Introduction (Part 1) - Gastric Carcinoma [Corrected 7].docx

**INTRODUCTION** **[1 Gastric Cancer Background: Classification and Clinical Approaches]** The paragraph provides a concise description of the various classification modalities of stomach cancer and clinical methods to classify its relevance to the management of diseases and methods of treatment....

**INTRODUCTION** **[1 Gastric Cancer Background: Classification and Clinical Approaches]** The paragraph provides a concise description of the various classification modalities of stomach cancer and clinical methods to classify its relevance to the management of diseases and methods of treatment. **[1.1 Introduction to Gastric Carcinoma:]** *1.1.1 Global Incidence and Epidemiology* Gastric cancer (GC) is an important health issue, as it causes approximately 700,000 deaths worldwide every year^1^. This high percentage of mortality highlights the need to develop novel and effective options for the prevention as well as the treatment of this disease. Stomach cancer frequency varies in different parts of the world, being most common in Asia, Africa, South America, and Eastern Europe^2^. These areas of the world are characterized by distinct epidemiological patterns, which are likely to result from specific interactions among genetic, environmental and lifestyle factors. In contrast, Western countries show a persistent decline in GC incidence. It is possible that this decline is the result of better dietary habits, increased food storage, and an improved awareness of associated risk factors^1^. In these last countries, it is very interesting to notice that there is an increase in tumors affecting the proximal region of the stomach. The increase in gastric cancers localizing to the proximal part of the organ may be due to a higher prevalence of risk factors including obesity and gastroesophageal reflux. From a global, regional and local point of view, the incidence of stomach cancer displayed a remarkable variance in most countries between 1990 and 2017^3^. Nevertheless, the worldwide number of cases and deaths continues to be on the rise, notwithstanding the declining trends observed in certain areas. This increase in the number of individuals at risk of suffering from stomach cancer rise may be ascribed to the population growth and aging^1^. *1.1.2 Pathogenesis and Risk Factors* The pathogenesis of gastric cancer is complex and multifactorial, as it involves a combination of factors such as lifestyle, environmental factors and genetic predisposition. Infections involving Helicobacter pylori, a bacterium colonizing the stomach lining and resulting in chronic inflammation, have been identified as one of the major risk factors in gastric cancer. The strong association between Helicobacter pylori infections and stomach cancer resulted in the classification of this bacterium in group I carcinogens by The World Health Organization^4^. Dietary habits also play a fundamental role in the genesis of stomach cancer. High-sodium diets as well as the consumption of smoked and processed meat increase the risk of developing this type of tumor. Indeed, these dietary habits cause chronic irritation and inflammation of the stomach lining, two processes enhancing the growth of cancerous cells^5^. Smoking is another stomach cancer predisposing factor. In fact, tobacco contains carcinogenic chemicals, which may impair the stomach lining resulting in the development of cancer. Hereditariness is another factor controlling the incidence of stomach cancer. Indeed, there are groups of individuals who have higher risk of stomach cancer, as the disease clusters in relatives, suggesting a hereditary predisposition. These subgroups are associated with distinct risk factors and have diverse clinical outcomes therefore accentuating the significance of genetics in the pathogenesis of certain subtypes of gastric cancer ^5^. *1.1.3 Diagnostic and Screening Advances* The advances in the diagnosis and screening of stomach cancer have resulted in the early detection and control of this tumor type, making a substantial difference in terms of patients outcomes. Endoscopic procedures have revolutionized the means of detecting gastric cancer. Indeed, the current endoscopic methods permit the examination of stomach coating and the detection of cancerous growth at an early