Exploration Study of Molecular Biomarkers for Tumor-related Anxiety and Depression

Exploration Research on Molecular Markers of Tumor-Related Anxiety and Depression I.Research Background Tumors are major diseases threatening the health of the Chinese population. In 2020, China reported 4.57 million new cases and 3 million deaths from malignant tumors, both ranking first globally \[1\]. Tumor-related anxiety and depression are psychological and mental disorders affecting 30%-70% of tumor patients, ranking as one of the most common comorbidities in tumor clinical settings. Annually, over 10 million tumor patients globally experience reduced treatment adherence and lower quality of life due to tumor-related psychological disorders \[2\]. Tumor-related anxiety and depression pose significant harm to patients, not only exacerbating their physical discomfort but also significantly reducing treatment adherence and clinical efficacy, increasing the risk of tumor recurrence and metastasis, and directly leading to poorer long-term survival outcomes. However, to date, there is still a lack of specific early screening molecular markers for tumor-related anxiety and depression in clinical practice. Current intervention strategies primarily rely on symptomatic psychological counseling and non-specific anti-anxiety and antidepressant medications, lacking targeted and precise intervention approaches, resulting in many patients' psychological disorders not being identified or effectively treated early. The field of tumor psychological diagnosis and treatment in China is underdeveloped, with an incomplete clinical diagnostic system, showing a significant gap compared to developed Western countries. Surgery, radiotherapy, chemotherapy, and immunotherapy are the main clinical treatment methods for malignant tumors. Due to the complex pathogenesis of tumors, diverse pathological types, and individual differences in patients' physiological conditions and psychological tolerance, the onset, severity, and intervention outcomes of tumor-related anxiety and depression exhibit significant heterogeneity. There remains substantial room for improvement in the precise screening, risk stratification, and targeted intervention of these psychological disorders. Building on the extensive clinical tumor samples from the Chinese population and molecular mechanism research data accumulated by our team \[3\], as well as the foundational research confirming that tumor-derived proteins can mediate central nervous system inflammation and emotional abnormalities, there are currently no reported clinical studies on the correlation between tumor-derived proteins and the levels of anxiety and depression in tumor patients. It is urgent to conduct clinical research to clarify the intrinsic relationship between the two, providing new molecular targets and clinical evidence for the early screening and precise intervention of tumor-related anxiety and depression.

Main References

1. Hyuna Sung., et al., Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries, CA CANCER J CLIN 2021;71:209-249. 2. Vita G., et al., Antidepressants for the treatment of depression in people with cancer. Cochrane Database Syst Rev. 2023 Mar 31;3(3):CD011006. 3. Xu Chen., et al. GRP75 triggers white adipose tissue browning to promote cancer-associated cachexia. Signal Transduction and Targeted Therapy. 2024, 26;9(1):253.

II.Research Objectives and Significance

1. Research Objectives To identify and validate molecular biomarkers associated with tumor-related anxiety and depression. By integrating psychological assessment data from clinical cancer patients with molecular detection results, and utilizing clinically accessible samples such as tumor tissues and sera from clinical cohorts, this study aims to clinically validate the potential regulatory tumor-derived proteins previously identified by our team. The goal is to clarify the clinical value of tumor-derived proteins as molecular biomarkers for tumor-related anxiety and depression, providing a molecular basis for early screening and risk stratification of these conditions. Alternatively, it seeks to establish a tumor-related anxiety and depression risk assessment model based on the expression levels of tumor-derived proteins, offering a reference for the precise identification and targeted intervention of psychological disorders in cancer patients. 2. Research Significance The research outcomes will yield proprietary intellectual property rights for novel molecular targets and associated biomarkers for the screening and intervention of tumor-related anxiety and depression, and promote their translation into clinical diagnostic and therapeutic applications. This study will provide critical data for classifying cancer patients into psychological intervention tiers based on their anxiety and depression risk levels, supporting the precise screening and personalized intervention of psychological disorders in clinical oncology, and contributing to the enhancement of the comprehensive cancer treatment system.

III.Implementation Plan

1\. Inclusion/Exclusion Criteria 1.1. Inclusion Criteria

1. Patients with solid tumors aged ≥18 years and an expected survival period of ≥3 months; 2. Patients who meet clinical diagnostic criteria and are pathologically/histologically confirmed as having solid tumors, including liver cancer patients (diagnosable by imaging); 3. Patients who can complete standardized stratified assessments for tumor-related anxiety and depression, and are able to cooperate with researchers in completing psychological scales such as the Self-Rating Anxiety Scale (SAS) and the Self-Rating Depression Scale (SDS). They have not received any anti-anxiety/depression medications, professional psychological counseling, or psychiatric interventions before scale assessment; 4. Patients with clear consciousness, normal language communication, comprehension, and cognitive abilities, without a history of psychiatric disorders, and who can independently provide feedback on research-related information and cooperate with follow-up; 5. Patients who voluntarily participate in the study, fully understand the research objectives, procedures, potential risks, and benefits, and have signed a written informed consent form; 6. Patients who can cooperate in completing the required laboratory tests (complete blood count, blood biochemistry, coagulation function, etc.) and clinical data collection before and during the perioperative period to ensure the completeness of research data.

