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Safari MH, Rahimzadeh P, Alaei E, Alimohammadi M, Esfandiari N, Daneshi S, Malgard N, Farahani N, Taheriazam A, Hashemi M. Targeting ferroptosis in gastrointestinal tumors: Interplay of iron-dependent cell death and autophagy. Mol Cell Probes 2025; 79:102013. [PMID: 39837469 DOI: 10.1016/j.mcp.2025.102013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 01/06/2025] [Accepted: 01/18/2025] [Indexed: 01/23/2025]
Abstract
Ferroptosis is a regulated cell death mechanism distinct from apoptosis, autophagy, and necroptosis, marked by iron accumulation and lipid peroxidation. Since its identification in 2012, it has developed into a potential therapeutic target, especially concerning GI disorders like PC, HCC, GC, and CRC. This interest arises from the distinctive role of ferroptosis in the progression of diseases, presenting a new avenue for treatment where existing therapies fall short. Recent studies emphasize the promise of focusing on ferroptosis to fight GI cancers, showcasing its unique pathophysiological mechanisms compared to other types of cell death. By comprehending how ferroptosis aids in the onset and advancement of GI diseases, scientists aim to discover novel drug targets and treatment approaches. Investigating ferroptosis in gastrointestinal disorders reveals exciting possibilities for novel therapies, potentially revolutionizing cancer treatment and providing renewed hope for individuals affected by these tumors.
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Affiliation(s)
- Mohamad Hosein Safari
- Department of Internal Medicine, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Elmira Alaei
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Negin Esfandiari
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Neda Malgard
- Department of Internal Medicine, Firoozgar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Mazurek M, Jaros M, Gliwa AM, Sitarz MZ, Dudzińska E, Zinkiewicz K, Sitarz R. Epstein-Barr Virus (EBV) and Human Papilloma Virus (HPV) in Gastric Cancers, with Special Reference to Gastric Cancer at a Young Age-A Pilot Study in Poland. Int J Mol Sci 2025; 26:711. [PMID: 39859425 PMCID: PMC11765604 DOI: 10.3390/ijms26020711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 01/06/2025] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
Gastric cancer (GC) is one of the most common cancers in the world. It is a multi-factorial disease influenced by both genetic and environmental factors such as diet, obesity, radiation exposure, and infectious agents. Viral infections usually lead to chronic inflammation, which can initiate the development of cancers. To date, only a few studies have been published about Epstein-Barr virus (EBV) and human papillomavirus (HPV) infections in the context of the development of GC. In particular, research on the development of cancer among people under 45 years of age, including the impacts of EBV and HPV, is rare, and clear results have not been obtained. The aim of this study was to analyze the frequency of occurrence of EBV and HPV in GC, particularly in early-onset gastric cancer (EOGC). Tissue material from 135 patients with GC, including 84 men and 51 women, was examined. RT-PCR was performed to detect EBV, and PCR was performed to detect HPV. There were no significant impacts of EBV and HPV infections on any subtype of GC. There was also no statistically significant dependence of gender and location of the tumor on any subtype of GC. Further research on the impacts of infectious agents such as EBV and HPV on GC should be conducted using larger populations.
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Affiliation(s)
- Marek Mazurek
- Department of Surgical Oncology, Masovian Cancer Hospital, 05-135 Wieliszew, Poland;
- Department of Normal, Clinical and Imaging Anatomy, Medical University of Lublin, 20-950 Lublin, Poland; (M.J.); (A.M.G.)
| | - Małgorzata Jaros
- Department of Normal, Clinical and Imaging Anatomy, Medical University of Lublin, 20-950 Lublin, Poland; (M.J.); (A.M.G.)
| | - Anna M. Gliwa
- Department of Normal, Clinical and Imaging Anatomy, Medical University of Lublin, 20-950 Lublin, Poland; (M.J.); (A.M.G.)
| | - Monika Z. Sitarz
- Department of Conservative Dentistry with Endodontics, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Ewa Dudzińska
- Department of Dietetics and Nutrition Education, Medical University of Lublin, 20-093 Lublin, Poland;
| | - Krzysztof Zinkiewicz
- Independent Laboratory of Diagnostic, Interventional Endoscopy of the Department of Oncology, Medical University of Lublin, 20-081 Lublin, Poland;
| | - Robert Sitarz
- Department of Normal, Clinical and Imaging Anatomy, Medical University of Lublin, 20-950 Lublin, Poland; (M.J.); (A.M.G.)
- Department of Surgical Oncology, St. John’s Cancer Center, 20-090 Lublin, Poland
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Magahis PT, Cornet N, Tang L, Arora K, Hingorani N, King S, Markowitz AJ, Schattner M, Shimada S, Maron SB, Vardhana S, Lumish M, Cercek A, Janjigian YY, Coit D, Mendelsohn RB, Berger MF, Strong VE, Stadler ZK, Laszkowska M. Differences in Ancestry and Presence of Gastric Precursor Lesions in Individuals With Young- and Average-Onset Gastric Cancer. Cancer Med 2024; 13:e70451. [PMID: 39629931 PMCID: PMC11615756 DOI: 10.1002/cam4.70451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 11/11/2024] [Accepted: 11/14/2024] [Indexed: 12/08/2024] Open
Abstract
BACKGROUND There has been a paradoxical rise in young-onset gastric cancer (YOGC), defined as gastric cancer (GC) diagnosed before age 50. Precursor lesions may contribute to pathogenesis, though their role in progression to different histologic subtypes is unclear. The impact of self-reported race is also poorly characterized and may be unreliable as a proxy for genetic differences. We aimed to compare differences in histology and genetic ancestry between YOGC and average-onset gastric cancer (AOGC). METHODS This retrospective cohort included all patients with GC at Memorial Sloan Kettering (MSK) from January 2013 to March 2021. Data on demographics, tumor characteristics, and precursor lesions were collected. Genetic ancestry was inferred from MSK-Integrated Mutation Profiling of Actionable Cancer Targets panel. RESULTS Of 1685 individuals with GC, 290 had YOGC. Compared to AOGC, individuals with YOGC tended to be female, Hispanic, foreign-born, and feature diffuse-type histology. YOGC was less likely to have precursor lesions, including intestinal metaplasia (20% vs. 37%, p < 0.01) and dysplasia (4% vs. 14%, p < 0.01). Of 560 patients with ancestry data, 127 had YOGC. Admixed, East Asian, and South Asian ancestries were more likely to present with YOGC while Europeans presented with AOGC. Intestinal metaplasia was enriched among East Asians, maintained when stratifying by histology and GC onset. CONCLUSIONS We observed YOGC was more common in East and South Asians, and while YOGC may be less likely to develop in the setting of precursor lesions these high-risk states may also be enriched in East Asians. Future research is needed to understand drivers behind such differences and outcome disparities given these individuals may be less amenable to endoscopic interventions.
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Affiliation(s)
| | - Nicole Cornet
- Department of MedicineWeill Cornell MedicineNew YorkNew YorkUSA
| | - Laura Tang
- Department of Pathology and Laboratory MedicineMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Kanika Arora
- Department of Pathology and Laboratory MedicineMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
- Marie‐Josée and Henry R. Kravis Center for Molecular OncologyMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Neha Hingorani
- Gastroenterology, Hepatology, and Nutrition Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Stephanie King
- Gastroenterology, Hepatology, and Nutrition Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Arnold J. Markowitz
- Department of MedicineWeill Cornell MedicineNew YorkNew YorkUSA
- Gastroenterology, Hepatology, and Nutrition Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Mark Schattner
- Department of MedicineWeill Cornell MedicineNew YorkNew YorkUSA
- Gastroenterology, Hepatology, and Nutrition Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Shoji Shimada
- Gastric and Mixed Tumor Service, Department of SurgeryMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Steven B. Maron
- Department of MedicineWeill Cornell MedicineNew YorkNew YorkUSA
- Gastrointestinal Oncology Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Santosha Vardhana
- Department of MedicineWeill Cornell MedicineNew YorkNew YorkUSA
- Gastrointestinal Oncology Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Melissa Lumish
- Gastrointestinal Oncology Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Andrea Cercek
- Department of MedicineWeill Cornell MedicineNew YorkNew YorkUSA
- Gastrointestinal Oncology Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Yelena Y. Janjigian
- Department of MedicineWeill Cornell MedicineNew YorkNew YorkUSA
- Gastrointestinal Oncology Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Daniel Coit
- Department of MedicineWeill Cornell MedicineNew YorkNew YorkUSA
- Gastric and Mixed Tumor Service, Department of SurgeryMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Robin B. Mendelsohn
- Department of MedicineWeill Cornell MedicineNew YorkNew YorkUSA
- Gastroenterology, Hepatology, and Nutrition Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Michael F. Berger
- Department of Pathology and Laboratory MedicineMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
- Marie‐Josée and Henry R. Kravis Center for Molecular OncologyMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Vivian E. Strong
- Department of MedicineWeill Cornell MedicineNew YorkNew YorkUSA
- Gastric and Mixed Tumor Service, Department of SurgeryMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Zsofia K. Stadler
- Gastrointestinal Oncology Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
- Clinical Genetics Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Monika Laszkowska
- Department of MedicineWeill Cornell MedicineNew YorkNew YorkUSA
- Gastroenterology, Hepatology, and Nutrition Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
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Liu Y, Zhang X, Gan L, Chen Z, Wang X, Zhang J, Chen J, Tan C, Sheng W, Xu M. Trends, clinicopathological features, surgical treatment patterns and prognoses of early-onset versus late-onset gastric cancer: A retrospective cohort study. J Adv Res 2024:S2090-1232(24)00548-4. [PMID: 39586373 DOI: 10.1016/j.jare.2024.11.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 11/19/2024] [Accepted: 11/22/2024] [Indexed: 11/27/2024] Open
Abstract
INTRODUCTION This study investigates the differences between early-onset gastric carcinoma (EOGC) and late-onset gastric carcinoma (LOGC) by examining trends, demographics, clinical and molecular features, treatments, and outcomes at a leading cancer center in China. OBJECTIVES To delineate the distinctions between EOGC and LOGC in terms of patient characteristics, disease progression, and treatment outcomes, and to suggest appropriate screening strategies. METHODS We analyzed 18,877 gastric carcinoma cases treated at Fudan University Shanghai Cancer Center (FUSCC) from 2000 to 2022. Descriptive statistics were performed using IBM SPSS. Survival rates were assessed via the Kaplan-Meier method and log-rank test, while COX regression analysis identified factors affecting disease-free survival (DFS) and overall survival (OS). RESULTS The average age of gastric cancer diagnosis has increased slightly since 2000, with a steady rise in both EOGC and LOGC cases, though EOGC's proportion has slightly decreased. EOGC had a higher proportion of female patients and was more common in the gastric body and antrum pylorus. EOGC cases showed lower levels of cancer biomarkers, HER2 expression, vascular and lymphatic invasion, and lower differentiation and invasion depth. They also exhibited more advanced N and TNM staging, Borrmann IV type, and low adhesive carcinoma. EOGC underwent more extensive D2 lymphadenectomy and neoadjuvant chemotherapy. There were no significant differences in Claudin18.2 and MMR protein status between EOGC and LOGC. EOGC had higher rates of ovarian and peritoneal metastases, with a better early prognosis but faster late-stage progression. CONCLUSION EOGC and LOGC cases have increased over the past two decades. EOGC presents unique clinical and pathological features, requiring thorough surgical treatment and has a better early prognosis but more rapid late-stage progression. Enhanced screening for younger adults is recommended to address the rising EOGC trend.
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Affiliation(s)
- Yingxue Liu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Institute of Pathology, Fudan University, Shanghai 200032, China
| | - Xiaoyan Zhang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Institute of Pathology, Fudan University, Shanghai 200032, China
| | - Lu Gan
- Department of Medical Oncology, Fudan University Zhongshan Hospital, Shanghai 200032, China
| | - Zhikai Chen
- Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xin Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Institute of Pathology, Fudan University, Shanghai 200032, China
| | - Jiayu Zhang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Institute of Pathology, Fudan University, Shanghai 200032, China
| | - Jie Chen
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Second Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Cong Tan
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Institute of Pathology, Fudan University, Shanghai 200032, China
| | - Weiqi Sheng
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Institute of Pathology, Fudan University, Shanghai 200032, China.
| | - Midie Xu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Institute of Pathology, Fudan University, Shanghai 200032, China.