stage. Combined with the development of novel biomarkers, these methods have greatly improved the detection of malignancies in their early stages, allowing for an earlier start of treatment, thus giving more chances of successful cures^6^. The detailed characterization and molecular profiling of stomach tumors have facilitated the advancements in diagnostic procedures aimed at targeted therapy. Molecular profiling allows the clinician to identify different molecular subtypes of gastric cancer favoring the personalized treatment of this tumor. This has been very useful in identifying individuals likely to respond to specific treatment, avoiding redundant or ineffective medication^7^. The genomic and transcriptomic data provide information regarding the alterations of the genome and transcriptome observed in gastric cancer cells. This provides clues as to the possible causes of the disease and the development of prospective therapeutic strategies. **[1.2 Molecular and Pathological Classification:]** *1.2.1 Lauren's Classification System* In 1960, the classification of Lauren was still an important technique in distinguishing or classifying stomach tumors. It had been in use for decades. According to this classification, two histological subtypes of gastric cancer are distinguishable, *i.e.* "*Intestinal*" and "*Diffuse*" ^8^. *Intestinal* stomach tumors show a well-differentiated histological phenotype and they are associated with environmental risk factors. The incidence rate of *Intestinal* gastric cancers type is particularly high in specific geographical areas, suggesting a link with regional risk factors^9^. In contrast, the *Diffuse* type of gastric cancer is characterized by a poorly-differentiated histological phenotype is widespread all over the world and it is more likely to be due to genetic causes. *Diffuse* gastric cancer is less influenced by environmental factors than the *Intestinal* counterpart in terms of a stronger hereditary predisposition^10^. The Lauren's classification has been expanded to include molecular markers, such as HER2, which is a key factor in the personalized treatment of gastric cancer^11^. Due to its simplicity and long-running history in the medical field, the Lauren's method is the classification system, which is used most frequently in the clinics. In spite of significant limitations, such as the inability to classify mixed-type malignancies, the Lauren\'s classification system is still broadly applied in the fields of stomach cancer scientific research and therapeutic practice. Being increasingly hinged on molecular traits^12^, the Lauren\'s classification system will provide crucial insights into the prediction and treatment mechanisms of gastric cancer, especially in the context of personalized treatment of this tumor. *1.2.2 WHO Classification and Subtypes* The World Health Organization (WHO) classification includes most of the known histological subtypes of stomach carcinoma, such as the papillary, tubular, signet ring, and mucinous forms of this tumor. This classification is known for its overwhelming definition of different gastric tumor types, regardless of their incidence, since it gives a costly opinion on different histological aspects of gastric cancer^13^. Therefore, the WHO classification is an effective classification in clinical practice and research studies, as it permits broad comparisons among different studies and it assists in identifying patient subgroups with distinct clinical characteristics or outcomes. The WHO Classification of gastric tumors according to the histological phenotype permits a better understanding of the biological behavior and prognosis that accompany each histologic subtype. This accurate classification of stomach tumors helps in directing therapy choices and predicting what can be expected from patients^14^. This comprehensive approach helps in gaining a better appreciation of stomach cancer for therapeutic as well as diagnostic planning. The WHO classification not only represents the framework to classify tumors of the stomach based on histological markers, but it also represents a useful platform for the integration of the molecular and genomic data with the diagnostic and therapeutic procedures. With the trend of customized medicine becoming increasingly popular in cancer care, where treatments are