1.2. Exclusion Criteria

1. Pregnant or lactating women; 2. Patients aged \<21 years at first visit and with an expected survival period of \<3 months; 3. Patients who have previously received anti-anxiety/depression medications or professional psychological interventions; 4. Patients with a history or current diagnosis of psychiatric disorders, including schizophrenia, bipolar disorder, severe cognitive dysfunction, mental retardation, or those who cannot cooperate with SAS/SDS scale assessment or have contraindications to scale evaluation; 5. Patients with severe organ dysfunction or severe underlying diseases, including: liver failure (Child-Pugh C grade), renal failure (serum creatinine \>250 μmol/L or \>2.83 mg/dL), New York Heart Association (NYHA) Class IV heart failure, active pulmonary tuberculosis, HIV infection, etc. (to be determined); 6. Patients with contraindications to tumor tissue or blood sample collection, including coagulation disorders (INR \>1.5, platelets \<50×10⁹/L), severe bleeding tendency, or surgical specimens that cannot meet detection requirements (e.g., \>50% necrotic tissue, insufficient tissue amount); 7. Patients with emotional abnormalities due to non-tumor factors, including hyperthyroidism/hypothyroidism, severe malnutrition, chronic wasting diseases, or psychological stress disorders; 8. Patients who have undergone non-tumor-related surgical procedures, enteral/parenteral nutrition support within the past 1 month, or have clinical symptoms such as gastrointestinal mechanical obstruction, intractable vomiting, ascites, significant edema, or large pleural effusion; 9. Patients who are planned or currently using medications that may affect emotional assessment or protein expression detection during the study, including: long-term oral corticosteroids, 5-HT receptor agonists/antagonists (SSRIs, etc., even short-term use within 2 weeks before sampling is excluded), antipsychotic drugs, or gestagenic synthetic steroid derivatives (short-term inhaled/local use of steroids or intermittent use of inhaled bronchodilators are excluded); 10. Patients with incomplete clinical data, inability to cooperate with research-related follow-up and testing, or those who refuse to sign the informed consent form or have poor compliance.

2\. Recruitment Procedure This study does not involve outpatients recruitment. The blood and tumor tissues selected from clinical patients are all derived from hospitalized patients. The blood is the remaining portion after routine blood tests, and the tumor tissues are the remaining portions collected after surgery, with priority given to ensuring no impact on pathology diagnosis.The remaining tissue samples and blood analyses will be stored in the -80°C freezer in this department for subsequent new scientific research.

3\. Research Process In the field of comprehensive tumor diagnosis and treatment, achieving precise screening and targeted intervention for psychological disorders is a key goal to improve the quality of life of tumor patients and enhance the comprehensive management system for tumor treatment. Malignant tumors, as systemic diseases, not only affect patients physically but also easily trigger psychological and mental disorders such as anxiety and depression. The high incidence and concealment of tumor-related anxiety and depression make them an important yet often overlooked aspect in tumor clinical diagnosis and treatment. This project fully leverages the rich clinical resources and molecular detection platforms of the collaborating institutions to conduct in-depth analysis and stratification of solid tumor patients from the perspective of molecular expression - psychological phenotype association. It aims to explore molecular markers that can precisely correlate with the levels of anxiety and depression in tumor patients, as well as detection indicators suitable for clinical screening, thereby promoting the precise identification and intervention of tumor-related anxiety and depression and improving the comprehensive tumor diagnosis and treatment system.

1. Research Subjects and Sample Size Determination The subjects of this study are solid tumor patients, with no additional healthy control group. A total of 500 solid tumor patients meeting the inclusion criteria will be enrolled, and they will be divided into an anxiety and depression group and a non-anxiety and depression group based on the scores from the anxiety and depression scale. In determining the sample size, the research team used a scientifically rigorous calculation method, employing the MedCalc software to calculate the sample size based on the AUC value. The specific parameters are set as follows: estimated AUC = 0.9, significance level α = 0.05, and power 1-β = 0.9. The null hypothesis is set as AUC = 0.8. Considering clinical realities, the incidence of anxiety and depression in tumor patients is approximately 30%-50%. Through precise calculations, it is determined that at least 50 patients in the anxiety and depression group and at least 50 patients in the non-anxiety and depression group should be enrolled, with a total sample size of 100. This is sufficient to meet the statistical requirements for the correlation analysis of molecular markers and anxiety and depression levels in this study, ensuring the reliability and representativeness of the results. 2. Research Foundation and Preliminary Exploration Bef

• A tumor-related anxiety and depression risk assessment model established based on the expression levels of tumor-derived proteins [Time frame: 2027.05]