predict the curative effect of the new auxiliary treatment for gastric cancer or screen medicines for treating gastric cancer.
2. The invention is carried out in a liquid biopsy mode, can realize noninvasive and real-time monitoring, and has low cost, convenient use and good stability. Only 1 milliliter of plasma is needed each time, the damage to a patient is small, the risk of damage to the body of the patient caused by molecular typing identification of enough tumor tissues obtained by performing multiple tissue biopsies through a gastroscope is avoided, multiple sampling and evaluation along with treatment can be realized, the detection cost is greatly reduced, and the use is convenient.
3. Compared with RNA and protein molecules in blood plasma, the biomarker provided by the invention benefits from the protection of exosome membrane structures, has more stable molecular expression level, higher sensitivity and specificity and important clinical application value.
4. By utilizing the technical scheme of the invention, before treatment starts, the screening of the sensitive crowd of the gastric cancer new auxiliary chemotherapy can be realized by only a small amount of blood samples, the curative effect of the gastric cancer patients on the new auxiliary chemotherapy is predicted, and the realization of the optimal treatment strategy of the gastric cancer patients is greatly promoted.
5. The invention evaluates the treatment effect by evaluating the pathological response of the tumor, and is more direct, reliable and effective compared with the prior screening markers according to the survival of patients.
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The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate the invention and together with the embodiments of the invention, serve to explain the invention. In the drawings:
fig. 1: the technical scheme of the invention is as follows;
fig. 2: exosome identification results (Western Blot, projection electron microscope, nanotracer technique);
fig. 3: performing differential analysis on TPM values of the exosome RNAs;
fig. 4: panels a-C are intersections of two sets of differential markers;
fig. 5: training set and verification set AUC graphs of two molecular models;
fig. 6: AUC diagram of three molecular model training set and validation set;
fig. 7: AUC plot of training set and validation set of four molecular models.
Detailed Description
The preferred embodiments of the present invention will be described below with reference to the accompanying drawings, it being understood that the preferred embodiments described herein are for illustration and explanation of the present invention only, and are not intended to limit the present invention. The overall process of the invention is shown in fig. 1.
EXAMPLE 1 screening of exosome RNA for neoadjuvant chemotherapy efficacy
1. Incorporating an object
We randomly selected 10 healthy human volunteers and 20 progressive gastric cancer (AGC) patients as inclusion subjects. Healthy human volunteers were from Beijing university first hospital and gastric cancer patients were from Beijing university tumor hospital gastrointestinal tumor center-ward. Both groups of men account for 90%, and the ratio of men to women is 9:1; the average age was 57 years, and the age range was 43-73 years. Each of the 20 AGC patients received neoadjuvant chemotherapy (both of which are recommended by the chinese clinical society of oncology (CSCO) guidelines (2021 edition)) with SOX (oxaliplatin-tegafur) or XELOX (oxaliplatin-capecitabine) regimen: oxaliplatin (130 mg/m) 2 ) Intravenous administration of tegafur (40-60 mg/m) 2 ) Or capecitabine (1000 mg/m) 2 ) Oral administration is carried out on days 1-14, and every 3 weeks, the treatment course is 3-5. Of the patients incorporated, 10 patients had good efficacy and 10 patients had poor efficacy.
The above patient efficacy is differentiated according to the following judgment method and criteria: judging the curative effect by 2 auxiliary doctors or pathologists with the names according to the pathological conditions of the resected specimens after the operation, wherein the primary cancer focus is obviously retracted, and no cancer cells or only scattered cancer cells are good in curative effect; the shrinkage of cancer focus is not obvious, and no tumor cell necrosis or only a small part of cancer cell necrosis is poor in curative effect.
2. Plasma collection:
before the patient receives the preoperative new adjuvant chemotherapy, 8-10 parts of the morning, 2.0mL of peripheral blood of the patient is collected in a fasting state, centrifuged for 10 minutes at 4 ℃ and 3000rpm, 1.0mL of plasma is extracted, and the plasma is stored in a refrigerator at-80 ℃. The same procedure was used for plasma collection after the healthy subjects signed informed consent.
3. Exosome extraction:
after thawing the plasma, it was first filtered through a 0.22um filter (EMD Millipore, billerica, mass.) and the filtered plasma was applied to a 10.0 mL-washed SEC exclusion column (Echobiotech, china), 10.0mL PBS was added, one fraction was taken per 0.5mL, fractions 4-8 were collected, and then concentrated to 50uL using a 100kDa ultrafilter (Merck, germany), and exosomes were detected using Western blot, transmission electron microscopy and nanotracer techniques (FIG. 2), and quantitative analysis was performed on the extracted exosomes by BCA kit (Pierce Biotechnology, rockford, calif.).