becoming custom-made on the basis of the individual genetic properties of each tumor^14^, this integration is bound to increase its importance. *1.2.3 Molecular Subtypes and Genomic Characterization* The recent advances in molecular biology have led to the identification of several malignant subtypes of gastric cancer characterized by peculiar genomic and transcriptome patterns. These subtypes provide more information on tumor biology and they are likely to modify the prognosis and the therapeutic strategies of gastric cancer ^15^. The Cancer Genome Atlas (TCGA) project was decisive in the classification of gastric tumors into one of four major molecular subtypes: Epstein-Barr virus (*EBV*)-positive, microsatellite instability (MSI), genomically stable (*GS*), and chromosomal instability (*CIN*). *EBV*-positive tumors are characterized by the presence of the Epstein-Barr virus in cancer cells. By converse, the *MSI* subtype relies on a high degree of genetic alterations, which is due to a number of abnormalities in the DNA repair pathways. The *GS* subtype is common in younger patients and it exhibits fewer genetic abnormalities relative to the other subtypes. Finally, the CIN subtype is characterized by chromosomal abnormalities and it is associated with a poor prognosis^16^. These molecular subgroups exist because they harbor specific genetic alterations and potentially actionable targets, which has important implications in terms of prognosis and treatment. *MSI* tumors may be more responsive to immunotherapy, since they display a high mutational burden. By converse, *EBV*-positive tumors may be more susceptible to targeted therapies^17^. **[1.3 Clinical Management and Treatment Strategies:]** *1.3.1 Surgical and Non-Surgical Approaches* The personalized treatment of patients suffering from a heterogeneous type of tumor, like gastric cancer, requires combinations of surgical and non-surgical procedures. In the early stages of this disease, surgical removal of the tumor is the sole therapeutic option available. The extent and location of the tumor determine the surgical approach to implement. This may involve endoscopic mucosal resection, distal esophagectomy, partial/total gastrectomy, or combinations of all these methods^18^. In the United States^19^, laparoscopic-assisted gastrectomy, a non-intrusive and fast procedure, is another surgical approach which led to a marked decline of therapeutic problems in old patients. Depending on the patient\'s health status, the existence of specific biomarkers and the gastric cancer stage, non-invasive methods, including radiotherapy, chemotherapy and targeted-therapy, may be used too. If tumor shrinkage is the main therapeutic objective or tumor progression prevents surgical removal, these types of treatments acquire further importance^20^. The cancer staging system released by the eighth version of the American Joint Committee on Cancer\'s (AJCC; year 2017) provides a much-needed guidance in the diagnosis and treatment of stomach cancer. Consequently, the selection of a staging approach enables more accurate and comprehensive assessment of tumor progression, thus facilitating the implementation of a precise treatment strategy^21^. *1.3.2 Chemotherapy and Targeted Treatment Options* As further detailed in section 1.4.1, TP53, ARID1A and HER2 mutations are associated with gastric cancer prognosis. Because of their correlation with treatment efficacy, these genetic variants play a crucial role in both tumor behavior and therapy^22^. The use of targeted pharmacological agents in the treatment of stomach cancer is also on the rise. In this context, HER2 positivity^23^ is one of the molecular markers which correlate with increased overall survival in patients treated with trastuzumab, ramucirumab, and pembrolizumab. Since targeted therapies are not always successful and they are often provided in conjunction with conventional chemotherapy regimens, stomach cancer treatment requires further and novel therapeutic approaches. In locally advanced disease, the National Comprehensive disease Network (NCCN) guidelines support chemo-radiation or perioperative chemotherapy before surgery. Patients with advanced gastric cancer present with increased survival rates following loco-regional treatments, which reduce tumor size and improve surgical outcomes^24^. *1.3.3 