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Kővári B, Carneiro F, Lauwers GY. Epithelial tumours of the stomach. MORSON AND DAWSON'S GASTROINTESTINAL PATHOLOGY 2024:227-286. [DOI: 10.1002/9781119423195.ch13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Mazurek M, Szewc M, Sitarz MZ, Dudzińska E, Sitarz R. Gastric Cancer: An Up-to-Date Review with New Insights into Early-Onset Gastric Cancer. Cancers (Basel) 2024; 16:3163. [PMID: 39335135 PMCID: PMC11430327 DOI: 10.3390/cancers16183163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 09/06/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Gastric cancer (GC) is the fifth most frequently diagnosed cancer and the fifth most common cause of cancer death in the world. Regarding the age at which the diagnosis was made, GC is divided into early-onset gastric cancer (EOGC-up to 45 years of age) and conventional GC (older than 45). EOGC constitutes approximately 10% of all GCs. Numerous reports indicate that EOGC is more aggressive than conventional GC and is often discovered at an advanced tumor stage, which has an impact on the five-year survival rate. The median survival rate for advanced-stage GC is very poor, amounting to less than 12 months. Risk factors for GC include family history, alcohol consumption, smoking, Helicobacter pylori, and Epstein-Barr virus infection. It has been shown that a proper diet and lifestyle can play a preventive role in GC. However, research indicates that risk factors for conventional GC are less correlated with EOGC. In addition, the unclear etiology of EOGC and the late diagnosis of this disease limit the possibilities of effective treatment. Genetic factors are considered a likely cause of EOGC, as young patients are less exposed to environmental carcinogens. Research characterizing GC in young patients is scarce. This comprehensive study presents all aspects: epidemiology, risk factors, new treatment strategies, and future directions.
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Affiliation(s)
- Marek Mazurek
- Department of Surgical Oncology, Masovian Cancer Hospital, 05-135 Wieliszew, Poland;
| | - Monika Szewc
- Department of Normal, Clinical and Imaging Anatomy, Medical University of Lublin, 20-950 Lublin, Poland;
| | - Monika Z. Sitarz
- Department of Conservative Dentistry with Endodontics, Medical University of Lublin, 20-950 Lublin, Poland;
| | - Ewa Dudzińska
- Department of Dietetics and Nutrition Education, Medical University of Lublin, 20-950 Lublin, Poland;
| | - Robert Sitarz
- Department of Normal, Clinical and Imaging Anatomy, Medical University of Lublin, 20-950 Lublin, Poland;
- Department of Surgical Oncology, St. John’s Cancer Center, 20-090 Lublin, Poland
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Vishwanath A, Krishna S, Manudhane AP, Hart PA, Krishna SG. Early-Onset Gastrointestinal Malignancies: An Investigation into a Rising Concern. Cancers (Basel) 2024; 16:1553. [PMID: 38672634 PMCID: PMC11049592 DOI: 10.3390/cancers16081553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 04/11/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
There is growing recognition of early-onset gastrointestinal (GI) malignancies in young adults < 50 years of age. While much of the literature has emphasized colorectal cancer, these also include esophageal, gastric, liver, pancreatic, and biliary tract malignancies. Various factors, including lifestyle, hereditary, and environmental elements, have been proposed to explain the rising incidence of GI malignancies in the younger population. This review aims to provide an overview of the recent literature, including global trends and information regarding genetic and environmental risk factors.
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Affiliation(s)
- Aayush Vishwanath
- Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA;
| | - Shreyas Krishna
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University, Columbus, OH 43210, USA; (S.K.); (A.P.M.)
| | - Albert P. Manudhane
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University, Columbus, OH 43210, USA; (S.K.); (A.P.M.)
| | - Phil A. Hart
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University, Columbus, OH 43210, USA; (S.K.); (A.P.M.)
| | - Somashekar G. Krishna
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University, Columbus, OH 43210, USA; (S.K.); (A.P.M.)
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Alghamdi IG. Epidemiology of gastric cancer in Saudi Arabia from 2004 to 2017. Mol Clin Oncol 2023; 19:93. [PMID: 37854329 PMCID: PMC10580241 DOI: 10.3892/mco.2023.2689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 09/14/2023] [Indexed: 10/20/2023] Open
Abstract
Gastric cancer (GC), a prevalent disease which globally affects both men and women, was predicted by the International Agency for Research on Cancer in 2020 to have an age-standardized incidence rate (ASIR) in Saudi Arabia of 2.7 per 100,000 individuals for all ages and sexes (ranked 15th), and an age-standardized mortality rate of 2.1 per 100,000 individuals (ranked 12th). The present retrospective study aimed to investigate the prevalence of GC across all administrative regions in Saudi Arabia. Specifically, the present study sought to examine the incidence of diagnosed cases, age-specific incidence rates, crude incidence rates (CIRs) and ASIRs adjusted for age, year and region. To meet this aim, this retrospective descriptive epidemiological analysis was conducted on all cases of GC recorded in the Saudi Cancer Registry (SCR) between January 2004 and December 2017. The collected data were subjected to a range of statistical analyses (using SPSS version 20.0), including descriptive analyses, independent sample t-tests, the Kruskal-Wallis test and sex ratio analysis. In the SCR, a total of 4,066 cases of GC were recorded between 2004 and 2017. The regions with the highest overall ASIRs of GC for both men and women were found to be Riyadh, Najran and the Eastern Region, with rates ranging from 2.2-4.0 per 100,000 individuals. Conversely, Jazan had the lowest ASIRs, with rates of 1.5 and 0.5 per 100,000 individuals for men and women, respectively. The overall ASIRs of GC were found to be significantly higher in men compared with women, with a ratio of 2.8 per 100,000 individuals (P<0.05). In conclusion, the present study has revealed that, between 2004 and 2017, there was a slight decrease in the values of both CIR and ASIR of GC in Saudi Arabia.
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Affiliation(s)
- Ibrahim G. Alghamdi
- Public Health Department, College of Applied Medical Sciences, University of AL-Baha, AL Baha 65527, Kingdom of Saudi Arabia
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Falgout L, Gensler LL. Two Pediatric Cases Within a Familial Cluster and Hereditary Diffuse Gastric Carcinoma: A Tale of 2 Sisters. ACG Case Rep J 2023; 10:e01100. [PMID: 37476473 PMCID: PMC10356119 DOI: 10.14309/crj.0000000000001100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 06/12/2023] [Indexed: 07/22/2023] Open
Abstract
Hereditary diffuse gastric cancer is a familial form of poorly differentiated signet ring cell carcinoma (SRCC) caused by a mutation in the CDH1/E-cadherin gene-mediating cell adhesion. CDH1 mutations are inherited in an autosomal dominant fashion and exhibit a high level of penetrance. SRCC diagnosis is exceedingly rare in the pediatric population. We report a case of SRCC in 2 sisters (10 and 15 years) and their father (41 years).
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Affiliation(s)
- Lacey Falgout
- Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA
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Torrejon NV, Deshpande S, Wei W, Tullio K, Kamath SD. Proportion of Early-Onset Gastric and Esophagus Cancers Has Changed Over Time With Disproportionate Impact on Black and Hispanic Patients. JCO Oncol Pract 2022; 18:e759-e769. [PMID: 35544654 DOI: 10.1200/op.21.00692] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
PURPOSE The proportion of gastroesophageal junction adenocarcinoma is increasing. This study evaluated trends in early-onset gastric and esophageal cancers and compared socioeconomic and clinical characteristics between early-onset versus late-onset disease. MATERIALS AND METHODS We included all patients with gastric and esophageal cancer from 2004 to 2015 from the National Cancer Database. Patients were categorized by age < 50, 50-69, and ≥ 70 years. Differences in pathologic and socioeconomic factors between early-onset and late-onset cancers were assessed by using chi-square test. The effects of demographic and socioeconomic factors on overall survival (OS) were assessed using Cox models. RESULTS The proportion of patients with early-onset gastric cancer increased from 23.9% in 2004-2006 to 26.2% in 2013-2015, whereas the proportion of early-onset esophageal cancer decreased from 27.3% in 2004-2006 to 23.1% in 2013-2015. For both malignancies, the early-onset group was more likely to be Black or Hispanic and more likely to be diagnosed with stage IV cancer. Black patients had the worst median OS in both malignancies. In gastric cancer, within the Black patient group, patients experienced worse OS if they had government insurance versus private insurance (hazard ratio 1.2; 95% CI, 1.1 to 1.3; P value < .0001) or if they were in the lowest community median income category versus the highest category (hazard ratio 1.2; 95% CI, 1.1 to 1.3; P value < .0001). CONCLUSION Early-onset gastric cancer is increasing, whereas early-onset esophageal cancer is declining. Early-onset gastric cancer disproportionately affects non-White patients, particularly Hispanic patients. Black patients have worse outcomes compared with other races for both gastric and esophageal cancer.
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Affiliation(s)
| | | | - Wei Wei
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH
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Tang CT, Chen SH. Higher Lymph Node Metastasis Rate and Poorer Prognosis of Intestinal-Type Gastric Cancer Compared to Diffuse-Type Gastric Cancer in Early-Onset Early-Stage Gastric Cancer: A Retrospective Study. Front Med (Lausanne) 2021; 8:758977. [PMID: 35004729 PMCID: PMC8732774 DOI: 10.3389/fmed.2021.758977] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 11/24/2021] [Indexed: 12/19/2022] Open
Abstract
Background: The incidence of early-onset gastric cancer (GC) that was diagnosed at <50 years is increasing, but there is a knowledge gap on early-onset early-stage GC (EEGC) that was defined as early-onset GC limited to the mucosa or submucosa. Therefore, we comprehensively analysed the clinical features based on Lauren type. Methods: Logistic and Cox analyses were used to investigate risk factors for lymph node metastasis (LNM) and prognosis, respectively. Propensity score matching (PSM) was used to adjust confounding factors. Protein mass spectrometry analysis was used to explore the molecular mechanism of LNM. Result: Our study included 581 patients with EEGC from the Surveillance, Epidemiology, and End Results (SEER) database and 226 patients with EEGC from our own centre. We identified intestinal type, T1b stage, and tumour size (>3 cm) as risk factors for LNM using SEER and our own data. We also found that the prognosis of patients with intestinal-type EEGC was poorer than patients with diffuse-type EEGC, and T1b stage and positive LNM were hazard factors for survival. After analysing the expression of proteins between positive and negative LNM in the intestinal or diffuse type, we found no similar proteins between these groups. The differentially expressed genes (DEGs) in the intestinal type functioned as epithelial cell signalling in Helicobacter pylori. The DEGs in the diffuse type functioned in the tricarboxylic acid cycle (TCA cycle) and oxidative phosphorylation. Conclusion: For EEGC, our study was the first report to demonstrate that the intestinal type was a risk factor for LNM and survival compared to the diffuse type, and the oncogenic expression promoting the occurrence of LNM was different. These findings suggest that clinicians should pay more attention to intestinal-type EEGC than diffuse-type EEGC.
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Ieni A, Pizzimenti C, Giuffrè G, Caruso RA, Tuccari G. Autophagy-related prognostic signature in HER2 positive gastric carcinomas. Curr Mol Med 2021; 22:809-818. [PMID: 34814818 DOI: 10.2174/1566524021666211123093532] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 02/10/2021] [Accepted: 02/26/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The immunohistochemical analysis of autophagy-related proteins (ATGs) has been recently applied in human pathology to study differentiation and cancer progression. The aim of the present study is to analyze a cohort of gastric carcinomas (GC) by five ATG antisera (Beclin-1, LC3A/B, p62, ULK-1 and AMBRA-1), also evaluating their possible relationship with clinicopathological parameters, HER2 status and final outcome of patients. METHODS A cohort of 123 GCs has been studied by ATG antisera utilizing Masuda's criteria that define positive cases in which at least two out of five protein expressions were documented. RESULTS The immunohistochemical signature for autophagy (A-IHC) was 49.59% as a whole. The percentage of A-IHC ranged from 31% for poorly cohesive carcinomas to 56% for adenocarcinomas. The performance of each ATG immunomarker documented high values for sensitivity, specificity and efficiency for LC3A/B, Beclin-1 and p62. In univariate analysis of GC, grade, stage, Ki67 expression, HER2 status as well as A-IHC appeared as emerged as relevant parameters with a high p-value (p < 0.001). Finally, in multivariate analysis, HER2 status, stage and A-IHC emerged as independent prognostic variables. In the comparison of survival curves, GC cases immunoreactive for A-IHC exhibited a shorter survival with a worse outcome. CONCLUSIONS We have hypothesized that A-IHC could represent an additional morphological tool to provide prognostic elements in order to identify patients affected by aggressive with shorter survival and worse outcome.
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Affiliation(s)
- Antonio Ieni
- Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", Section of Pathology, University of Messina, Messina. Italy
| | - Cristina Pizzimenti
- Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", Section of Pathology, University of Messina, Messina. Italy
| | - Giuseppe Giuffrè
- Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", Section of Pathology, University of Messina, Messina. Italy
| | - Rosario Alberto Caruso
- Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", Section of Pathology, University of Messina, Messina. Italy
| | - Giovanni Tuccari
- Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", Section of Pathology, University of Messina, Messina. Italy
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13
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Businello G, Angerilli V, Parente P, Realdon S, Savarino E, Farinati F, Grillo F, Vanoli A, Galuppini F, Paccagnella S, Pennelli G, Mastracci L, Saragoni L, Fassan M. Molecular Landscapes of Gastric Pre-Neoplastic and Pre-Invasive Lesions. Int J Mol Sci 2021; 22:9950. [PMID: 34576114 PMCID: PMC8468646 DOI: 10.3390/ijms22189950] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/03/2021] [Accepted: 09/11/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric carcinoma (GC) represents one of the most common and most lethal malignancies worldwide. The histopathological characterization of GC precursor lesions has provided great knowledge about gastric carcinogenesis, with the consequent introduction of effective strategies of primary and secondary prevention. In recent years, a large amount of data about the molecular events in GC development is emerging, flanking the histomorphological descriptions. In this review, we describe the landscape of molecular alterations in gastric pre-invasive lesions with a glance at their potential use in the diagnostic and therapeutic decision-making process.
