CN116837095A - Biomarker for prognosis evaluation of head and neck squamous cell carcinoma immune combined chemotherapy and application thereof - Google Patents
Biomarker for prognosis evaluation of head and neck squamous cell carcinoma immune combined chemotherapy and application thereof Download PDFInfo
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Abstract
The invention discloses a biomarker for prognosis evaluation of head and neck squamous cell carcinoma immune combined chemotherapy and application thereof. The invention discovers that prognosis of immunotherapy combined chemotherapy of head and neck squamous cell carcinoma can be predicted by jointly detecting FAT1 and LRPIB gene mutation sites, wherein the FAT1 mutation sites comprise R885, R937, S1200, R1627, Q1694, S2826Kfs, S2838, S3373 and R3400; the mutation site of LRP1B includes W1394C/S, N2353I/Kfs X36, N2507D/I, A2729S/V, L2858P/V; the kit can also be used for detecting prognosis and survival time of head and neck squamous cell carcinoma immune combined chemotherapy according to detection reagents or kits developed by the detection markers.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a biomarker for prognosis evaluation of head and neck squamous cell carcinoma immune combined chemotherapy and application thereof.
Background
Cancer morbidity and mortality have increased rapidly worldwide as the population ages and grows for the twentieth century, and malignancy has become the most threatening disease to human health and life. Morbidity and mortality of head and neck tumors rule out the sixth malignancy, with squamous carcinoma accounting for 90%. Risk factors for head and neck squamous cell carcinoma mainly include smoking, drinking, chewing betel nut, bacterial and viral infection, malnutrition, etc. The main treatments for head and neck squamous cell carcinoma that can be resected over the past decades include surgery, radiation and chemotherapy, however the five year survival rate of patients remains around 50%, worse, only around 27%. In addition, markers and molecular typing for head and neck squamous cell carcinoma treatment have not been found by the academy to date. The reason for this may be that the range covered by various markers and typing is too wide and there is no subdivision study on patients and treatments for related gene expression.
Head and Neck Squamous Cell Carcinoma (HNSCC) is usually resected by surgery and then adjunctively treated according to pathological analysis, although surgery and radiation therapy have advanced in oral and oropharyngeal squamous carcinoma patients, their prognosis is still relatively poor.
In recent years, tumor immune checkpoint therapy gradually becomes a research and development hot spot, and a great breakthrough is continuously obtained. Unlike cytotoxic drugs or monoclonal antibodies or small molecule tyrosine kinase inhibitors targeting tumor driving genes, tumor immune checkpoint therapy does not directly act on tumor cells, but removes immune escape mechanisms of the tumor cells by blocking inhibition signals of proliferation and activation of the T cells, restores T cell activity, and improves effective recognition and killing of the T cells on the tumor cells. Tumor immune checkpoint targets which have shown obvious clinical effects at present comprise programmed death receptors, programmed death receptor 1/ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte anti-4 (CTLA-4), wherein the PD1/PD-L1 targeted immune checkpoint inhibitor has better clinical application prospect due to better safety and wider indication. Programmed death receptor-1 (PD-1, CD 279) is a type I transmembrane protein with a molecular weight of 55kD, a member of the CD28 family of T cell costimulatory molecules, which also includes CD28, CTLA-4, ICOS and BTLA. PD-1 contains an intracellular membrane proximal Immunoreceptor Tyrosine Inhibitory Motif (ITIM) and a membrane distal immunoreceptor tyrosine opening Guan Jixu (ITSM). Two specific ligands for PD-1 have been identified: PD-L1 (B7-H1/CD 274) and PD-L2 (B7-DC/CD 273). PD-L1 and PD-L2 have been demonstrated to down regulate T cell activation upon binding to PD-1 in both the mouse and human systems. PD-1 transmits negative signals by recruiting SHP-2 to phosphorylated tyrosine residues of the ITSM cytoplasmic region. Immune Checkpoint Inhibitors (ICIS) are a widely effective class of immunotherapy that can block the inhibitory immune checkpoint pathway to reactivate immune responses to cancer. PD-L1, which is normally expressed by tumor cells, is linked to a PD-1 protein that can be expressed by T cells, resulting in the suppression of the T cell immune response, which is one of the mechanisms of tumor immune escape. The novel adjuvant immune checkpoint therapy has achieved significant clinical efficacy in melanoma, non-small cell lung cancer, bladder cancer and glioblastoma. In 2016, PD-1 blocker sodium Wu Liyou and palbociclizumab were approved by FAD for patients with recurrent/metastatic head and neck squamous cell carcinoma, including oral and oropharyngeal squamous carcinoma, with a response rate of about 20% and overall survival benefit compared to chemotherapy.