Emerging Therapies and Clinical Trials* With the introduction of novel treatment strategies, gastric cancer therapy is advancing and focusing on patient evaluation. The molecular characterization of stomach cancers has uncovered novel markers and potential therapeutic targets that may ameliorate the prognosis of this deadly illness^25^. The major goal of these molecular studies is to develop novel and effective therapeutic agents, such as immune-therapeutics, cell-structure remodeling compounds and receptor tyrosine-kinase inhibitors. By focusing on specific pathways involved in the growth and metastatic behavior of the neoplastic cell, the development of these novel therapeutics is likely to result in effective and tailored treatments of gastric cancer^26^. The design of specific clinical trials is required to support the effectiveness of these new medications in treating stomach cancer and overcoming resistance to chemotherapeutics. In fact, new treatment guidelines and the incorporation of novel therapeutic approaches in the clinical practice cannot rely solely on the results obtained in pre-clinical studies. Indeed, sometimes, the results of clinical trials are not in line with what is observed at the pre-clinical level. For instance, both HER2-positive and negative gastric cancer patients have been shown to respond to immune-therapies based on pembrolizumab and nivolumab^27^. In conclusion, pre-clinical research and clinical trials have played and will continue to play a key role in increasing our knowledge on stomach cancer and the development of improved approaches to the personalized treatment of this neoplastic disease. Overall, there is a general recognition that the new therapeutic approaches under development are likely to revolutionize the field of stomach cancer treatment. **[1.4 Prognostic Factors and Biomarkers:]** *1.4.1 Role of Genetic Markers in Prognosis* The prognosis of gastric cancer is influenced by the high variability of specific genetic markers. Some of these markers are associated with a more aggressive disease trajectory, while others correlate with better therapeutic responses. For instance, mutations of the TP53, ARID1A and HER2 genes fall within the genetic alterations which are linked to gastric cancer prognosis. In this context, it is of particular importance to understand which genetic alterations affect tumor progression and influence prognosis as well as sensitivity/resistance to therapeutic agents^6^. Additional predictive factors include the DNA methylation pattern and the MSI status of cancer cells. The importance of genomic profiling in driving treatment decisions is underscored by the fact that patients with high MSI are often characterized by a better prognosis and react to immunotherapy in a different and better manner^28^. Furthermore, new studies indicate that the expression profiles of microRNAs and long non-coding RNAs represent novel and accurate prognostic indicators. Indeed, these non-coding RNAs are not only markers of tumor development and patient outcomes, but they regulate gene expression as well ^29^. *1.4.2 Tumor Markers and Predictive Value* In the clinical practice, tumor markers such as carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA), are commonly employed to monitor the progression of gastric cancer and the efficacy of anti-tumor treatments. In addition to stomach cancer, these markers are used to monitor pancreatic and colorectal carcinomas. These indicators increase in predictive power when combined with emerging molecular biomarkers^30^. Recently, new serum markers for the early detection and monitoring of stomach cancer have been identified, including specific microRNAs. Due to their capacity to regulate gene expression and to identify tumors in their initial stages, these microRNAs show promising potential to detect early-stage cancer^31^. In addition, HER2 and PD-L1, which have been discovered with genomic profiling studies, are two promising indicators of targeted therapy. These indicators provide information on specific treatments, such as trastuzumab for HER2-positive malignancies and immunotherapies for PD-L1-positive tumors^7^. **[1.5 Gastric Cancer Resistance and Challenges:]** *1.5.1 Mechanisms of Drug Resistance* Drug resistance is a significant obstacle to the successful treatment of gastric