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Affiliation(s)
- Gianluca Businello
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (V.A.); (F.G.); (S.P.); (G.P.)
| | - Valentina Angerilli
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (V.A.); (F.G.); (S.P.); (G.P.)
| | - Paola Parente
- Pathology Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy;
| | - Stefano Realdon
- Veneto Institute of Oncology (IOV-IRCCS), 35128 Padua, Italy;
| | - Edoardo Savarino
- Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35121 Padua, Italy; (E.S.); (F.F.)
| | - Fabio Farinati
- Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35121 Padua, Italy; (E.S.); (F.F.)
| | - Federica Grillo
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova, 16132 Genova, Italy; (F.G.); (L.M.)
- Ospedale Policlinico San Martino, IRCCS for Oncology and Neuroscience, 16132 Genova, Italy
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, 27100 Pavia, Italy;
| | - Francesca Galuppini
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (V.A.); (F.G.); (S.P.); (G.P.)
| | - Silvia Paccagnella
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (V.A.); (F.G.); (S.P.); (G.P.)
| | - Gianmaria Pennelli
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (V.A.); (F.G.); (S.P.); (G.P.)
| | - Luca Mastracci
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova, 16132 Genova, Italy; (F.G.); (L.M.)
- Ospedale Policlinico San Martino, IRCCS for Oncology and Neuroscience, 16132 Genova, Italy
| | - Luca Saragoni
- UO Anatomia Patologica, Ospedale G.B. Morgagni-L. Pierantoni, 47121 Forlì, Italy;
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (V.A.); (F.G.); (S.P.); (G.P.)
- Veneto Institute of Oncology (IOV-IRCCS), 35128 Padua, Italy;
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14
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Liu J, Feng W, Liu M, Rao H, Li X, Teng Y, Yang X, Xu J, Gao W, Li L. Stomach-specific c-Myc overexpression drives gastric adenoma in mice through AKT/mammalian target of rapamycin signaling. Bosn J Basic Med Sci 2021; 21:434-446. [PMID: 33259779 PMCID: PMC8292868 DOI: 10.17305/bjbms.2020.4978] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 11/16/2020] [Indexed: 12/30/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant cancers in the world. c-Myc, a well-known oncogene, is commonly amplified in many cancers, including gastric cancer. However, it is still not completely understood how c-Myc functions in GC. Here, we generated a stomach-specific c-Myc transgenic mouse model to investigate its role in GC. We found that overexpression of c-Myc in Atp4b+ gastric parietal cells could induce gastric adenoma in mice. Mechanistically, c-Myc promoted tumorigenesis via the AKT/mTOR pathway. Furthermore, AKT inhibitor (MK-2206) or mTOR inhibitor (Rapamycin) inhibited the proliferation of c-Myc overexpressing gastric cancer cell lines. Thus, our findings highlight that gastric tumorigenesis can be induced by c-Myc overexpression through activation of the AKT/mTOR pathway.
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Affiliation(s)
- Jing Liu
- State Key Laboratory of Oncogenes and Related Genes, Renji Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Wenxin Feng
- State Key Laboratory of Oncogenes and Related Genes, Renji Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Min Liu
- State Key Laboratory of Oncogenes and Related Genes, Renji Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Hanyu Rao
- State Key Laboratory of Oncogenes and Related Genes, Renji Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoxue Li
- State Key Laboratory of Oncogenes and Related Genes, Renji Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Yan Teng
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
| | - Xiao Yang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
| | - Jin Xu
- School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Weiqiang Gao
- State Key Laboratory of Oncogenes and Related Genes, Renji Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Li Li
- State Key Laboratory of Oncogenes and Related Genes, Renji Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
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15
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Pocurull A, Herrera-Pariente C, Carballal S, Llach J, Sánchez A, Carot L, Botargues JM, Cuatrecasas M, Ocaña T, Balaguer F, Bujanda L, Moreira L. Clinical, Molecular and Genetic Characteristics of Early Onset Gastric Cancer: Analysis of a Large Multicenter Study. Cancers (Basel) 2021; 13:3132. [PMID: 34201547 PMCID: PMC8269053 DOI: 10.3390/cancers13133132] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 06/18/2021] [Accepted: 06/18/2021] [Indexed: 12/20/2022] Open
Abstract
Gastric adenocarcinoma (GC) is a common tumor with high morbidity and mortality. Only 7% of patients with GC are diagnosed before age 50 (early onset gastric cancer (EOGC)), and their characteristics have been poorly described. We aimed to describe clinical, molecular, and genetic characteristics of EOGC. A total of 309 patients with EOGC were retrospectively studied in four Spanish centers. Personal information, family history, and tumor information were registered. Germinal genetic analysis was performed in patients who met current criteria of a hereditary syndrome at the time of diagnosis. The median age at diagnosis was 44 years. The majority (73.3%) of tumors were diffuse, and 78.3% were diagnosed in an advanced stage. Familial aggregation of GC was present in 18/117 (15.4%) cases, and 5/117 (4.3%) met criteria for familial GC. MMR-IHC was performed in 126/309 (40.7%) tumors: 4/126 (3.1%) had loss of expression in MLH1/PMS2, without an associated germline mutation. Sixteen germline genetic analyses were performed, detecting a pathogenic variant in four (25%) cases: one in BRCA2, one in TP53, and two in CDH1. Most EOGC are diffuse and diagnosed in an advanced stage. In these patients, DNA MMR system deficiency is uncommon. Although familial aggregation was observed in only 15% of cases, a germline mutation was found in 25% of patients tested with clinical criteria. This demonstrates that EOGC has a marked genetic heterogeneity, reinforcing the importance of an accurate genetic counseling and enhancing the emerging use of multigene panels.
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Affiliation(s)
- Anna Pocurull
- Gastroenterology Department, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain; (A.P.); (C.H.-P.); (S.C.); (J.L.); (A.S.); (T.O.); (F.B.)
| | - Cristina Herrera-Pariente
- Gastroenterology Department, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain; (A.P.); (C.H.-P.); (S.C.); (J.L.); (A.S.); (T.O.); (F.B.)
| | - Sabela Carballal
- Gastroenterology Department, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain; (A.P.); (C.H.-P.); (S.C.); (J.L.); (A.S.); (T.O.); (F.B.)
| | - Joan Llach
- Gastroenterology Department, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain; (A.P.); (C.H.-P.); (S.C.); (J.L.); (A.S.); (T.O.); (F.B.)
| | - Ariadna Sánchez
- Gastroenterology Department, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain; (A.P.); (C.H.-P.); (S.C.); (J.L.); (A.S.); (T.O.); (F.B.)
| | - Laura Carot
- Gastroenterology Department, Hospital del Mar, 08003 Barcelona, Spain;
| | - Josep María Botargues
- Gastroenterology Department, Hospital Universitari de Bellvitge, 08097 Barcelona, Spain;
| | - Miriam Cuatrecasas
- Department Pathology, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain;
| | - Teresa Ocaña
- Gastroenterology Department, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain; (A.P.); (C.H.-P.); (S.C.); (J.L.); (A.S.); (T.O.); (F.B.)
| | - Francesc Balaguer
- Gastroenterology Department, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain; (A.P.); (C.H.-P.); (S.C.); (J.L.); (A.S.); (T.O.); (F.B.)
| | - Luis Bujanda
- Gastroenterology Department, Biodonostia Health Research Institute, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Universidad del País Vasco (UPV/EHU), 20014 San Sebastián, Spain;
| | - Leticia Moreira
- Gastroenterology Department, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain; (A.P.); (C.H.-P.); (S.C.); (J.L.); (A.S.); (T.O.); (F.B.)
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16
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Machlowska J, Kapusta P, Szlendak M, Bogdali A, Morsink F, Wołkow P, Maciejewski R, Offerhaus GJA, Sitarz R. Status of CHEK2 and p53 in patients with early-onset and conventional gastric cancer. Oncol Lett 2021; 21:348. [PMID: 33747205 PMCID: PMC7967923 DOI: 10.3892/ol.2021.12609] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 02/08/2021] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) is the fourth most common cause of cancer-associated death. Based on the age at diagnosis, GC is divided into early-onset GC (EOGC; ≤45 years) and conventional GC (CGC; >45 years). Mutations in the cell cycle checkpoint kinase 2 (CHEK2) and TP53 genes are associated with several types of cancer; however, their genetic defects in GC remain poorly understood. The aim of the present study was to determine the subcellular distribution of the CHEK2 protein and its redistribution following DNA damage, to improve the understanding of the DNA damage response. Genetic alterations and patterns of expression of CHEK2 and p53 proteins were investigated to identify potential biological markers and indicators of GC development. Additionally, the affected signaling pathways and their clinical importance in GC development and associated syndromes were investigated. A total of 196 GC samples (89 CGC and 107 EOGC samples) were used in the present study. DNA from 53 samples (18 CGC and 35 EOGC samples) was sequenced using targeted next-generation sequencing technology to identify and compare common and rare mutations associated with GC. Subsequently, the cytoplasmic and nuclear expression levels of CHEK2, phosphorylated (p)-CHEK2 at threonine 68 and p53 in GC tissues were determined via immunohistochemistry. Sequencing resulted in the identification of 63 single nucleotide polymorphisms (SNPs) in the CHEK2 gene amongst 5 different variants, and the intron variant c.319+379A>G was the most common SNP. In the TP53 gene, 57 different alterations were detected amongst 9 variant types, and the missense variant c.215C>G was the most common. Nuclear CHEK2 expression was high in both the EOGC and CGC subtypes. However, the prevalence of cytoplasmic CHEK2 expression (P<0.001) and nuclear p-CHEK2 expression (P=0.011) was significantly higher in CGC compared with in EOGC tissues. There was a statistically significant difference between high and low cytoplasmic CHEK2 expression in patients with p53-positive EOGC compared with in patients with p53-positive CGC (P=0.002). The present study was designed to determine the association between CHEK2 and p53 expression patterns in patients with EOGC and CGC, as well as genetic alterations in the CHEK2 and TP53 genes.
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Affiliation(s)
- Julita Machlowska
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, 31-034 Kraków, Poland
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland
| | - Przemysław Kapusta
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, 31-034 Kraków, Poland
| | - Małgorzata Szlendak
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland
- Department of Surgical Oncology, Medical University of Lublin, 20-090 Lublin, Poland
| | - Anna Bogdali
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, 31-034 Kraków, Poland
| | - Folkert Morsink
- Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Paweł Wołkow
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, 31-034 Kraków, Poland
| | - Ryszard Maciejewski
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland
| | - G. Johan A. Offerhaus
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland
- Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Robert Sitarz
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland
- Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
- Department of Surgery, Center of Oncology of The Lublin Region St. Jana z Dukli, 20-090 Lublin, Poland
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17
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Ma Z, Liu X, Paul ME, Chen M, Zheng P, Chen H. Comparative investigation of early-onset gastric cancer. Oncol Lett 2021; 21:374. [PMID: 33777198 DOI: 10.3892/ol.2021.12635] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 02/09/2021] [Indexed: 12/22/2022] Open
Abstract
Early-onset gastric cancer (EOGC) is a serious social burden. For patients with EOGC, typically considered as those aged <45 years, the underlying cause of the disease remains unclear. In addition, several misunderstandings of EOGC remain in clinical practice. Upon diagnosis, numerous patients with EOGC are already at an advanced stage (stage IV) of the disease and are unable to benefit from treatment. Moreover, several conclusions and data obtained from different EOGC studies appear to be to contradictory. The literature indicates that the incidence of EOGC is gradually rising, and that EOGC differs from traditional and familial gastric cancer in terms of clinicopathological characteristics. Patients with EOGC typically exhibit low survival rates, poor prognosis, rapid disease progression, a low degree of differentiation (signet-ring cell tumors are common) and rapid lymph node and distant metastasis, among other characteristics. The molecular genetic mechanisms of EOGC are also significantly different from those of traditional gastric cancer. An improved definition of EOCG may provide a reference for clinical diagnosis and treatment, and clear guidelines may serve as a basis for more accurate diagnosis and the development of effective treatment strategies.
