CN109652547B - Application of ASMT/CYP1A1 molecular label in predicting solid tumor clinical prognosis or immune characteristics - Google Patents

Application of ASMT/CYP1A1 molecular label in predicting solid tumor clinical prognosis or immune characteristics Download PDF

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CN109652547B
CN109652547B CN201910036333.2A CN201910036333A CN109652547B CN 109652547 B CN109652547 B CN 109652547B CN 201910036333 A CN201910036333 A CN 201910036333A CN 109652547 B CN109652547 B CN 109652547B
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孙颖
吕佳蔚
陈雨沛
郑子奇
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Sun Yat Sen University Cancer Center
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Abstract

The invention discloses application of ASMT/CYP1A1 molecular tags in predicting clinical prognosis or immune characteristics of solid tumors. The inventor conducts bioinformatics analysis of a large sample by researching the transcriptome and the genome data of 6658 tumor samples in total of 14 solid tumors, and confirms the relation between the ASMT/CYP1A1 ratio level and the clinical prognosis of patients, the tumor mutation level and the tumor neoantigen load in different solid tumors. The clinical prognosis of the cervical cancer, gastric cancer and melanin patients in the High Index group is considerable, and the result of multi-factor analysis shows that the result of ASMT/CYP1A1 is an independent prediction Index of the clinical prognosis of the tumor patients; in addition, the prognosis for patients with colorectal cancer, head and neck squamous carcinoma, renal cancer, liver cancer, prostate cancer, melanoma, in the Low Index group, although worse, there was more mutation burden and/or neoplastic antigens suggesting that this group of patients is more likely to benefit from immunotherapy.