cancer. Environmental, genetic, and epigenetic factors contribute to the heterogeneity of resistance mechanisms. In certain situations, GNAS mutations, EGFR and MET amplifications as well as other genetic abnormalities are likely to cause acquired resistance to drugs in stomach cancer. For instance, in a small subset of gastric tumors resulting from amplification of the EGFR gene, overexpression of the EGFR protein induces the proliferation, invasion and survival of cancer cells. Targeted drugs, such as tyrosine kinase inhibitors and monoclonal antibodies, represent potential therapeutic approaches to gastric cancers characterized by amplification of the EGFR gene. The variable response rates of gastric cancer patients to different therapies can be explained, albeit partially, by alterations in EGFR expression and co-existing genetic changes. The identification of patients showing amplification of the EGFR gene is likely to define the individuals who may benefit from EGFR-targeted treatment^32^. In gastric cancer, amplification of the MET gene is associated with an aggressive tumor behavior and a poor prognosis, as this genomic abnormality activates a number of signaling pathways increasing cell proliferation, angiogenesis and metastatic propensity. For this reason, clinical trials on the two MET inhibitors, Crisetinib and capmatinib, are conducted in patients characterized by amplification of the MET gene. Interestingly, treatments blocking the MET signaling pathway have been shown to reduce tumor growth and metastasis. Due to the intricate interaction of multiple signaling pathways, combinations of MET inhibitors and targeted drugs or chemotherapy represent potential strategies in the treatment of gastric cancer^33^. In spite of the low frequency of GNAS mutations in gastric cancer, these genetic abnormalities play a role in oncogenesis through pathogenic signaling pathways. These alterations result in elevated cyclic AMP levels, which promote cell proliferation and might trigger the initiation/progression of gastric cancer. In cancer, direct treatment of GNAS mutations is difficult, although potentially useful in terms of gaining information on tumor biology. With respect to this, a possible and effective treatment approach is represented by targeting of proteins laying downstream of the GNAS-mediated pathways^34^. The above mentioned genetic alterations may activate signaling pathways, which could make targeted treatment unsuccessful^35^. In addition, resistance to targeted therapy is influenced by the molecular heterogeneity of cancer. Indeed, the numerous alterations found in tumor cells make it challenging to treat cancer cells effectively^36^. Furthermore, the role that the tumor microenvironment plays in promoting drug resistance is another important aspect to consider. This is due to the possibility that interactions between cancer cells and the surrounding stroma might reduce the therapeutic impact. Apart from their impact on drug delivery and response, cancer cells have the ability to develop resistance mechanisms by employing the tumor microenvironment^37^. *1.5.2 Overcoming Therapeutic Challenges* In order to overcome the therapeutic problems faced by gastric cancer patients, it is necessary to develop therapies, which increase responsiveness to treatment and circumvent drug resistance. Combinations of drugs targeting different pathways associated with the progression of stomach cancer are important examples of this strategy. The integration of anti-EGFR antibodies and antibody-drug conjugates (ADCs) is an interesting combinatorial approach, which was used to reduce resistance to EGFR-targeted drugs. The application is seen as a potential therapy for treatment resistance since the targeting of cancer cells continued even after cytotoxic chemicals were administered to their location to limit tumor growth or regeneration^26^. Precision medicine approaches, which use genetic profiling to identify specific therapeutic targets in individual patients, are also undergoing clinical trials. These techniques examine the DNA of tumors to identify specific molecular alterations, which may lead to the development of new drugs. By tailoring treatments to the specific characteristics of each tumor, precision medicine aims at maximizing therapeutic sensitivity, while decreasing the insurgence