4. Exosome RNA extraction:
total RNA of the exosomes was extracted using a miRNeasy plasma kit (Qiagen, cat.No. 2170004).
5. Sequencing of exosomes mRNA, miRNA and lncRNA
We prepared sequencing of total plasma-derived exosome RNAs obtained from the above subjects. An exosome RNA expression library was constructed based on SMARTer Stranded Total RNA-Seq Kit V2 (Takara Bio USA, inc.) Kit detection and quantified based on the unique molecular structure (UMI) of the RNA. Templates and corresponding reads are generated at the Illumina Hiseq platform. The TPM values for each of the RNAs were calculated by bioinformatics (FIG. 3).
6. Differential analysis of exosome mRNA, miRNA and lncRNA
Differential analysis based on TPM values of exosome RNAs makes it difficult to determine the cell source after exosomes are excreted outside the cell. Therefore, we first analyzed the difference in expression of the exosome RNA between healthy and gastric cancer patients using the Mann-Whitney U test method, and screened the exosome RNA associated with gastric cancer. Then we further analyzed differentially expressed exosome RNAs of patients with good and poor efficacy, and we took the intersection of the two analyses as exosome RNAs associated with neoadjuvant chemotherapy of gastric cancer for subsequent analysis in order to eliminate the interference that may be caused by individual differences (fig. 4).
7. Exosome RNA biomarker screening related to novel adjuvant chemotherapy efficacy
By analyzing the P value, the fold difference (FC) and the area under the subject working curve (ROC) (AUC) of gastric cancer patients with good curative effects of novel adjuvant chemotherapy by screening the exosome mRNA, miRNA and lncRNA, the exosome RNAs with P less than 0.05, AUC more than 0.80 and fold difference less than 0.67 or more than 1.50 are selected, and 31 exosome RNAs are screened out (table 1).
TABLE 1 differential expression of exosome RNA with area under the curve AUC exceeding 0.8.
Figure BDA0003696715760000081
Example 2 verification of exosome RNA biomarkers associated with neoadjuvant chemotherapeutic efficacy
To further verify the predictive efficacy of exosome RNAs, we comprehensively screened 18 exosome RNAs with higher differential fold (specifically 9 exosome miRNAs (miR-27 a-3p, miR-335-5p, miR-454-3p, miR-152-3p, miR-181a-5p, miR-1843, let-7i-5p, miR-130a-3p and miR-1307-3 p), 5 exosome mRNAs (LZIC, KMT2E, DAPP1, DAB2 and SRSF 6) and 4 lncRNAs (lncPTMA-209, lncRMRP-202, lncRPS24-210 and lncFTH 1-211)), and verified in a new independent 43 progressive gastric cancer patient queue using real-time fluorescent quantitative PCR (qRT-PCR). The new 43 patients were also progressive gastric cancer patients and received neoadjuvant chemotherapy and D2 gastric cancer ablation with SOX or XELOX regimen, 19 of which had good efficacy and 24 had poor efficacy. Wherein the treatment method, the treatment efficacy standard, the plasma collection method, the exosome, and the extraction method of exosome RNA of the analysis subject were the same as in example 1.
By PrimeScript TM The RT reagent Kit (Perfect Real Time) (TAKARA, RR 037A) was subjected to qRT-PCR, and the expression level of the above genes was measured, and further, the exosome RNAs having statistically significant differences, which were consistent with the expression trends of the candidate sequencing groups shown in Table 1, were selected. The primers and probes used (wherein U6 and ENSG00000198804 are reference genes) are listed in Table 2.
TABLE 2 probe and primer sequences for RNA
Figure BDA0003696715760000091
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Figure BDA0003696715760000101
And (3) screening 8 exosome RNAs with better predicted curative effects of the neoadjuvant chemotherapy by combining the AUC, the expression trend consistency, the statistical difference and the difference multiple of the exosome RNAs in a training set and a verification set, wherein the 8 exosome RNAs comprise 4 exosome miRNAs (let-7 i-5p, miR-1307-3p, miR-181a-5p and miR-1843), 2 exosome mRNAs (LZIC and SRSF 6) and 2 exosome lncRNAs (lncFTH 1-211 and lncPTMA-209), and the exosome RNA verification data are consistent with the expression trend of the candidate sequencing group shown in the table 1 and have the difference of statistical significance between patients with good curative effects and patients with bad curative effects.
Table 3 shows the results of verification of single exosome RNA associated with neoadjuvant chemotherapy efficacy.
Figure BDA0003696715760000102
In addition, the expression amounts of miR-335-5P, miR-454-3P, lncRMRP-202 and lncRPS24-210 are different between patients with good curative effect and poor curative effect in a verification set (P is less than 0.05), but the trend is opposite to that of a sequencing group, and no statistical difference exists after the two groups of data are integrated; the expression levels of the other 6 exosome RNAs showed no significant difference between patients with good and poor efficacy in the validation set.