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Affiliation(s)
- Zhen Ma
- The Second Clinical Medical College, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu 730030, P.R. China.,Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Xiaolong Liu
- The Second Clinical Medical College, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Maswikiti Ewetse Paul
- The Second Clinical Medical College, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Mali Chen
- Department of Labor, Delivery and Recovery, Gansu Provincial Maternity and Childcare Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Peng Zheng
- The Second Clinical Medical College, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Hao Chen
- The Second Clinical Medical College, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu 730030, P.R. China.,Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
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18
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Forma A, Tyczyńska M, Kędzierawski P, Gietka K, Sitarz M. Gastric carcinogenesis: a comprehensive review of the angiogenic pathways. Clin J Gastroenterol 2020; 14:14-25. [PMID: 33206367 PMCID: PMC7886717 DOI: 10.1007/s12328-020-01295-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 10/31/2020] [Indexed: 12/12/2022]
Abstract
Gastric cancer (GC) is undoubtedly one of the most prevalent malignancies worldwide. Since GC is the second leading cause of cancer-related deaths with nearly one million new diagnoses reported every year, there is a need for the development of new, effective treatment strategies of GC. Gastric carcinogenesis is a complex process that is induced by numerous factors and further stimulated by many pro-oncogenic pathways. Angiogenesis is the process of the new blood vessels formation from the already existing ones and it significantly contributes to the progression of gastric tumorigenesis and the growth of the cancerous tissues. The newly formed vessels provide cancer cells with proper nutrition, growth factors, and oxygen supply that are crucial for tumor growth and progression. Tumor-associated vessels differ from the physiological ones both morphologically and functionally. They are usually inefficient and unevenly distributed due to structural transformations. Thus, the development of the angiogenesis inhibitors that possess therapeutic effects has been the main focus of recent studies. Angiogenesis inhibitors mostly affect the vascular endothelial growth factor (VEGF) pathway since it is a major factor that stimulates the pro-angiogenic pathways. The aim of this review was to describe and summarize other promising molecular pathways that might be crucial in further improvements in GC therapies. This article provides an overview of how a meaningful role in tumor progression the angiogenetic process has. Furthermore, this review includes a description of the most important angiogenic factors as well as pathways and their involvement in gastric carcinogenesis.
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Affiliation(s)
- Alicja Forma
- Department of Forensic Medicine, Medical University of Lublin, 20-090, Lublin, Poland.
| | - Magdalena Tyczyńska
- Department of Human Anatomy, Medical University of Lublin, 20-090, Lublin, Poland
| | - Paweł Kędzierawski
- Department of Forensic Medicine, Medical University of Lublin, 20-090, Lublin, Poland
| | - Klaudyna Gietka
- Department of Forensic Medicine, Medical University of Lublin, 20-090, Lublin, Poland
| | - Monika Sitarz
- Department of Conservative Dentistry with Endodontics, Medical University of Lublin, 20-090, Lublin, Poland
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19
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Khan A, Ituarte PHG, Raoof M, Melstrom L, Li H, Yuan YC, Lai L, Benjamin Paz I, Goel A, Fong Y, Woo Y. Disparate and Alarming Impact of Gastrointestinal Cancers in Young Adult Patients. Ann Surg Oncol 2020; 28:785-796. [PMID: 32740736 DOI: 10.1245/s10434-020-08969-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 07/11/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND The rise in the incidence of gastric cancer (GC) and colorectal cancer (CRC) in young adults (YA) remains unexplained. We aim to identify differences in these malignancies between YA and older patients. PATIENTS AND METHODS We retrospectively analyzed the California Cancer Registry for all GC and CRC cases from 2000 to 2012. Pearson's Chi square analysis and stepwise regression model with backward elimination were used to analyze differences in demographic, clinical, and histopathologic features, and log-rank test to compare survival between young (≤ 40 years) and older adults (41-90 years) with GC or CRC, separately. RESULTS We analyzed 19,368 cases of GC and 117,415 cases of CRC. YA accounted for 4.6% of GC (n = 883) and 2.8% of CRC (n = 3273) patients. Compared with older patients, YA were more likely to be Hispanic (P < 0.0001) and have poorly differentiated (P < 0.0001), higher histologic grade (P < 0.0001), and signet ring features (P < 0.0001). Synchronous peritoneal metastases were more common in YA patients (32.1% vs. 14.1% GC, 8.8% vs. 5.4% CRC, P < 0.0001). The 5-year overall survival (OS) of YA with CRC or GC was longer than that of older patients with the same stage of malignancy; except YA with stage I GC, who demonstrated poor OS and disease-specific survival (DSS) (65.1% and 67.9%, respectively) which were significantly worse than those of adults aged 41-49 years (70.7% and 76.2%, respectively) and 50-64 years (69.1% and 78.1%, respectively). CONCLUSIONS YA with GC or CRC have distinctly worse clinical and histopathologic features compared with older patients and are disproportionately of Hispanic ethnicity. These results contribute to improving understanding of younger versus older GI cancer patients.
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Affiliation(s)
- Amir Khan
- Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
| | - Philip H G Ituarte
- Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
| | - Mustafa Raoof
- Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
| | - Laleh Melstrom
- Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
| | - Haiqing Li
- Department of Computational Quantitative Medicine, Center for Informatics, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Yate-Ching Yuan
- Department of Computational Quantitative Medicine, Center for Informatics, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Lily Lai
- Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
| | - I Benjamin Paz
- Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Yuman Fong
- Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
| | - Yanghee Woo
- Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA.
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20
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Machlowska J, Baj J, Sitarz M, Maciejewski R, Sitarz R. Gastric Cancer: Epidemiology, Risk Factors, Classification, Genomic Characteristics and Treatment Strategies. Int J Mol Sci 2020; 21:4012. [PMID: 32512697 PMCID: PMC7312039 DOI: 10.3390/ijms21114012] [Citation(s) in RCA: 818] [Impact Index Per Article: 163.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 05/31/2020] [Accepted: 06/01/2020] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies worldwide and it is the fourth leading cause of cancer-related death. GC is a multifactorial disease, where both environmental and genetic factors can have an impact on its occurrence and development. The incidence rate of GC rises progressively with age; the median age at diagnosis is 70 years. However, approximately 10% of gastric carcinomas are detected at the age of 45 or younger. Early-onset gastric cancer is a good model to study genetic alterations related to the carcinogenesis process, as young patients are less exposed to environmental carcinogens. Carcinogenesis is a multistage disease process specified by the progressive development of mutations and epigenetic alterations in the expression of various genes, which are responsible for the occurrence of the disease.
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Affiliation(s)
- Julita Machlowska
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, 31-034 Kraków, Poland;
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (J.B.); (R.M.)
| | - Jacek Baj
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (J.B.); (R.M.)
| | - Monika Sitarz
- Department of Conservative Dentistry with Endodontics, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Ryszard Maciejewski
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (J.B.); (R.M.)
| | - Robert Sitarz
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (J.B.); (R.M.)
- Department of Surgery, Center of Oncology of the Lublin Region St. Jana z Dukli, 20-090 Lublin, Poland
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21
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Li J. Gastric Cancer in Young Adults: A Different Clinical Entity from Carcinogenesis to Prognosis. Gastroenterol Res Pract 2020; 2020:9512707. [PMID: 32190044 PMCID: PMC7071806 DOI: 10.1155/2020/9512707] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 02/13/2020] [Indexed: 02/07/2023] Open
Abstract
Approximately 5.0% of gastric cancer (GC) patients are diagnosed before the age of 40 and are not candidates for screening programs in most countries and regions. The incidence of gastric cancer in young adults (GCYA) has declined over time in most countries except in the United States. Genetic alterations, environmental factors, and lifestyle may predispose some young adults to GC. According to molecular classifications, the cancer of most GCYA patients belongs to the genomically stable or microsatellite stable/epithelial-mesenchymal transition subtype, with the common genetic aberrations being mutations in CDH1. What characterizes GCYA are a higher prevalence in females, more aggressive tumor behaviors, diagnosis at advanced stages, fewer comorbidities and being better treatment candidates, and a similar or better survival outcome when compared with older patients. Considering the greater loss of life-years in younger patients, lowering the incidence of GC and diagnosing at a relatively early stage are the two most effective ways to decrease GC mortality. To achieve these goals, the low awareness of GCYA among general people, policy-makers, clinicians, and researchers should be changed.
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Affiliation(s)
- Jian Li
- Department of General Surgery, The Third Hospital of Mianyang Sichuan Mental Health Center, Mianyang, Sichuan 621000, China
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22
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Expression of Oncostatin M in Early Gastric Cancer and Precancerous Lesions. Gastroenterol Res Pract 2019; 2019:3616140. [PMID: 31871447 PMCID: PMC6913316 DOI: 10.1155/2019/3616140] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 09/16/2019] [Accepted: 09/30/2019] [Indexed: 12/11/2022] Open
Abstract
Objective To detect the expression of the Oncostatin M (OSM) gene and encoded protein in the mucosal epithelium of chronic gastritis, intestinal metaplasia (IM), low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), early gastric cancer (EGC), and advanced gastric cancer (AGC) samples and to explore the correlation and clinicopathological significance of OSM expression in the process of gastric carcinogenesis. Methods The expression levels of OSM in chronic gastritis, IM, LGIN, HGIN, EGC, and AGC samples were detected by gene chip, real-time quantitative PCR, and immunohistochemical methods. The expression levels of OSM in the gastric mucosa were analyzed, and its correlation with clinical pathology was studied. Results The expression level of OSM in gastric HGIN and EGC tissues was significantly higher than that in LGIN tissues based on expression profiling (P < 0.001). The expression of the OSM gene in EGC was higher than that in HGIN (unpaired t test, P < 0.05) and LGIN (unpaired t test, P < 0.01) by qPCR. The expression of OSM in LGIN was significantly lower than that in HGIN (P = 0.008) and EGC (P = 0.044) by immunohistochemical staining. The expression of OSM in HGIN tissues was significantly higher than that in AGC (P = 0.007). Conclusion Alterations in the expression of the OSM gene may be involved in the malignant transformation of the gastric mucosal epithelium. Because of the significant difference in the cancerization rate and clinical management between LGIN and HGIN, the difference in the staining intensity of OSM between LGIN and HGIN may be one of the early markers of gastric intraepithelial neoplasia.
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23
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A Raman-based serum constituents’ analysis for gastric cancer diagnosis: In vitro study. Talanta 2019; 204:826-832. [DOI: 10.1016/j.talanta.2019.06.068] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 05/25/2019] [Accepted: 06/17/2019] [Indexed: 11/18/2022]
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24
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Bergquist JR, Leiting JL, Habermann EB, Cleary SP, Kendrick ML, Smoot RL, Nagorney DM, Truty MJ, Grotz TE. Early-onset gastric cancer is a distinct disease with worrisome trends and oncogenic features. Surgery 2019; 166:547-555. [PMID: 31331685 DOI: 10.1016/j.surg.2019.04.036] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 04/11/2019] [Accepted: 04/17/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Overall the incidence of gastric cancer is declining in the United States; however, the incidence of early-onset gastric cancer is increasing. We sought to elucidate clinical and genomic characteristics and risk factors for early-onset gastric cancer compared with late-onset gastric cancer. METHODS We utilized the Surveillance, Epidemiology, and End Results database (1973-2015), the Behavioral Risk Factor Surveillance Survey, and The Cancer Genome Atlas to characterize early-onset gastric cancer. RESULTS The incidence of early-onset gastric cancer increased during the study period and now comprises >30% of all gastric cancer in the United States. Early-onset gastric cancer was associated with higher grade (55.2 vs 46.9%), signet-ring cells (19.0 vs 10.4%), diffuse histology (25.7 vs 15.0%), and metastatic disease (49.5 vs 40.9%, all P < .01) compared with late-onset gastric cancer. Early-onset gastric cancer was more likely to be Epstein-Barr virus (7.7 vs 5.1%) or genomically stable (22.5 vs 8.1%) subtype, whereas late-onset gastric cancer was more likely to be microsatellite instability subtype (18.6 vs 5.6%; all P < .01). Risk factors for gastric cancer were less correlated with early-onset gastric cancer compared with late-onset gastric cancer. CONCLUSION The incidence of early-onset gastric cancer has been steadily increasing in the United States, comprising >30% of new gastric cancer cases today. Early-onset gastric cancer is genetically and clinically distinct from traditional gastric cancer. Additional investigations are warranted to better understand this alarming phenomenon.
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Affiliation(s)
- John R Bergquist
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN; Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Surgical Outcomes Program, Rochester, MN
| | - Jennifer L Leiting
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN
| | - Elizabeth B Habermann
- Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Surgical Outcomes Program, Rochester, MN
| | - Sean P Cleary
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN
| | - Michael L Kendrick
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN
| | - Rory L Smoot
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN
| | - David M Nagorney
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN
| | - Mark J Truty
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN
| | - Travis E Grotz
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN.