Description

Application of ASMT/CYP1A1 molecular label in predicting solid tumor clinical prognosis or immune characteristics
Technical Field
The invention relates to a marker for predicting clinical prognosis of solid tumors and immune body mutation level and/or new antigen load and application thereof.
Background
Tumors are the third largest disease threatening human health. In 2018, there were about 1819 million new cancer cases and 960 million cancer death cases all over the world. The incidence of tumors is on the trend of declining year by year along with the progress of medical technology and the enhancement of cancer prevention consciousness of people, and the death rate of partial cancer species is still high. It is therefore important to accurately assess the prognosis of a patient with a tumor and to select an appropriate treatment regimen based on its characteristics. In recent years, immunotherapy is rapidly developed and becomes a fourth big anticancer weapon after surgery, radiotherapy, chemotherapy and targeted therapy. Related immunotherapeutic drugs, such as Nivolumab and Pembrolizumab, anti-PD-1 monoclonal antibodies, have proven effective in a number of cancer species and have been approved by the FDA in the United states for the treatment of patients with melanoma, lung cancer, head and neck tumors, and the like. However, immunotherapy is only effective for a portion of patients, and there is a need for specific biomarkers that can screen suitable tumor patients for immunotherapy to improve therapeutic benefit. Predictors that have been shown to be effective in a variety of tumors include: the level of somatic mutations and the level of neoantigens.
Melatonin (Melatonin) was first isolated as an indole capable of whitening skin by Lemer et al and was named Melatonin. In mammals and humans, it is an amine hormone produced by pineal, and can provide time information for the organism, ensuring the synchronization of circadian rhythm and seasonal rhythm. Therefore, melatonin expression also varies periodically in humans. According to the literature reported in the past, melatonin has an antitumor effect. For example, melatonin can be produced by reducing αvβ3The expression level of integrin inhibits the ability of glioma cells to migrate to the surrounding microenvironment. In addition, melatonin can reduce the number of peripheral fibroblasts and endothelial cells of a tumor tissue by down-regulating the expression of anti-adipocyte factors in the breast cancer tissue, thereby promoting the metastasis of the breast cancer. Meanwhile, research results show that melatonin plays a role in the generation and development of solid tumors, the regulation of the immune state of the body and the likeThe intended effect. For example, melatonin can inhibit the occurrence of breast cancer and the proliferation of abnormal breast tumor cells by repairing DNA damage; in addition, melatonin in humans promotes activation of various immune cells, antigen presentation processes, etc. to regulate immune responses.
Although theoretical research shows that the melatonin microenvironment and the effect of the melatonin microenvironment in tumor patients have good prospect in clinical application. However, due to the periodicity (rhythmicity) of melatonin secretion, levels of melatonin measured by peripheral blood often do not accurately reflect the levels and characteristics of the patient's tumor-melatonin microenvironment. Secondly, the synthesis and metabolism of melatonin are affected by various enzymes, and the synthesis and metabolism network thereof is relatively complex. Considering that the functions and expression levels of melatonin synthesizing and metabolizing biological enzymes in patients are separated from the tumor melatonin microenvironment itself in time and space, in practical clinical application, it is generally considered difficult to effectively predict the clinical prognosis and/or immune body mutation level and/or neoantigen characteristics of solid tumors based on the levels of melatonin in patients. Therefore, the search of the marker capable of reflecting the level of the melatonin in the tumor microenvironment in the tumor tissues has important clinical application value. However, there is no molecular tag currently available for related applications.
Disclosure of Invention
The invention aims to provide clinical application of a molecular marker ASMT/CYP1A1, which is used for describing a tumor melatonin microenvironment and effectively predicting the clinical prognosis of solid tumors and the level of immune body mutation and/or neoantigen load.
The inventor finds that the tumor melatonin microenvironment of solid tumor patients can be effectively classified by calculating the ratio of the expression levels of ASMT and CYP1A1 to describe the tumor melatonin microenvironment, and the tumor melatonin microenvironment is divided into High Index and Low Index groups by mean median. The relationship between The ASMT/CYP1A1 ratio level and The clinical prognosis, The tumor mutation level and The tumor neoantigen load of patients in different solid tumors is proved by performing bioinformatics analysis on a large sample of 6658 tumor samples of 14 solid tumors (bladder Cancer, breast Cancer, cervical Cancer, colon Cancer, head and neck squamous Cancer, kidney Cancer, hepatocellular carcinoma, lung adenocarcinoma, lung squamous carcinoma, pancreatic Cancer, prostate Cancer, skin Cancer, gastric Cancer and thyroid Cancer) in a public database, namely Cancer Genome map (TCGA). The clinical prognosis of the cervical cancer, gastric cancer and melanin patients in the High Index group is considerable, and the result of multi-factor analysis shows that the result of ASMT/CYP1A1 is an independent prediction Index of the clinical prognosis of the tumor patients; in addition, the prognosis of Low Index patients in colorectal, head and neck squamous, renal, liver, prostate, and melanoma patients is poor, but there are more mutation loads and neoplastic antigens, suggesting that this group of patients are more likely to benefit from immunotherapy.
The technical scheme adopted by the invention is as follows:
the application of the kit for determining the expression quantity ratio of ASMT and CYP1A1 in the preparation of a kit for predicting the clinical prognosis of solid tumors.
As a further improvement of the above application, the solid tumor is selected from cervical cancer, gastric cancer and melanoma.
Application of a kit for determining the expression quantity ratio of ASMT and CYP1A1 in preparing a kit for predicting the mutation level and/or antigen load of solid tumor immune bodies.
As a further improvement of the above use, the solid tumor is selected from: colorectal cancer, head and neck squamous cancer, kidney cancer, liver cancer, prostate cancer, and melanoma.
As a further improvement of the above application, the expression level of ASMT and CYP1A1 is the expression level of mRNA.
As a further improvement of the above application, the expression levels of ASMT and CYP1A1 are the expression levels in solid tumors.
As a further improvement of the application, the kit for determining the expression quantity ratio of ASMT and CYP1A1 is a kit for detecting the expression quantity of ASMT and CYP1A1 mRNA.
The invention has the beneficial effects that:
the method of the invention describes the tumor melatonin microenvironment by calculating the ratio of the ASMT and CYP1A1 expression levels, can effectively predict the clinical prognosis, the immune body mutation level and the new antigen characteristics of different groups of patients in solid tumors, guides clinical medication and improves the treatment effect. Particularly, the method can effectively predict the clinical prognosis of patients with cervical cancer, gastric cancer and melanoma, and the immune body mutation level and/or new antigen characteristics of patients with colorectal cancer, head and neck squamous carcinoma, renal cancer, liver cancer, prostatic cancer and melanoma, and further predict the possible immune treatment benefit.
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FIG. 1 is a graph of ASMT/CYP1A1 levels for 14 solid tumors (bladder, breast, cervical, colon, head and neck squamous, kidney, hepatocellular, lung adenocarcinoma, lung squamous, pancreatic, prostate, skin, gastric, and thyroid) in the TCGA database;
FIGS. 2 to 5 show the Overall Survival (OS) of the High Index and Low Index groups in the tissues of patients with cervical cancer, gastric cancer and melanoma in the TCGA database;
FIG. 6 is the levels of mutations in the TCGA database in the High Index and Low Index groups in colorectal, head and neck squamous, kidney, liver, prostate, and melanoma patient tissues;
FIG. 7 is the neoantigen burden in the TCGA database for the High Index and Low Index groups in tissues from patients with rectal, head and neck squamous, renal, hepatic, prostate, melanoma (colorectal and pancreatic cancers are excluded because there is insufficient neoantigen data).
Detailed Description
The invention is further illustrated below with reference to specific experiments, it being understood that the following is only intended to illustrate the invention and is not intended to limit the scope of the invention.
ASMT/CYP1A1 ratio profile in different solid tumors
By analyzing transcriptome and genome data of 6,658 tumor samples of 14 solid tumors (bladder cancer, breast cancer, cervical cancer, colon cancer, head and neck squamous carcinoma, kidney cancer, hepatocellular carcinoma, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, prostate cancer, skin cancer, gastric cancer and thyroid cancer) in the public database TCGA, the ratio of ASMT to CYP1a1 (ASMT/CYP1a1) in each tumor tissue was calculated, which reflects the level of melatonin in the tumor tissue. The results of ASMT/CYP1A1 were divided into High Index and Low Index (FIG. 1) groups according to median.
Correlation of ASMT/CYP1A1 ratio in different solid tumors with clinical prognosis
The results of the Kaplan-Meier survival analysis and the Cox presentation hazards multifactor model show that: among cervical cancer, gastric cancer and melanoma, the High Index group patients had longer overall survival and better clinical prognosis, and could be used as independent prediction Index of clinical prognosis of tumor patients (fig. 2-5). After important factors such as sex, age, race, tumor stage and the like are balanced, the total survival (overall survival) of the cervical cancer patients in the High Index group is obviously higher than that of the cervical cancer patients in the Low Index group, and the difference has statistical significance (adjusted risk ratio [ AHR ]. sup.0.62; 95% Confidence Interval (CI). sup.0.39-0.98; P. sup.0.04). Similarly, patients with gastric cancer (AHR 0.71; 95% CI 0.52-0.97, P0.03) and melanoma (AHR 0.74; 95% CI 0.55-0.98; P0.04) survived the High index group significantly better than the Low index group. In addition, no significant survival advantage was observed in patients with bladder cancer, breast cancer, lung cancer, etc. in the High Index group. The molecular label also has the specificity, and has good prediction effect on specific solid tumors.
Correlation of ASMT/CYP1A1 ratio to immune characteristics in different solid tumors
Close physiological relation exists between the pineal body and the immune system of the organism, and the fact that the melatonin level in the tumor microenvironment can influence the immune characteristics and the treatment effect of tumor patients is suggested. More and more studies have shown that: the mutation level and the tumor neoantigen load in different tumors can be used as the prediction index of the curative effect of the immunotherapy. Thus, we compared the mutation levels in different tumor melatonin microenvironments (High Index vs Low Index group) and the burden of tumor neoantigens and found that tumor patients in the Low Index group had higher mutation levels (P <0.05) in tissues of patients with colorectal, head and neck squamous, renal, prostate, and melanoma (fig. 6); tumor patients in the Low Index group had high tumor neoantigen burden (P <0.05) in head and neck squamous cell carcinoma, liver cancer, prostate cancer patient tissues (fig. 7). However, no obvious mutation level and/or tumor neoantigen load difference is observed in the High index compared with the Low index group in the patients with bladder cancer, breast cancer, cervical cancer and the like.