In sum, let-7i-5p, miR-1307-3p, miR-181a-5p, miR-1843, LZIC, SRSF6, lncFTH1-211 and lncPTMA-209 are exosome RNA molecules (Table 3) related to the curative effect of gastric cancer neoadjuvant chemotherapy, and the single-molecule AUC is distributed in 0.723-0.812, so that the screening effect is high, the AUC is high in both training set and verification set, the stability is high, and the screening method can be used for screening and curative effect prediction of clinical gastric cancer neoadjuvant chemotherapy sensitive people.
Example 3 construction and validation of exosome RNA model related to neoadjuvant chemotherapy efficacy
To explore further better assessment methods, we normalized the expression of 8 exosome RNAs (including 4 exosome miRNAs: let-7i-5p, miR-1307-3p, miR-181a-5p and miR-1843;2 exosome mRNAs: LZIC and SRSF6; and 2 exosome lncRNAs: lncFTH1-211 and lncPTMA-209) in the sequencing and validation groups patients by the Z-score method, and then constructed a multi-index model by existing data.
By using a logistic regression method, we firstly construct two molecular model groups, three molecular model groups and four molecular model groups respectively from the 8 exosomes, find that in the three model groups, the evaluation effect is 3 in two molecular models with AUC greater than 0.80 in a training set and a verification set, 6 in three molecular models and 2 in four molecular models (Table 4, fig. 5-7), and the AUC of the three molecular models in the training set is greater than 0.90, so that the specificity, the sensitivity and the stability of the three molecular models are higher, and the models can effectively screen potential gastric cancer patients sensitive to the novel auxiliary chemotherapy and predict the curative effect of the novel auxiliary chemotherapy. And the AUC of the molecular model, the three-molecular model and the four-molecular model is further improved compared with that of the single-molecular model through comparison.
TABLE 4 model with training and validation set AUC above 0.8
Figure BDA0003696715760000111
Figure BDA0003696715760000121
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.

Claims (5)

1. The application of the biomarker in preparing products for screening sensitive crowd of new auxiliary chemotherapy of gastric cancer patients and/or predicting the curative effect of the new auxiliary chemotherapy of gastric cancer patients is characterized in that the biomarker is as follows: let-7i-5p+lncFTH1-211, let-7i-5p+LZIC, let-7i-5p+lncPTMA209, let-7i-5p+miR-1307-3p+lncFTH1-211, miR-1843+let-7i-5p+LZIC, let-7i-5p+miR-1307-3p+LZIC, miR-1843+let-7i-5p+lncPTMA209, miR-181a-5p+let-7i-5p+LZIC, miR-181 a-5p+LZIC, let-7i-5p+miR-1307-3p+LZIC or miR-181 a-5p+miR-7 i-5p+miR-1307-3p+LZIC;
wherein the gastric cancer refers to advanced gastric cancer; the biomarker is a plasma exosome biomarker, the neoadjuvant chemotherapy is an oxaliplatin-tigioscheme or an oxaliplatin-capecitabine scheme, and the product comprises a reagent for detecting the expression level of the biomarker.
2. The use of claim 1, wherein the reagent comprises a fluorescent quantitative PCR detection reagent.
3. The use according to claim 2, wherein the reagent comprises a detection primer and/or a probe.
4. The use according to claim 1, wherein the product is a reagent, a kit or a gene chip.
5. Use of a kit or a gene chip for the preparation of a product for screening a population susceptible to neoadjuvant chemotherapy in gastric cancer patients and/or for predicting the efficacy of neoadjuvant chemotherapy in gastric cancer patients, wherein the kit comprises a reagent for detecting the expression level of a biomarker, and the gene chip comprises a probe for detecting the expression level of a composition of biomarkers, wherein the biomarker is: let-7i-5p+lncFTH1-211, let-7i-5p+LZIC, let-7i-5p+lncPTMA209, let-7i-5p+miR-1307-3p+lncFTH1-211, miR-1843+let-7i-5p+LZIC, let-7i-5p+miR-1307-3p+LZIC, miR-1843+let-7i-5p+lncPTMA209, miR-181a-5p+let-7i-5p+LZIC, miR-181 a-5p+LZIC, let-7i-5p+miR-1307-3p+LZIC or miR-181 a-5p+miR-7 i-5p+miR-1307-3p+LZIC;
wherein the gastric cancer refers to advanced gastric cancer; the biomarker is a plasma exosome biomarker, and the neoadjuvant chemotherapy is an oxaliplatin-tigioscheme or an oxaliplatin-capecitabine scheme.
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