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25
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Yoon JH, Park YG, Nam SW, Park WS. The diagnostic value of serum gastrokine 1 (GKN1) protein in gastric cancer. Cancer Med 2019; 8:5507-5514. [PMID: 31376239 PMCID: PMC6745860 DOI: 10.1002/cam4.2457] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 07/16/2019] [Accepted: 07/16/2019] [Indexed: 12/16/2022] Open
Abstract
Early detection of cancer provides effective treatment and saves lives. The objective of this study was to determine whether serum gastrokine 1 (GKN1) protein is a gastric cancer-specific diagnostic biomarker. The serum concentration of GKN1 in healthy individuals (median: 6.34 ng/μL, interquartile range (IQR): 5.66-7.54 ng/μL) was significantly higher compared with the levels in gastric cancer patients (median: 3.48 ng/μL, IQR: 2.90-4.11 ng/μL; P < .0001). At the optimum cutoff (4.94 ng/μL) of serum GKN1 protein, the sensitivity and specificity were 91.2% and 96.0%, respectively, for gastric cancer. Using serum GKN1 protein as the diagnostic reference, the ROC curve showed a satisfactory diagnostic efficacy with an AUC value of 0.9954 (95% CI 0.9919-0.9988) and Youden index of 0.8740. In addition, the diagnostic accuracy of the serum GKN1 protein at the optimum cutoff was 0.9675. Interestingly, serum GKN1 concentrations in patients with advanced gastric cancer (AGC; median: 3.11 ng/μL, IQR: 2.72-3.72 ng/μL) were lower than in patients with early gastric cancer (EGC; median: 4.31 ng/μL, IQR: 3.88-4.88 ng/μL). The diagnostic accuracies at the optimum serum GKN1 cutoff were 0.8912 and 0.9589 for EGC and AGC, respectively. Furthermore, the serum GKN1 concentrations robustly discriminated the patients with gastric cancer from the patients with colorectal, liver, lung, breast, pancreatic, ovary, and prostatic cancers with AUC values greater than 0.94. These data suggest that serum GKN1 is a promising and highly specific diagnostic biomarker for the prompt detection of early and advanced gastric cancers.
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Affiliation(s)
- Jung Hwan Yoon
- Department of Pathology, College of MedicineThe Catholic University of KoreaSeoulSouth Korea
- Functional RNomics Research Center, College of MedicineThe Catholic University of KoreaSeoulSouth Korea
| | - Yong Gyu Park
- Department of Biostatistics, College of MedicineThe Catholic University of KoreaSeoulRepublic of Korea
| | - Suk Woo Nam
- Department of Pathology, College of MedicineThe Catholic University of KoreaSeoulSouth Korea
- Functional RNomics Research Center, College of MedicineThe Catholic University of KoreaSeoulSouth Korea
| | - Won Sang Park
- Department of Pathology, College of MedicineThe Catholic University of KoreaSeoulSouth Korea
- Functional RNomics Research Center, College of MedicineThe Catholic University of KoreaSeoulSouth Korea
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26
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Kim HS, Kim JW, Hwang IG, Lee HS, Kim WH. Expression of DNA Damage Response Markers in Early-Onset or Familial Gastric Cancers. Asian Pac J Cancer Prev 2019; 20:1369-1376. [PMID: 31127894 PMCID: PMC6857889 DOI: 10.31557/apjcp.2019.20.5.1369] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Background: Early-onset or familial gastric cancer (GC) is known to have clinicopathologic profiles different from those of sporadic GC. We aimed to compare DNA damage response marker expression between early-onset or familial GC and sporadic GC. Methods: GC samples were obtained from patients who underwent gastrectomy for GC at Seoul National University Hospital. Immunohistochemical analyses of various DNA damage response markers, including BRCA1, BRCA2, MRE11, RAD51C, and γH2AX, were performed using 54 early-onset GC, 59 familial GC, and 337 sporadic GC tissue microarray samples. Correlations between marker expression and clinicopathologic features were evaluated by univariate and multivariate analyses, and overall survival was analyzed. Results: The rate of γH2AX positivity was significantly higher (p < 0.001) in early-onset or familial GC than in sporadic GC. In contrast, the rates of MRE11 negativity and RAD51C negativity were significantly higher in sporadic GC than in early-onset or familial GC. BRCA1 negativity was associated with decreased overall survival in sporadic GC (p = 0.002), and MRE11 negativity was associated with decreased overall survival in sporadic GC (p = 0.012). Conclusion: Our results show significant differences in DNA damage response marker expression between early-onset or familial GC and sporadic GC.
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Affiliation(s)
- Hee Sung Kim
- Department of Pathology, Chung-Ang Univesity, College of Medicine, Seoul, South Korea
| | - Jong Won Kim
- Department of Surgery, Chung-Ang University, College of Medicine, Seoul, South Korea
| | - In Gyu Hwang
- Department of Internal Medicine, Chung-Ang University, College of Medicine, Seoul, South Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University, College of Medicine, Seoul, South Korea.
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27
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Machlowska J, Pucułek M, Sitarz M, Terlecki P, Maciejewski R, Sitarz R. State of the art for gastric signet ring cell carcinoma: from classification, prognosis, and genomic characteristics to specified treatments. Cancer Manag Res 2019; 11:2151-2161. [PMID: 30936747 PMCID: PMC6421895 DOI: 10.2147/cmar.s188622] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) is responsible for 9% of cancer deaths worldwide. Over 950,000 new cases are diagnosed each year, and about 90% of them are in advanced stage, requiring chemotherapy. In Europe there has been research based on pre- and postoperative chemotherapy treatment, using 5-fluorouracil, epirubicin, cisplatin, capecitabine, and docetaxel. Chemotherapy significantly impairs the quality of life of patients; however, the final effects are not always satisfactory. There is scientific evidence that gastric mucus tumors and signet ring cell carcinomas have a pattern of specific signatures, that distinguish them from other gastric cancer subtypes, and may be associated with a poor response to systematic treatment. Signet ring cell carcinoma is less chemosensitive than others, and the increase in the percentage of signet ring cells correlates with resistance to chemotherapy. Perioperative chemotherapy in advanced signet ring cell carcinomas is an independent factor of poor prognosis and survival, which is explained by the toxicity of neoadjuvant treatment. Therefore, curative surgical resection enhanced by standardized lymphadenectomy remains the recommended gold standard in GC therapy. According to presented studies, early detection and aggressive treatments for this subtype of GC is a reasonable approach. This review paper is mostly addressed to physicians who are interested in updating to the state of the art concerning different subtypes of gastric carcinoma.
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Affiliation(s)
- Julita Machlowska
- Department of Human Anatomy, Medical University of Lublin, Lublin, Poland,
| | - Małgorzata Pucułek
- Department of Human Anatomy, Medical University of Lublin, Lublin, Poland,
| | - Monika Sitarz
- Department of Conservative Dentistry and Endodontics, Medical University of Lublin, Lublin, Poland
| | - Paweł Terlecki
- Department of Surgery, St. John's Cancer Center, Lublin, Poland,
| | | | - Robert Sitarz
- Department of Human Anatomy, Medical University of Lublin, Lublin, Poland,
- Department of Surgery, St. John's Cancer Center, Lublin, Poland,
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28
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Luo W, Fedda F, Lynch P, Tan D. CDH1 Gene and Hereditary Diffuse Gastric Cancer Syndrome: Molecular and Histological Alterations and Implications for Diagnosis And Treatment. Front Pharmacol 2018; 9:1421. [PMID: 30568591 PMCID: PMC6290068 DOI: 10.3389/fphar.2018.01421] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer, a group of common malignancies, results in the most cancer mortality worldwide after only lung and colorectal cancer. Although familial gastric cancers have long been recognized, it was not until recently that they were discovered to be associated with mutations of specific genes. Mutations of CDH1, the gene encoding E-cadherin, are the most common germline mutations detected in gastric cancer and underlie hereditary diffuse gastric cancer (HDGC) syndrome. All reported HDGCs are the pure diffuse type by Lauren classification and are associated with dismal prognosis once the tumor invades the submucosa. Because CDH1 germline mutations are inherited in an autosomal-dominant fashion and have high penetrance, the International Gastric Cancer Linkage Consortium (IGCLC) developed criteria to facilitate the screening of CDH1 mutation carriers; these criteria have been proven to have excellent sensitivity and specificity. Recent histologic studies suggest that HDGC progresses through several stages. Even when the tumor becomes "invasive" in lamina propria, it may stay indolent for a long time. However, the molecular mechanisms that induce the transitions between stages and determine the length of the indolent phase remain to be determined. Although the standard management for CDH1 mutation carriers is prophylactic total gastrectomy, many questions must be answered before the surgery can be done. These include the optimal surveillance strategy, the best strategy to choose surgical candidates, and the ideal time to perform surgery. In addition to increasing the risk of gastric cancer, CDH1 germline mutations also increase the risk of invasive lobular carcinoma of the breast, and possibly colorectal adenocarcinoma, and are associated with blepharocheilodontic syndrome (a congenital development disorder). However, the optimal management of these conditions is less established owing to insufficient data regarding the risk of cancer development. This review focuses on molecular and histological findings in HDGC, as opposed to sporadic diffuse gastric cancer, and their implications for the management of CDH1 mutation carriers and the diagnosis and treatment of HDGC. Other conditions associated with CDH1 germline mutations and future research directions are also discussed.
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Affiliation(s)
- Wenyi Luo
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Faysal Fedda
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Patrick Lynch
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Dongfeng Tan
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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29
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Pucułek M, Machlowska J, Wierzbicki R, Baj J, Maciejewski R, Sitarz R. Helicobacter pylori associated factors in the development of gastric cancer with special reference to the early-onset subtype. Oncotarget 2018; 9:31146-31162. [PMID: 30123433 PMCID: PMC6089554 DOI: 10.18632/oncotarget.25757] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 06/22/2018] [Indexed: 02/07/2023] Open
Abstract
Nowadays, gastric cancer is one of the most common neoplasms and the fourth cause of cancer-related death on the world. Regarding the age at the diagnosis it is divided into early-onset gastric carcinoma (45 years or younger) and conventional gastric cancer (older than 45). Gastric carcinomas are rarely observed in young population and rely mostly on genetic factors, therefore provide the unique model to study genetic and environmental alternations. The latest research on early-onset gastric cancer are trying to explain molecular and genetic basis, because young patients are less exposed to environmental factors predisposing to cancer. In the general population, Helicobacter pylori, has been particularly associated with intestinal subtype of gastric cancers. The significant association of Helicobacter pylori infection in young patients with gastric cancers suggests that the bacterium has an etiologic role in both diffuse and intestinal subtypes of early-onset gastric cancers. In this paper we would like to ascertain the possible role of Helicobacter pylori infection in the development of gastric carcinoma in young patients. The review summarizes recent literature on early-onset gastric cancers with special reference to Helicobacter pylori infection.
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Affiliation(s)
| | | | - Ryszard Wierzbicki
- Department of Surgery with Trauma, Orthopaedic and Urological Subunit, Independent Public Health Care Center of the Ministry of Interior and Administration in Lublin, Poland
- Department of Surgical Oncology, Medical University of Lublin, Poland
| | - Jacek Baj
- Department of Human Anatomy, Medical University of Lublin, Poland
| | | | - Robert Sitarz
- Department of Human Anatomy, Medical University of Lublin, Poland
- Department of Surgery with Trauma, Orthopaedic and Urological Subunit, Independent Public Health Care Center of the Ministry of Interior and Administration in Lublin, Poland
- Department of Surgery, St. John's Cancer Center, Lublin, Poland
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30
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Gu D, Zheng R, Xin J, Li S, Chu H, Gong W, Qiang F, Zhang Z, Wang M, Du M, Chen J. Evaluation of GWAS-Identified Genetic Variants for Gastric Cancer Survival. EBioMedicine 2018; 33:82-87. [PMID: 29983348 PMCID: PMC6085567 DOI: 10.1016/j.ebiom.2018.06.028] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 06/03/2018] [Accepted: 06/22/2018] [Indexed: 12/31/2022] Open
Abstract
BACKGROUNDS Genome-wide association studies (GWASs) have identified several gastric cancer (GC) susceptibility loci in Asians, but their effects on disease outcome are still unknown. This study aimed to investigate whether these GWAS-identified genetic variants could serve as robust prognostic biomarkers for GC. METHODS A multistage clinical cohort, including a total of 2432 GC patients in the Chinese population, was used to identify the association between GWAS-identified risk variants and overall survival of GC. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed by Cox regression analysis, and the log-rank P was calculated by the log-rank test with the Kaplan-Meier method. RESULTS We found that rs2274223 A>G in PLCE1 was associated with increased GC survival in both training set (P = .011), which was independently replicated in validation set 1 (P = .045), but not in validation set 2. The area under the curve (AUC) from receiver-operator characteristic (ROC) curve showed this clinical relevance with onset age-dependence, especially in the subgroup of early-onset cases. Moreover, a significant improvement in overall survival prediction was identified when the rs2274223 genetic effect was included in the estimation; this result was also supported by the prognostic nomogram. In addition, patients with lower expression of PLCE1 showed benefits via longer survival, potentially due to the functional effect of rs2274223. INTERPRETATION This preliminary study suggests that a GWAS-identified genetic variant in PLCE1 may serve as a potential biomarker for GC survival. Additional replication with larger samples size is warranted to further investigation.