The combined immunization and chemotherapy has been greatly successful in lung cancer, nasopharyngeal carcinoma and other tumors according to the current domestic and foreign literature, and other tumors have been explored by clinical experiments. For example, a multi-center, randomized, double-blind study published in the new england journal of stage iii, evaluated the efficacy of the PD-L1 inhibitors Atezolizumab and Nab-paclitaxel in combination with placebo for the treatment of locally advanced or metastatic triple negative breast cancer, with overall OS being encouraging in the PD-L1 positive population. Therefore, how to more accurately assess the prognosis of immunotherapy in combination with chemotherapy is a problem that needs to be addressed in the art.
Disclosure of Invention
The invention aims to provide a biomarker for predicting the effect of HNSCC immunotherapy.
The technical scheme adopted by the invention is as follows:
in a first aspect of the invention, a biomarker is provided, comprising mutation sites of FAT1 and LRP 1B.
In some embodiments of the present invention, the mutation site of FAT1 includes R885, R937, S1200, R1627, Q1694, S2826Kfs, S2838, S3373, and R3400.
In some embodiments of the invention, the mutation site of LRP1B comprises W1394C/S, N2353I/Kfs X36, N2507D/I, A2729S/V, L2858P/V.
In a second aspect of the invention there is provided the use of a biomarker comprising a mutation site of FAT1 and/or LRP1B and/or a substance for detecting a biomarker in at least one of (a 1) to (a 4);
(a1) Preparing a product for evaluating or predicting prognosis risk of head and neck squamous cell carcinoma immune combination chemotherapy;
(a2) Preparing a product for predicting the applicability of the immune combination chemotherapy of the head and neck squamous cell carcinoma;
(a3) Preparing a product for predicting survival time of patients suffering from head and neck squamous cell carcinoma immune combined chemotherapy;
(a4) The method is used for preparing products for detecting the drug resistance of the head and neck squamous cell carcinoma immune combined chemotherapy.
In some embodiments of the present invention, the mutation site of FAT1 includes R885, R937, S1200, R1627, Q1694, S2826Kfs, S2838, S3373, and R3400.
In some embodiments of the invention, the mutation site of LRP1B comprises W1394C/S, N2353I/Kfs X36, N2507D/I, A2729S/V, L2858P/V.
In some embodiments of the invention, the immunotherapy comprises immune checkpoint inhibitor therapy, adoptive immunotherapy (e.g., CAR-T), cell therapy.
In some embodiments of the invention, the immune checkpoint inhibitor comprises a PD-1/PD-L1 antibody.
In some embodiments of the invention, the chemotherapeutic agent comprises paclitaxel, platinum, or other chemotherapeutic agents.
In some embodiments of the invention, the platinum group includes cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, and the like.
In some embodiments of the invention, the head and neck squamous carcinoma includes at least one of oral squamous carcinoma, adenoid cystic carcinoma, parotid carcinoma, gingival carcinoma, cheek carcinoma, laryngeal carcinoma, paranasal sinus carcinoma, oropharyngeal carcinoma, nasopharyngeal carcinoma.
In some embodiments of the invention, the substance comprises a primer and/or probe for detecting the biomarker.
In some embodiments of the invention, the product comprises at least one of a reagent, a kit, a test strip, a chip.
In a third aspect of the invention, there is provided a product comprising a substance for detecting a biomarker according to the first aspect of the invention.
In some embodiments of the invention, the substance comprises a primer and/or probe for the biomarker.
In some embodiments of the invention, the product comprises at least one of a reagent, a kit, a test strip, a chip.