Claims (8)

1. The application of the reagent for determining the expression quantity ratio of ASMT and CYP1A1 in the preparation of a kit for predicting the clinical prognosis of solid tumors, wherein the solid tumors are selected from cervical cancer, gastric cancer and melanoma.
2. The use of claim 1, wherein the amount of ASMT and CYP1a1 is the amount of mRNA expression.
3. Use according to claim 2, characterized in that: the expression quantity of ASMT and CYP1A1 is the expression quantity in solid tumors.
4. Use according to any one of claims 1 to 3, characterized in that: the reagent for determining the expression ratio of ASMT and CYP1A1 is a reagent for detecting the expression of ASMT and CYP1A1 mRNA.
5. The application of a reagent for determining the expression quantity ratio of ASMT and CYP1A1 in the preparation of a kit for predicting the immune body mutation level and/or antigen load of a solid tumor, wherein the solid tumor in the kit for predicting the immune body mutation level of the solid tumor is selected from colorectal cancer, head and neck squamous cell carcinoma, renal cancer, prostate cancer and melanoma; the solid tumor in the kit for predicting the solid tumor antigen load is selected from head and neck squamous cell carcinoma, renal carcinoma and prostate cancer.
6. Use according to claim 5, characterized in that: the expression quantity of the ASMT and the CYP1A1 is the expression quantity of mRNA thereof.
7. Use according to claim 6, characterized in that: the expression quantity of ASMT and CYP1A1 is the expression quantity in solid tumors.
8. Use according to any one of claims 5 to 7, wherein: the reagent for determining the expression ratio of ASMT and CYP1A1 is a reagent for detecting the expression of ASMT and CYP1A1 mRNA.
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