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Affiliation(s)
- Dongying Gu
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Rui Zheng
- Department of Environmental Genomics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Junyi Xin
- Department of Environmental Genomics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Shuwei Li
- Department of Environmental Genomics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Haiyan Chu
- Department of Environmental Genomics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Weida Gong
- Department of Surgery, Yixing Cancer Hospital, Yixing, China
| | - Fulin Qiang
- Core Laboratory, Nantong Tumor Hospital, Nantong, China
| | - Zhengdong Zhang
- Department of Environmental Genomics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Meilin Wang
- Department of Environmental Genomics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
| | - Mulong Du
- Department of Environmental Genomics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Department of Biostatistics, School of Public Heath, Nanjing Medical University, Nanjing, China.
| | - Jinfei Chen
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
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Hu Y, Yu K, Wang G, Zhang D, Shi C, Ding Y, Hong D, Zhang D, He H, Sun L, Zheng JN, Sun S, Qian F. Lanatoside C inhibits cell proliferation and induces apoptosis through attenuating Wnt/β-catenin/c-Myc signaling pathway in human gastric cancer cell. Biochem Pharmacol 2018; 150:280-292. [DOI: 10.1016/j.bcp.2018.02.023] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 02/16/2018] [Indexed: 02/06/2023]
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YWHAE silencing induces cell proliferation, invasion and migration through the up-regulation of CDC25B and MYC in gastric cancer cells: new insights about YWHAE role in the tumor development and metastasis process. Oncotarget 2018; 7:85393-85410. [PMID: 27863420 PMCID: PMC5356744 DOI: 10.18632/oncotarget.13381] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Accepted: 10/27/2016] [Indexed: 12/16/2022] Open
Abstract
We previously observed reduced YWHAE (14-3-3ε) protein expression in a small set of gastric cancer samples. YWHAE may act as a negative regulator of the cyclin CDC25B, which is a transcriptional target of MYC oncogene. The understanding of YWHAE role and its targets is important for the better knowledge of gastric carcinogenesis. Thus, we aimed to evaluate the relationship among YWHAE, CDC25B, and MYC in vitro and in vivo. For this, we analyzed the YWHAE, CDC25B, and MYC expression in YWHA-silenced, CDC25B-silenced, and MYC-silenced gastric cancer cell lines, as well as in gastric cancer and non-neoplastic gastric samples. In gastric cancer cell lines, YWHAE was able to inhibit the cell proliferation, invasion and migration through the reduction of MYC and CDC25B expression. Conversely, MYC induced the cell proliferation, invasion and migration through the induction of CDC25B and the reduction of YWHAE. Most of the tumors presented reduced YWHAE and increased CDC25B expression, which seems to be important for tumor development. Increased MYC expression was a common finding in gastric cancer and has a role in poor prognosis. In the tumor initiation, the opposite role of YWHAE and CDC25B in gastric carcinogenesis seems to be independent of MYC expression. However, the inversely correlation between YWHAE and MYC expression seems to be important for gastric cancer cells invasion and migration. The interaction between YWHAE and MYC and the activation of the pathways related to this interaction play a role in the metastasis process.
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Kwon MJ, Kim RN, Song K, Jeon S, Jeong HM, Kim JS, Han J, Hong S, Oh E, Choi JS, An J, Pollack JR, Choi YL, Park CK, Shin YK. Genes co-amplified with ERBB2 or MET as novel potential cancer-promoting genes in gastric cancer. Oncotarget 2017; 8:92209-92226. [PMID: 29190909 PMCID: PMC5696175 DOI: 10.18632/oncotarget.21150] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 08/27/2017] [Indexed: 12/18/2022] Open
Abstract
Gastric cancer (GC), one of the most common cancers worldwide, has a high mortality rate due to limited treatment options. Identifying novel and promising molecular targets is a major challenge that must be overcome if treatment of advanced GC is to be successful. Here, we used comparative genomic hybridization and gene expression microarrays to examine genome-wide DNA copy number alterations (CNAs) and global gene expression in 38 GC samples from old and young patients. We identified frequent CNAs, which included copy number gains on chromosomes 3q, 7p, 8q, 20p, and 20q and copy number losses on chromosomes 19p and 21p. The most frequently gained region was 7p21.1 (55%), whereas the most frequently deleted region was 21p11.1 (50%). Recurrent highly amplified regions 17q12 and 7q31.1-7q31.31 harbored two well-known oncogenes: ERBB2 and MET. Correlation analysis of CNAs and gene expression levels identified CAPZA2 (co-amplified with MET) and genes GRB7, MIEN1, PGAP3, and STARD3 (co-amplified with ERBB2) as potential candidate cancer-promoting genes (CPGs). Public dataset analysis confirmed co-amplification of these genes with MET or ERBB2 in GC tissue samples, and revealed that high expression (except for PGAP3) was significantly associated with shorter overall survival. Knockdown of these genes using small interfering RNA led to significant suppression of GC cell proliferation and migration. Reduced GC cell proliferation mediated by CAPZA2 knockdown was attributable to attenuated cell cycle progression and increased apoptosis. This study identified novel candidate CPGs co-amplified with MET or ERBB2, and suggests that they play a functional role in GC.
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Affiliation(s)
- Mi Jeong Kwon
- College of Pharmacy, Kyungpook National University, Daegu, Korea.,Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Korea
| | - Ryong Nam Kim
- Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy, Seoul National University, Seoul, Korea.,Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, Korea
| | - Kyoung Song
- R&D center, ABION Inc., Guro-gu, Seoul, Korea
| | - Sinyoung Jeon
- Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Hae Min Jeong
- Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Joo Seok Kim
- Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Jinil Han
- Gencurix, Inc., Guro-gu, Seoul, Korea
| | - Sungyoul Hong
- Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Ensel Oh
- Laboratory of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jong-Sun Choi
- The Center for Anti-cancer Companion Diagnostics, Institutes of Entrepreneurial BioConvergence, Seoul National University, Seoul, Korea
| | - Jungsuk An
- Department of Pathology, Gachon University Gil Medical Center, Incheon, Korea
| | - Jonathan R Pollack
- Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America
| | - Yoon-La Choi
- Laboratory of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea
| | - Cheol-Keun Park
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Kee Shin
- Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy, Seoul National University, Seoul, Korea.,Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, Korea.,The Center for Anti-cancer Companion Diagnostics, Institutes of Entrepreneurial BioConvergence, Seoul National University, Seoul, Korea.,Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea
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Merchant SJ, Kim J, Choi AH, Sun V, Chao J, Nelson R. A rising trend in the incidence of advanced gastric cancer in young Hispanic men. Gastric Cancer 2017; 20:226-234. [PMID: 26924751 PMCID: PMC5630456 DOI: 10.1007/s10120-016-0603-7] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 02/17/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although the incidence of gastric cancer has been decreasing, recent reports suggest an increased rate in select populations. We sought to evaluate trends in gastric cancer incidence to identify high-risk populations. METHODS Gastric cancer incidence rates from 1992 to 2011 were computed with use of the Surveillance, Epidemiology, and End Results (SEER) registry. We evaluated trends in incidence rates by calculating the annual percent change (APC) across three age groups (20-49 years, 50-64 years, and 65 years or older) and four racial/ethnic groups (Hispanics, non-Hispanic whites, blacks, and Asian/Pacific Islanders). RESULTS We identified 41,428 patients with gastric cancer. For the entire cohort during the study period, the APC was decreased. When patients were grouped according to sex, the APC was flat or decreased in women regardless of age or race/ethnicity. The APC was also flat or decreased for all men except young Hispanic men (20-49 years), who had an increased APC of nearly 1.6 % (1.55 %, 95 % confidence interval 0.26-2.86 %). Furthermore, young Hispanic men were the only group to have increased incidence of stage IV disease (APC 4.34 %, 95 % confidence interval 2.76-5.94 %) and poorly differentiated tumors (APC 2.08 %, 95 % confidence interval 0.48-3.70 %). CONCLUSIONS The APC of the incidence of gastric cancer in young Hispanic men places it among the top cancers with rising incidence in the USA. This is concomitant with increased incidence of advanced disease at presentation. This major public health concern warrants additional research to determine the cause of the increasing incidence in this group.
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Affiliation(s)
- Shaila J Merchant
- Division of Surgical Oncology, Queen's University, Kingston, ON, Canada
| | - Joseph Kim
- Division of Surgical Oncology, Stony Brook Medicine, Stony Brook, NY, USA
| | - Audrey H Choi
- Divisions of Surgical Oncology, City of Hope, Duarte, CA, USA
| | - Virginia Sun
- Nursing Research and Education, City of Hope, Duarte, CA, USA
| | - Joseph Chao
- Medical Oncology, City of Hope, Duarte, CA, USA
| | - Rebecca Nelson
- Department of Biostatistics, City of Hope, 1500 East Duarte Rd, Duarte, CA, 91010, USA.
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Zhang XY, Zhang PY. Gastric cancer: somatic genetics as a guide to therapy. J Med Genet 2016; 54:305-312. [PMID: 27609016 DOI: 10.1136/jmedgenet-2016-104171] [Citation(s) in RCA: 109] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2016] [Accepted: 08/11/2016] [Indexed: 12/28/2022]
Abstract
Gastric cancer is the leading cause of cancer-related mortality across the world, with poor prognosis and a median overall survival of ≤12 months for advanced stage gastric cancer. Environmental, genetic and other predisposing factors contribute to the development of gastric cancer and a predominant factor was found to be infection of Helicobacter pylori Advances in understanding the deranged signalling pathways that are critical for normal cellular homeostasis helped in the development of novel drugs that target specific proteins and pathways to curtail the growth of gastric cancer. Genetic studies revealed several single nucleotide polymorphisms, chromosomal aberrations and epigenetic alterations that likely play a major role in elevating the susceptibility to develop gastric cancer. Methylation pattern of specific genes may likely prove to be a valid biomarker for early detection of gastric cancer, but much progress is needed to establish specific markers. Important developments have been made in targeting human epidermal growth factor receptor-2 and vascular endothelial growth factor receptor 2 for treating advanced gastro-oesophageal junction cancer, using specific monoclonal antibodies. Lack of efficacy with regard to targeting other signalling pathways including mesenchymal-epithelial transition/hepatocyte growth factor and mammalian target of rapamycin is probably due to suboptimal patient selection for these clinical trials, which is probably due to the lack of appropriate biomarkers, to decide on responsive patient population. Besides the development of antagonists for the cell growth-related signalling pathways, advances are also being made to tackle gastric cancer by immunotherapies, targeting immune check-points, which may hold promise for better treatment options in future.
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Affiliation(s)
- Xiao-Ying Zhang
- Nanjing University of Chinese Medicine, Information Institute, Nanjing, Jiangsu, China
| | - Pei-Ying Zhang
- Xuzhou Central Hospital, Xuzhou, Jiangsu Province, China.,The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu Province, China.,Xuzhou Clinical School of Xuzhou Medical College, Xuzhou, Jiangsu Province, China.,Xuzhou Clinical Medical College of Nanjing University of Chinese Medicine, Xuzhou, Jiangsu Province, China
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Ling ZQ, Ge MH, Lu XX, Han J, Wu YC, Liu X, Zhu X, Hong LL. Ndrg2 promoter hypermethylation triggered by helicobacter pylori infection correlates with poor patients survival in human gastric carcinoma. Oncotarget 2016; 6:8210-25. [PMID: 25823664 PMCID: PMC4480746 DOI: 10.18632/oncotarget.3601] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2014] [Accepted: 02/03/2015] [Indexed: 12/26/2022] Open
Abstract
N-myc downstream regulated gene 2 (Ndrg2) is a candidate suppressor of cancer metastasis. We found that Ndrg2 promoter was frequently hypermethylated in gastric cancer cell lines and in 292 gastric tumor tissues. This resulted in down-regulation of Ndrg2 mRNA and protein. Ndrg2 promoter methylation was associated with H. pylori infection and worse prognosis of gastric cancer patients, which is an independent prognostic factor for the disease-free survival (DFS). We found that H. pylori silenced Ndrg2 by activating the NF-κB pathway and up-regulating DNMT3b, promoting gastric cancer progression. These findings uncover a previously unrecognized role for H. pylori infection in gastric cancer.
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Affiliation(s)
- Zhi-Qiang Ling
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, China
| | - Ming-Hua Ge
- Department of Tumor Surgery, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, China
| | - Xiao-Xiao Lu
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, China
| | - Jin Han
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, China
| | - Yi-Chen Wu
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, China
| | - Xiang Liu
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, China
| | - Xin Zhu
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, China
| | - Lian-Lian Hong
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, China
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Zhou F, Shi J, Fang C, Zou X, Huang Q. Gastric Carcinomas in Young (Younger than 40 Years) Chinese Patients: Clinicopathology, Family History, and Postresection Survival. Medicine (Baltimore) 2016; 95:e2873. [PMID: 26945372 PMCID: PMC4782856 DOI: 10.1097/md.0000000000002873] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Little is known about clinicopathological characteristics of gastric carcinoma (GC) in young (≤40 years) Chinese patients. We aimed in this study to analyze those features along with family history and prognostic factors after resection. We retrospectively reviewed all 4671 GC resections (surgical and endoscopic) performed at our center from 2004 to 2014 and identified 152 (3.2%) consecutive young patients. Patient demographics, clinical results, family history, and endoscopic-pathological findings were analyzed along with the older (>41 years) GC controls recruited in the same study period. Clinicopathological factors related to postresection outcomes were assessed statistically. The trend of GC resections in young patients was not changed over the study period. Compared to old GCs, the young GC cohort was predominant in women, positive family history, middle gastric location, the diffuse histology type, shorter duration of symptoms, and advanced stage (pIII+pIV, 53.3%). Radical resection was carried out in 90.1% (n = 137) with a better 5-year survival rate (70.3%) than palliative surgery (0%, n = 15). There was no significant difference in clinicopathological characteristics between familial GC (FGC, n = 38) and sporadic GC (SGC, n = 114) groups. Very young patients (≤ 30 years, n = 38) showed lower Helicobacter pylori (Hp) infection and significantly higher perineural invasion rates, compared to older (31-40 years) patients. Hp infection was more commonly seen in the Lauren's intestinal type and early pT stages (T1+T2). Independent prognostic factors for worse outcomes included higher serum CA 72-4, CA 125 levels, positive resection margin, and stage pIII-pIV tumors. The 5-year survival rate was significantly higher in patients with radical resection than those without. GCs in young Chinese patients were prevalent in women with advanced stages but showed no significant differences in clinicopathology between FGC and SGC groups. High serum CA 72-4 and CA 125 levels may help identify patients with worse outcomes. Radical resection improved postresection survival.