In a fourth aspect of the invention, there is provided a head and neck squamous cell carcinoma prognosis evaluation system comprising the following modules:
(a5) The data collection module is used for collecting patient samples and measuring the detection result of the marker in the first aspect of the invention;
(a6) Comparing the detection result with normal sample data, and judging the prognosis level of the head and neck squamous cell carcinoma according to the comparison result; if FAT1 and LRP1B are co-mutated, the prognosis is judged to be bad, and if FAT1 and LRP1B are not co-mutated, the prognosis is good.
In some embodiments of the invention, the sample comprises head and neck squamous carcinoma tissue and/or cells of the patient.
The beneficial effects of the invention are as follows:
the invention discovers that prognosis of immunotherapy combined chemotherapy (especially PD-1 monoclonal antibody combined chemotherapy) of head and neck squamous cell carcinoma can be predicted by combined detection of FAT1 and LRPIB genes, so that FAT1 and LRPIB gene co-mutation can be used as a prognosis marker of head and neck squamous cell carcinoma, wherein mutation sites of FAT1 comprise R885, R937, S1200, R1627, Q1694, S2826Kfs, S2838, S3373 and R3400; the mutation sites of LRP1B include W1394C/S, N2353I/Kfs X36, N2507D/I, A2729S/V, L2858P/V. The detection reagent or the kit can be developed according to the reagent for detecting the marker, and can detect prognosis and survival time of the head and neck squamous cell carcinoma; providing important reference basis for risk assessment, prognosis and subsequent targeted treatment of head and neck squamous cell carcinoma; the accuracy of TMB in HNSCCC immunochemical effect prediction is also improved.
Drawings
Fig. 1: mutation spectra of the first 30 differential mutant genes in the horizontal group and TMB low-level group in TCGA data MB.
Fig. 2: TCGA data TMB high level group and mutation profile of the first 30 differential mutant genes in the level group in TMB.
Fig. 3: mutation frequencies of FAT1 and LRP1B genes in the HNSCC cohort collected by the applicant.
Fig. 4: mutation types of FAT1 and LRP1B genes in the HNSCC cohort collected by applicant.
Fig. 5: prognosis and resistance analysis of FAT1 and LRP1B mutations; wherein FIG. 5A shows the mutation frequencies of FAT1 and LRP1B genes in databases such as TCGA/MSKCC; FIG. 5B is a survival analysis of single and co-mutations of FAT1 and LRP1B genes in databases such as TCGA/MSKCC.
Detailed Description
The conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention.
Example 1
1. Using TCGA Whole Exome Sequencing (WES) data, pre 1/3 patients were classified into a TMB high level group (tmb.high), mid 1/3 patients as a TMB mid level group (tmb.med) and post 1/3 patients as a TMB low level group (tmb.low) according to Tumor Mutation Burden (TMB) levels, and genome screening was performed; the mutation frequency of 96 genes in TMB.med group was found to be higher than TMB.low (Table 1).
TABLE 1
The mutation spectra of the first 30 genes are shown in FIG. 1. Compared to the tmb.med group, patients in the tmb.high group had 1730 genes mutated more frequently, including TTN, MUC16, CSMD3, SYNE1, PCLO, etc. (fig. 2, where 46 genes overlap with table 1 (table 2).
TABLE 2
2. 520 gene sequencing was performed on 33 HNSCC patients to further explore TMB-related gene mutations; baseline patient characteristics of the internal cohorts are summarized in table 3, where chemotherapy includes paclitaxel, platinum-based therapies, including cisplatin, carboplatin.
TABLE 3 Table 3
The mutation frequencies are shown in Table 4.
TABLE 4 Table 4
As can be seen from table 4, among these mutant genes of 520 genome, only FAT1 and LRP1B increased in mutation frequency as TMB level increased, and the mutation frequency of the groups FAT1 and LRP1B in tmb.med/tmb.hightmb was higher than that of the tmb.low group (fig. 3), consistent with TCGA queue results. In addition, the FAT1 and LRP1B mutation types also differ in TMB, high group (fig. 4).