of drug resistance^7^. In recent years, we have experienced significant advancements in the use of immunotherapy or the treatment of stomach cancer, with particular reference to the application of immune-checkpoint inhibitors. The goal of this type of treatment is to strengthen the immune system in order to better detect and eliminate cancer cells. Clinical studies are now being conducted on patients with advanced stomach carcinomas to investigate the potential for better results when using various immunotherapies, either alone or in combination with other treatments^38^. *1.5.3 Future Perspectives in Gastric Cancer Research* Future research should be guided by a better understanding of the disease processes causing stomach cancer and by the development of more effective therapy options. Genetic and proteomic studies are likely to identify therapeutic targets and indications for stomach cancers. These include studies aimed at identifying unique genetic alterations and specific changes in protein expression patterns with the purpose of developing new treatments for stomach tumors^39^. Integrative genomic approaches aided by technologies such as liquid biopsies and single-cell sequencing have uncovered novel preclinical targets and new mechanisms of treatment resistance. Single-cell sequencing allows definition of the genetic makeup of individual cancer cells, which may help researchers to understand tumor heterogeneity and identify pathways underlying drug resistance. A non-invasive way to analyze tumor cells or DNA in the blood may be possible with liquid biopsies, which will advance our knowledge on tumor progression and medication response^40^. In the context of \"next-generation\" therapies, these approaches are essential in terms of precision oncology and gastric prevention. Indeed, a major research aim is the integration of proteomic and genetic data in order to develop safer and more effective tailored strategies of treatment. This approach has the potential to enhance patients\' survival rates and prognoses, particularly for individuals whose stomach or esophageal cancers are advanced or no longer responsive to therapy. **[BIBLIOGRAFIA:]** 1\. Sung, H. *et al.* Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. *CA. Cancer J. Clin.* **71**, 209--249 (2021).2. Luo, G. *et al.* Global patterns and trends in stomach cancer incidence: Age, period and birth cohort analysis. *Int. J. Cancer* **141**, 1333--1344 (2017).3. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990--2017: a systematic analysis for the Global Burden of Disease Study 2017. *Lancet Lond. Engl.* **392**, 1789--1858 (2018).4. Parsonnet, J. *et al.* Helicobacter pylori infection and the risk of gastric carcinoma. *N. Engl. J. Med.* **325**, 1127--1131 (1991).5. Tan, P. & Yeoh, K.-G. Genetics and Molecular Pathogenesis of Gastric Adenocarcinoma. *Gastroenterology* **149**, 1153-1162.e3 (2015).6. Bass, A. J. *et al.* Comprehensive molecular characterization of gastric adenocarcinoma. *Nature* **513**, 202--209 (2014).7. Cristescu, R. *et al.* Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. *Nat. Med.* **21**, 449--456 (2015).8. Chen, Y.-C. *et al.* Clinicopathological Variation of Lauren Classification in Gastric Cancer. *Pathol. Oncol. Res. POR* **22**, 197--202 (2016).9. Lynch, H. T., Grady, W., Suriano, G. & Huntsman, D. Gastric cancer: new genetic developments. *J. Surg. Oncol.* **90**, 114--133; discussion 133 (2005).10. MA, J., SHEN, H., KAPESA, L. & ZENG, S. Lauren classification and individualized chemotherapy in gastric cancer. *Oncol. Lett.* **11**, 2959--2964 (2016).11. Berlth, F., Bollschweiler, E., Drebber, U., Hoelscher, A. H. & Moenig, S. Pathohistological classification systems in gastric cancer: Diagnostic relevance and prognostic value. *World J. Gastroenterol.* **20**, 5679 (2014).12. Qiu, M. *et al.* Lauren classification combined with HER2 status is a better prognostic factor in Chinese gastric cancer patients. *BMC Cancer* **14**, 823 (2014).13. Kushima, R. The updated WHO classification of digestive system tumours-gastric adenocarcinoma and dysplasia. *Pathol.* **43**, 8--15 (2022).14. Hu, B. *et al.* Gastric cancer: Classification, histology and application of molecular pathology. *J. Gastrointest. Oncol.* **3**, 251--261 (2012).15. Sohn, B. H. *et al.