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Affiliation(s)
- Fan Zhou
- From the Gastroenterology Department (FZ, CF, XZ), Drum Tower Hospital Affiliated to Nanjing University Medical School; Pathology Department (JS, QH), Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu, China; and Pathology Department (QH), VA Boston Healthcare System and Harvard Medical School, Boston, MA
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Skierucha M, Milne ANA, Offerhaus GJA, Polkowski WP, Maciejewski R, Sitarz R. Molecular alterations in gastric cancer with special reference to the early-onset subtype. World J Gastroenterol 2016; 22:2460-2474. [PMID: 26937134 PMCID: PMC4768192 DOI: 10.3748/wjg.v22.i8.2460] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 11/06/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
Currently, gastric cancer (GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the pro-carcinogenic activity of important genes. These factors include genetic susceptibility expressed in a single-nucleotide polymorphism, various acquired mutations (chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances (e.g., Helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma (EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesis are modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanding features of EOGC.
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Khaleghian M, Jahanzad I, Shakoori A, Emami Razavi A, Azimi C. Association Between Amplification and Expression of C-MYC Gene and Clinicopathological Characteristics of Stomach Cancer. IRANIAN RED CRESCENT MEDICAL JOURNAL 2016; 18:e21221. [PMID: 27175302 PMCID: PMC4863201 DOI: 10.5812/ircmj.21221] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 08/04/2014] [Accepted: 08/28/2014] [Indexed: 02/07/2023]
Abstract
Background: The incidence rate of gastric cancer in western countries has shown a remarkable decline in the recent years while it is still the most common cancer among males in Iran. The proto-oncogene MYC, located at 8q24.1, regulates almost 15% of human genes and is activated in 20% of all tumors. The amplification of MYC and overexpression of its protein product are observed in 15 - 30% of gastric neoplasias. Objectives: The objective of this study was to find the preferences of Chromogenic In Situ Hybridization (CISH) and Immunohistochemistry (IHC) in diagnosis and prognosis of gastric cancer. Patients and Methods: We studied 102 samples of gastric cancer in Iran and all the patients had undergone primary surgical resection at the Cancer Institute Hospital, Tehran University of Medical Sciences. The CISH and IHC techniques were applied for all our samples. All of the samples had adenocarcinoma gastric cancer and were selected randomly. Also, the type of study was cross sectional. The sample size was 100 patients. Results: Our data revealed that both diffuse and intestinal types of gastric cancer occurred significantly more in males than females. Our results showed that there was an indication of some correlation between grades and CISH, although the difference was not significant. Our data also showed that CISH positive patients (43%) were more frequent compared to IHC positive patients (14.7%). There was a correlation between CISH and IHC. These results revealed that there was a significant difference between grades and IHC. There was also no statistical difference between CISH amplification in diffuse and intestinal types. Conclusions: From the results, it could be concluded that for administration of the treatment of stomach cancer, and progress and prognosis of tumor, which is important for patients and clinicians, the CISH is a better and more feasible test than IHC, in regards to sensitivity and specificity.
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Affiliation(s)
- Malihea Khaleghian
- Department of Medical Genetics, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Issa Jahanzad
- Department of Pathology, Immunohistochemistry Laboratory, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Abbas Shakoori
- Department of Medical Genetics, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Amirnader Emami Razavi
- Department of Pathology, Iran National Tumor Bank, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Cyrus Azimi
- Department of Medical Genetics, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, IR Iran
- Corresponding Author: Cyrus Azimi, Department of Medical Genetics, Cancer Institute of Iran, Tehran University of Medical Sciences, P. O. Box: 1419733141, Tehran, IR Iran. Tel/Fax: +98-2166945120, E-mail:
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40
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Hudler P. Challenges of deciphering gastric cancer heterogeneity. World J Gastroenterol 2015; 21:10510-10527. [PMID: 26457012 PMCID: PMC4588074 DOI: 10.3748/wjg.v21.i37.10510] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Revised: 06/19/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is in decline in most developed countries; however, it still accounts for a notable fraction of global mortality and morbidity related to cancer. High-throughput methods are rapidly changing our view and understanding of the molecular basis of gastric carcinogenesis. Today, it is widely accepted that the molecular complexity and heterogeneity, both inter- and intra-tumour, of gastric adenocarcinomas present significant obstacles in elucidating specific biomarkers for early detection of the disease. Although genome-wide sequencing and gene expression studies have revealed the intricate nature of the molecular changes that occur in tumour landscapes, the collected data and results are complex and sometimes contradictory. Several aberrant molecules have already been tested in clinical trials, although their diagnostic and prognostic utilities have not been confirmed thus far. The gold standard for the detection of sporadic gastric cancer is still the gastric endoscopy, which is considered invasive. In addition, genome-wide association studies have confirmed that genetic variations are important contributors to increased cancer risk and could participate in the initiation of malignant transformation. This hypothesis could in part explain the late onset of sporadic gastric cancers. The elaborate interplay of polymorphic low penetrance genes and lifestyle and environmental risk factors requires additional research to decipher their relative impacts on tumorigenesis. The purpose of this article is to present details of the molecular heterogeneity of sporadic gastric cancers at the DNA, RNA, and proteome levels and to discuss issues relevant to the translation of basic research data to clinically valuable tools. The focus of this work is the identification of relevant molecular changes that could be detected non-invasively.
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Ouyang H, Xu J, Zhu Z, Long T, Yu C. Rapid discrimination of malignant lesions from normal gastric tissues utilizing Raman spectroscopy system: a meta-analysis. J Cancer Res Clin Oncol 2015; 141:1835-44. [PMID: 25912559 DOI: 10.1007/s00432-015-1971-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 04/13/2015] [Indexed: 12/14/2022]
Abstract
OBJECTIVES To systematically analyze the diagnostic accuracy of Raman spectroscopy system (RAS) in the rapid diagnosis of gastric cancer with histopathology as the reference standard. METHODS We searched a wide range of electronic databases for all published researches that assessed the diagnostic accuracy of RAS to detect gastric carcinoma. Full papers were obtained for potentially eligible studies and evaluated according to predefined criteria. The Quality Assessment of Diagnostic Accuracy Studies checklist was used to assess the quality of included studies. From each study, we extracted information on diagnostic performance of RAS. After exploring heterogeneity, we adopted a random effects model to pool related effect sizes. RESULTS The initial literature search identified 257 reference articles in which 15 relevant articles with 15 data sets were selected and reviewed. The pooled sensitivity and specificity of RAS in diagnosing gastric cancer were 0.89 (95 % CI 0.84-0.92) and 0.92 (95 % CI 0.88-0.95), respectively. The positive likelihood ratio, the negative likelihood ratio, and the area under the curve were 10 (95 % CI 6.5-15.3), 0.13 (95 % CI 0.08-0.22), and 0.96 (95 % CI 0.94-0.97), respectively. All the pooled estimates, calculated by random and fixed effect models, were similar. There was no evidence of considerable publication bias. CONCLUSIONS RAS is an objective and sensitive optical diagnostic technology for detecting gastric cancer and has advantages of being noninvasive to the body, real-time diagnosis, and ease of use. Consequently, it does deserve to be recommended.
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Affiliation(s)
- Huan Ouyang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Anhui Medical University, No. 218, Jixi Road, Hefei, 230022, China,
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Noncoding Genomics in Gastric Cancer and the Gastric Precancerous Cascade: Pathogenesis and Biomarkers. DISEASE MARKERS 2015; 2015:503762. [PMID: 26379360 PMCID: PMC4563069 DOI: 10.1155/2015/503762] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2015] [Revised: 07/22/2015] [Accepted: 07/26/2015] [Indexed: 12/17/2022]
Abstract
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death, whose patterns vary among geographical regions and ethnicities. It is a multifactorial disease, and its development depends on infection by Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV), host genetic factors, and environmental factors. The heterogeneity of the disease has begun to be unraveled by a comprehensive mutational evaluation of primary tumors. The low-abundance of mutations suggests that other mechanisms participate in the evolution of the disease, such as those found through analyses of noncoding genomics. Noncoding genomics includes single nucleotide polymorphisms (SNPs), regulation of gene expression through DNA methylation of promoter sites, miRNAs, other noncoding RNAs in regulatory regions, and other topics. These processes and molecules ultimately control gene expression. Potential biomarkers are appearing from analyses of noncoding genomics. This review focuses on noncoding genomics and potential biomarkers in the context of gastric cancer and the gastric precancerous cascade.
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Khaleghian M, Jahanzad I, Shakoori A, Ardalan FA, Azimi C. Study of C-MYC amplification and expression in Iranian gastric cancer samples using CISH and IHC methods. Adv Biomed Res 2015; 4:116. [PMID: 26261818 PMCID: PMC4513308 DOI: 10.4103/2277-9175.157841] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Accepted: 09/03/2014] [Indexed: 12/13/2022] Open
Abstract
Background: Gastric cancer is the fourth most frequent malignancy and the second cause of cancer-related mortality worldwide. It has been suggested that in gastric carcinogenesis, the C-MYC gene has an important function. The objective of this study is to establish the preference of Chromogenic in situ hybridization (CISH) and Immunohistochemistry (IHC) in the diagnosis and prognosis of gastric cancer. Materials and Methods: Samples comprised of 50 randomly selected patients of whom 40 were male and 10 female. To evaluate the MYC copy number and its protein expression, CISH and IHC analyses were performed for 50 gastric adenocarcinomas, in Iran. Results: The location of the tumor in 64% of the patients was the fundus, and in 72% of patients, the tumors were of a diffuse type; 22 samples showed no amplification, and 28 samples were with amplification. MYC immunoreactivity was observed in 13 samples. Twelve samples showed both MYC amplification and MYC immunoreactivity. In addition, among the 28 CISH+ samples, 12 samples had positive signals for IHC and 16 samples had negative signals for IHC. A majority of the IHC-negative patients had no amplification, but only one patient with IHC positive had no amplification. Conclusion: Our conclusion was that for the management and treatment of gastric cancer, and for special attention of clinicians, for prognosis and tumor progression, the CISH was a better and more feasible test than IHC, in regard to the sensitivity and specificity.
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Affiliation(s)
- Malihea Khaleghian
- Department of Medical Genetics, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Issa Jahanzad
- Department of Pathology, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Shakoori
- Department of Medical Genetics, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Farid Azmoudeh Ardalan
- Department of Pathology, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Cyrus Azimi
- Department of Medical Genetics, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
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Yang X, Cai H, Liang Y, Chen L, Wang X, Si R, Qu K, Jiang Z, Ma B, Miao C, Li J, Wang B, Gao P. Inhibition of c-Myc by let-7b mimic reverses mutidrug resistance in gastric cancer cells. Oncol Rep 2015; 33:1723-30. [PMID: 25633261 DOI: 10.3892/or.2015.3757] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Accepted: 12/23/2014] [Indexed: 12/13/2022] Open
Abstract
Chemotherapy is one of the few effective choices for patients with advanced or recurrent gastric cancer (GC). However, the development of mutidrug resistance (MDR) to cancer chemotherapy is a major obstacle to the effective treatment of advanced GC. Additionally, the mechanism of MDR remains to be determined. In the present study, we tested IC50 of cisplatin (DDP), vincristine (VCR) and 5-fluorouracil (5-FU) in SGC7901, SGC7901/DDP and SGC7901/VCR gastric cancer cells using an MTT assay. The expression of let-7b and c-Myc in these cells was detected by qPCR and western blot analysis. The relationship between let-7b and c-Myc was explored using a luciferase reporter assay. Transfection of let-7b mimic or inhibitor was used to confirm the effect of let-7b on drug sensitivity in chemotherapy via the regulation of c-Myc expression. We found that the expression of let-7b was lower in chemotherapy-resistant SGC7901/DDP and SGC7901/VCR gastric cancer cells than that in chemotherapy-sensitive SGC7901 cells. By contrast, the expression of c-Myc was higher in SGC7901/DDP and SGC7901/VCR cells than that in SGC7901 cells. Furthermore, we confirmed that let-7b suppresses c-Myc gene expression at the mRNA and protein levels in a sequence-specific manner, while transfection of let-7b mimic increases drug sensitivity in chemotherapy-resistant SGC7901/DDP and SGC7901/VCR cells by targeting downregulation of c-Myc. In SGC7901 drug-sensitive cells, however, the sensitivity of chemotherapy was significantly decreased following let-7b inhibitor transfection. The present study results demonstrated that let-7b increases drug sensitivity in chemotherapy‑resistant SGC7901/DDP and SGC7901/VCR gastric cancer cells by targeting the downregulation of c-Myc and that, let-7b mimic reverses MDR by promoting cancer stem cell differentiation controlled by double-negative autoregulatory loops (Lin28/let-7 and Myc/let-7) and a double-positive autoregulatory loop (Lin28/Lin28B/Myc) existing in GC cells, which remains to be confirmed.