The applicant further investigated the FAT1 and LRP1B mutation sites, wherein the FAT1 (nm_ 005245) mutation sites were as follows: r885, R937, S1200, R1627, Q1694, S2826Kfs, S2838, S3373, R3400;
the LRP1B (nm_ 018557) mutation sites were as follows: W1394C/S, N2353I/Kfs. 36, N2507D/I, A2729S/V, L2858P/V.
Example 2
The results in example 1 show that the FAT1 and LRP1B mutations are associated with TMB; applicants hypothesize that FAT1 and LRP1B mutation co-mutations may affect survival time of HNSCC patients.
To understand the effect of FAT1 and LRP1B mutations on HNSCC patients, the frequency of mutations in HNSCC was first analyzed. Mutation frequencies of FAT1 and LRP1B in the TCGA queue exceeded 20% and 15%, respectively (fig. 5A). In addition, the mutation frequency of FAT1 in other queues is also greater than 8% (fig. 5A). Next, survival analysis was performed on all cohorts, and it can be seen that the OS of the patients with FAT1 mutated HNSCC was significantly lower than that of the patients with unmutated (p=0.0134) wild-type and LRP1B mutated patients, but that the OS of the patients with FAT1 and LRP1B co-mutated HNSCC was significantly lower than that of the unmutated patients (p < 0.0001), more significant than the single mutation differences of FAT1 and LRP1B (fig. 5B).
The prior research data of the invention show that: the mutation frequency of the TMB.med/TMB.high groups FAT1 and LRP1B is higher than that of the TMB.low group. Whereas co-mutations of FAT1 and LRP1 are predictive of a poorer prognosis than OS using TCGA database, can be used for prognosis evaluation of HNSCC patients.
The present invention has been described in detail in the above embodiments, but the present invention is not limited to the above examples, and various changes can be made within the knowledge of those skilled in the art without departing from the spirit of the present invention. Furthermore, embodiments of the invention and features of the embodiments may be combined with each other without conflict.
Claims (10)
1. A biomarker comprising mutation sites of FAT1 and LRP 1B.
2. The biomarker of claim 1, wherein the mutation site of FAT1 comprises R885, R937, S1200, R1627, Q1694, S2826Kfs, S2838, S3373, R3400.
3. The biomarker according to claim 1, wherein the mutation site of LRP1B comprises W1394C/S, N2353I/Kfs x 36, N2507D/I, A2729S/V, L2858P/V.
4. Use of a biomarker and/or a substance for detecting a biomarker in at least one of (a 1) to (a 4), wherein the biomarker is as defined in any of claims 1 to 3;
(a1) Preparing a product for evaluating or predicting prognosis risk of head and neck squamous cell carcinoma immune combination chemotherapy;
(a2) Preparing a product for predicting the applicability of the immune combination chemotherapy of the head and neck squamous cell carcinoma;
(a3) Preparing a product for predicting survival time of patients suffering from head and neck squamous cell carcinoma immune combined chemotherapy;
(a4) The method is used for preparing products for detecting the drug resistance of the head and neck squamous cell carcinoma immune combined chemotherapy.
5. The use according to claim 4, wherein the immunotherapy comprises immune checkpoint inhibitor therapy, adoptive immunotherapy, cell therapy.
6. The use of claim 5, wherein the immune checkpoint inhibitor comprises a PD-1/PD-L1 antibody.
7. The use according to any one of claims 4 to 6, wherein the substance comprises a primer and/or probe composition for detecting a biomarker according to any one of claims 1 to 3.
8. The use according to any one of claims 4 to 6, wherein the product comprises at least one of a reagent, a kit, a test paper, a chip.
9. A product, characterized in that the composition comprises a substance for detecting a biomarker according to any of claims 4 to 8.
10. A head and neck squamous carcinoma prognosis evaluation system comprising the following modules:
(a5) A data collection module for collecting a patient sample and determining the detection result of the marker according to any one of claims 1 to 3;
(a6) Comparing the detection result with normal sample data, and judging the prognosis level of the head and neck squamous cell carcinoma according to the comparison result; if FAT1 and LRP1B are co-mutated, the prognosis is judged to be bad, and if FAT1 and LRP1B are not co-mutated, the prognosis is good.
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