* Clinical Significance of Four Molecular Subtypes of Gastric Cancer Identified by The Cancer Genome Atlas Project. *Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res.* **23**, 4441--4449 (2017).16. Zhang, W. TCGA divides gastric cancer into four molecular subtypes: implications for individualized therapeutics. *Chin. J. Cancer* **33**, 469--470 (2014).17. Wang, Q., Liu, G. & Hu, C. Molecular Classification of Gastric Adenocarcinoma. *Gastroenterol. Res.* **12**, 275--282 (2019).18. Coburn, N. *et al.* Staging and surgical approaches in gastric cancer: A systematic review. *Cancer Treat. Rev.* **63**, 104--115 (2018).19. Wakahara, T. *et al.* Impact of Gastric Cancer Surgery in Elderly Patients. *Oncology* **94**, 79--84 (2018).20. Joshi, S. S. & Badgwell, B. D. Current treatment and recent progress in gastric cancer. *CA. Cancer J. Clin.* **71**, 264--279 (2021).21. Amin, M. B. *et al.* The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more 'personalized' approach to cancer staging. *CA. Cancer J. Clin.* **67**, 93--99 (2017).22. Sasako, M. *et al.* Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. *J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol.* **29**, 4387--4393 (2011).23. Smyth, E. C., Nilsson, M., Grabsch, H. I., van Grieken, N. C. & Lordick, F. Gastric cancer. *Lancet Lond. Engl.* **396**, 635--648 (2020).24. Shi, J. *et al.* Total neoadjuvant therapy for locally advanced gastric cancer and esophagogastric junction adenocarcinoma: study protocol for a prospective, multicenter, single-arm, phase II clinical trial. *BMC Gastroenterol.* **22**, 359 (2022).25. Kumar, V., Soni, P., Garg, M., Kamholz, S. & Chandra, A. B. Emerging Therapies in the Management of Advanced-Stage Gastric Cancer. *Front. Pharmacol.* **9**, 404 (2018).26. Sexton, R. E., Al Hallak, M. N., Diab, M. & Azmi, A. S. Gastric cancer: a comprehensive review of current and future treatment strategies. *Cancer Metastasis Rev.* **39**, 1179--1203 (2020).27. Ilson, D. H. Advances in the treatment of gastric cancer: 2020-2021. *Curr. Opin. Gastroenterol.* **37**, 615--618 (2021).28. Choi, Y. Y. *et al.* Is microsatellite instability a prognostic marker in gastric cancer? A systematic review with meta-analysis. *J. Surg. Oncol.* **110**, 129--135 (2014).29. Zha, B., Luo, Y., Kamili, M. & Zha, X. Non-coding RNAs and gastrointestinal cancers prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies. *Front. Oncol.* **13**, 1193665 (2023).30. Marrelli, D. *et al.* Clinical utility of CEA, CA 19-9, and CA 72-4 in the follow-up of patients with resectable gastric cancer. *Am. J. Surg.* **181**, 16--19 (2001).31. Li, X., Li, S., Zhang, Z. & Huang, D. Association of multiple tumor markers with newly diagnosed gastric cancer patients: a retrospective study. *PeerJ* **10**, e13488 (2022).32. Maron, S. B. *et al.* Targeted therapies for targeted populations: Anti-EGFR treatment for EGFR amplified gastroesophageal adenocarcinoma. *Cancer Discov.* **8**, 696--713 (2018).33. Frigault, M. M. *et al.* Mechanisms of Acquired Resistance to Savolitinib, a Selective MET Inhibitor in MET-Amplified Gastric Cancer. *JCO Precis. Oncol.* **4**, PO.19.00386 (2020).34. Nomura, R. *et al.* GNAS mutation as an alternative mechanism of activation of the Wnt/β-catenin signaling pathway in gastric adenocarcinoma of the fundic gland type. *Hum. Pathol.* **45**, 2488--2496 (2014).35. Marin, J. J. G. *et al.* Mechanisms of Resistance to Chemotherapy in Gastric Cancer. *Anticancer Agents Med. Chem.* **16**, 318--334 (2016).36. Nakamura, Y. *et al.* Emergence of Concurrent Multiple EGFR Mutations and MET Amplification in a Patient With EGFR-Amplified Advanced Gastric Cancer Treated With Cetuximab. *JCO Precis. Oncol.* **4**, PO.20.00263 (2020).37. Sathe, A. *et al.* Single-Cell Genomic Characterization Reveals the Cellular Reprogramming of the Gastric Tumor Microenvironment. *Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res.* **26**, 2640--2653 (2020).38. Högner, A. & Moehler, M. Immunotherapy in Gastric Cancer. *Curr. Oncol. Tor. Ont* **29**, 1559--1574 (2022).39. Guan, W.-L., He, Y. & Xu, R.-H. Gastric cancer treatment: recent progress and future perspectives. *J. Hematol. Oncol.J Hematol Oncol* **16**, 57 (2023).40. Roukos, D. H. Current status and future perspectives in gastric cancer management. *Cancer Treat. Rev.* **26**, 243--255 (2000).