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Affiliation(s)
- Xiaojun Yang
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Hui Cai
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Yuhe Liang
- Department of General Surgery, the People's Hospital of Baoji City, Baoji, Shaanxi 721000, P.R. China
| | - Lin Chen
- Department of Infectious Disease, the First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Xiangdong Wang
- Department of General Surgery, the People's Hospital of Baoji City, Baoji, Shaanxi 721000, P.R. China
| | - Ruohuang Si
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Kunpeng Qu
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Zebin Jiang
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Bingqiang Ma
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Changfeng Miao
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Jing Li
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Bin Wang
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Peng Gao
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
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Moreira-Nunes CA, Barros MBL, do Nascimento Borges B, Montenegro RC, Lamarão LM, Ribeiro HF, Bona AB, Assumpção PP, Rey JA, Pinto GR, Burbano RR. Genetic screening analysis of patients with hereditary diffuse gastric cancer from northern and northeastern Brazil. Hered Cancer Clin Pract 2014; 12:18. [PMID: 25180051 PMCID: PMC4150117 DOI: 10.1186/1897-4287-12-18] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 08/08/2014] [Indexed: 12/15/2022] Open
Abstract
Background Hereditary diffuse gastric cancer (HDGC) is a hereditary autosomal inherited syndrome associated with CDH1 germline mutations. In Brazil, gastrointestinal tumors are among the most prevalent tumor types and constitute a serious public health problem, especially in the northern and northeastern regions. This study aimed to investigate germline mutations, methylation pattern and genomic rearrangements in the CDH1 gene and quantitative changes in the DNA of HDGC patients in northern and northeastern Brazil. Methods Twenty-seven DNA samples from the members of four families affected by HDGC were analyzed using array comparative genomic hybridization (aCGH), DNA sequencing and methylation pattern. Results No evidence of gain and loss events or any rearrangements were found in any of the samples tested using aCGH. No promoter region hypermethylation was observed either. Two of the four families presented different types of germline mutations. The 185G > T and 1018A > G germline mutations detected in this study have been described in Asian and European families, respectively. The ancestors of the two families carrying these mutations had originated from those continents. Conclusion This is the first study to evaluate CDH1 gene germline mutations in Brazilian families with HDGC. In our study, 50% of the families showed no CDH1 gene alterations, and it is possible that in regions with a high incidence of gastric cancer, such as northern and northeastern Brazil, environmental factors might have induced the different genetic alterations analyzed in this study.
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Affiliation(s)
| | | | | | - Raquel Carvalho Montenegro
- Biological Science Institute, Federal University of Para, Belem, PA 66075110, Brazil.,Nucleus of Research in Oncology, Federal University of Para, Belem, PA 66073000, Brazil
| | - Leticia Martins Lamarão
- Center of Hematology and Hemotherapy of Para - HEMOPA Foundation, Belem, PA 66033000, Brazil
| | | | - Amanda Braga Bona
- Biological Science Institute, Federal University of Para, Belem, PA 66075110, Brazil
| | | | - Juan Antonio Rey
- Molecular Neuro-oncogenetics Laboratory, Research Unit-Unidad de Investigación, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Giovanny Rebouças Pinto
- Genetics and Molecular Biology Laboratory, Federal University of Piaui, Parnaiba, PI 64049-550, Brazil
| | - Rommel Rodriguez Burbano
- Biological Science Institute, Federal University of Para, Belem, PA 66075110, Brazil.,Nucleus of Research in Oncology, Federal University of Para, Belem, PA 66073000, Brazil
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Helicobacter pylori infection and markers of gastric cancer risk in Alaska Native persons: a retrospective case-control study. Can J Gastroenterol Hepatol 2014; 28:305-10. [PMID: 24945184 PMCID: PMC4072235 DOI: 10.1155/2014/892084] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Alaska Native persons experience gastric cancer incidence and mortality rates that are three to four times higher than in the general United States population. OBJECTIVE To evaluate pepsinogen I, pepsinogen I/II ratio, anti-Helicobacter pylori and cytotoxin-associated gene A (CagA) antibody levels, and blood group for their associations with gastric cancer development in Alaska Native people. METHODS The present analysis was a retrospective case-control study that matched gastric cancers reported to the Alaska Native Tumor Registry from 1969 to 2008 to three controls on known demographic risk factors for H pylori infection, using sera from the Alaska Area Specimen Bank. Conditional logistic regression evaluated associations between serum markers and gastric cancer. RESULTS A total of 122 gastric cancer cases were included, with sera predating cancer diagnosis (mean = 13 years) and 346 matched controls. One hundred twelve cases (91.8%) and 285 controls (82.4%) had evidence of previous or ongoing H pylori infection as measured by anti-H pylori antibody levels. Gastric cancer cases had a 2.63-fold increased odds of having positive anti-H pylori antibodies compared with their matched controls (P=0.01). In a multivariate model, noncardia gastric cancer (n=94) was associated with anti-H pylori antibodies (adjusted OR 3.92; P=0.004) and low pepsinogen I level (adjusted OR 6.04; P=0.04). No association between gastric cancer and blood group, anti-CagA antibodies or pepsinogen I/II ratio was found. CONCLUSION Alaska Native people with gastric cancer had increased odds of previous H pylori infection. Low pepsinogen I level may function as a precancer marker for noncardia cancer.
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Identifying gastric cancer related genes using the shortest path algorithm and protein-protein interaction network. BIOMED RESEARCH INTERNATIONAL 2014; 2014:371397. [PMID: 24729971 PMCID: PMC3963223 DOI: 10.1155/2014/371397] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Accepted: 02/03/2014] [Indexed: 01/07/2023]
Abstract
Gastric cancer, as one of the leading causes of cancer related deaths worldwide, causes about 800,000 deaths per year. Up to now, the mechanism underlying this disease is still not totally uncovered. Identification of related genes of this disease is an important step which can help to understand the mechanism underlying this disease, thereby designing effective treatments. In this study, some novel gastric cancer related genes were discovered based on the knowledge of known gastric cancer related ones. These genes were searched by applying the shortest path algorithm in protein-protein interaction network. The analysis results suggest that some of them are indeed involved in the biological process of gastric cancer, which indicates that they are the actual gastric cancer related genes with high probability. It is hopeful that the findings in this study may help promote the study of this disease and the methods can provide new insights to study various diseases.
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Jácome AAA, Wohnrath DR, Scapulatempo Neto C, Carneseca EC, Serrano SV, Viana LS, Nunes JS, Martinez EZ, Santos JS. Prognostic value of epidermal growth factor receptors in gastric cancer: a survival analysis by Weibull model incorporating long-term survivors. Gastric Cancer 2014; 17:76-86. [PMID: 23455716 PMCID: PMC3889290 DOI: 10.1007/s10120-013-0236-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Accepted: 01/03/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND There is no consensus about the prognostic role of HER2 expression and that of other members of the EGFR family in gastric cancer patients. The aim of this study was to evaluate the prognostic value of the EGFR family in gastric cancer. METHODS This retrospective study included 201 patients with gastric and esophagogastric junction adenocarcinoma stages 0-IV (AJCC 6th edition) who underwent primary tumor resection. Tissues from primary tumors were analyzed by tissue microarray technology and immunohistochemistry. Correlations between receptor expression and clinicopathological characteristics were performed according to the chi-square test. Survival analysis was calculated according to the Weibull model with a mixture model incorporating long-term survivors. Multivariate analysis of prognostic factors was performed by a regression model incorporating long-term survivors with the Weibull distribution. RESULTS Membrane expression of HER1, HER2, and HER4 were 9, 17, and 15 %, respectively. No membrane expression of HER3 was observed. Cytoplasmic expression of HER1, HER3, and HER4 were 45, 62, and 24 %, respectively. HER2 and HER3 expression were correlated (p < 0.001) and associated with intestinal-type histology (p = 0.001 and p < 0.001, respectively) and advanced age (p = 0.011 and p = 0.008, respectively). According to a regression model adjusted for age, surgical radicality, surgical modality, Laurén histology, adjuvant therapy, TNM stage, and receptor expressions, only TNM stage showed prognostic influence. CONCLUSIONS According to analysis by a parametric model, the EGFR family did not have prognostic influence in the gastric cancer population studied. The data presented showed a correlation between HER2 and HER3 expression, which might suggest a potential role for HER2-HER3 heterodimerization inhibitors.
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Affiliation(s)
- Alexandre Andrade Anjos Jácome
- Department of Medical Oncology, Barretos Cancer Hospital, Str. Antenor Duarte Villela, 1331, Barretos, SP, 14784-400, Brazil,
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Marcos-Pinto R, Dinis-Ribeiro M, Carneiro F, Wen X, Lopes C, Figueiredo C, Machado JC, Ferreira RM, Reis CA, Canedo P, Durães C, Ferreira J, Pedroto I, Areias J. First-degree relatives of early-onset gastric cancer patients show a high risk for gastric cancer: phenotype and genotype profile. Virchows Arch 2013; 463:391-9. [PMID: 23887584 DOI: 10.1007/s00428-013-1458-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2012] [Revised: 07/10/2013] [Accepted: 07/12/2013] [Indexed: 02/08/2023]
Abstract
First-degree relatives (FDR) of early-onset gastric cancer (EOGC) is presumed to be a population with a distinct molecular and phenotypic profile, regarding the prevalence of gastric premalignant conditions and the association with Helicobacter pylori infection and host proinflammatory gene polymorphisms. A case-control study was conducted with FDR of EOGC patients (n = 103) and age and gender matched controls (n = 101; ranging from spouses to neighbors and dyspeptics). Upper endoscopy was performed, Operative Link on Gastritis Assessment (OLGA) system used for staging and H. pylori (cagA and vacA) and host IL1B-511, IL1RN intron2 VNTR and IFNGR1-56 genotyping. Seventy percent of cases showed atrophy, while 19 % presented with high-stage gastritis (OLGA stage III or IV) (p < 0.001); gastric dysplasia was present in seven cases (vs none in controls) (p = 0.007). In cases, H. pylori was present in 82 % (vs 62 % in controls; p = 0.004) with vacA s1 and vacA m1 + strains significantly associated with the presence of atrophy; individuals homozygous for IL1B-511*T present a significantly higher risk for dysplasia. An increased global prevalence of IFNGR1-56*T/*T polymorphism (37 % in cases vs 24 % in controls; p = 0.03) was observed with no association with atrophic changes or dysplasia. All trends observed were kept when comparing FDR of EOGC with spouses, neighbors, or dyspeptic controls. We demonstrated that FDR of EOGC patients have an increased prevalence of high-risk OLGA stages and dysplasia that seem to be associated with high virulence H. pylori strains and pro-inflammatory host genotypes, including a possible population-specific risk marker. FDR of EOGC patients may merit specific management through endoscopic and histopathological adequate assessment of gastric mucosa and surveillance.
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López-Basave HN, Morales-Vásquez F, Ruiz-Molina JM, Namendys-Silva SA, Vela-Sarmiento I, Ruan JM, Rosciano AEP, Calderillo-Ruiz G, Díaz-Romero C, Herrera-Gómez A, Meneses-García AA. Gastric cancer in young people under 30 years of age: worse prognosis, or delay in diagnosis? Cancer Manag Res 2013; 5:31-6. [PMID: 23580357 PMCID: PMC3621605 DOI: 10.2147/cmar.s40377] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background Gastric cancer is an aggressive disease with nonspecific early symptoms. Its incidence and prognosis in young patients has shown considerable variability. Purpose of the study Our objective was to retrospectively study patients from our institution aged <30 years with gastric carcinoma. The study was undertaken to describe the experience of gastric cancer in this population, and to demonstrate its specific clinical and pathological characteristics. Materials and methods We reviewed the cases of histologically confirmed gastric cancer between 1985 and 2006 at the Instituto Nacional de Cancerología of Mexico (INCan); emphasis in our review was placed on clinical presentation, diagnostic and therapeutic intervention, pathology, and the results. Results Thirty cases of gastric carcinoma were reviewed. The patients’ median age was 27 years (range, 18–30 years) and the male:female ratio was 1:1. Conclusion Gastric cancer exhibits different behavior in patients aged, 30 years, but delay in diagnosis and the tumor’s behavior appear to be the most important factors in prognosis of the disease.
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Affiliation(s)
- Horacio Noé López-Basave
- Departamento de Cirugía Oncológica, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico
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