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Jeong SA, Lee JS, Seong BO, Oh SG, Ko CS, Min SH, Gong CS, Kim BS, Yoo MW, Yook JH, Lee IS, the Information Committee of the Korean Gastric Cancer Association. Proposal of age definition for early-onset gastric cancer based on the Korean Gastric Cancer Association nationwide survey data: a retrospective observational study. Ann Surg Treat Res 2025; 108:245-255. [PMID: 40226172 PMCID: PMC11982448 DOI: 10.4174/astr.2025.108.4.245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 12/30/2024] [Accepted: 01/07/2025] [Indexed: 04/15/2025] Open
Abstract
Purpose This study aimed to define an optimal age cutoff for early-onset gastric cancer (EOGC) and compare its characteristics with those of late-onset gastric cancer (LOGC) using nationwide survey data. Methods Using data from a nationwide survey, this comprehensive population-based study analyzed data spanning 3 years (2009, 2014, and 2019). The joinpoint analysis and interrupted time series (ITS) methodology were employed to identify age cutoffs for EOGC based on the sex ratio and tumor histology. Clinicopathologic characteristics and surgical outcomes were compared between the EOGC and LOGC groups. Results The age cutoff for defining EOGC was suggested to be 50 years, supported by joinpoint and ITS analyses. Early gastric cancer was predominantly present in the EOGC and LOGC groups. Patients with EOGC comprised 20.3% of the total study cohort and demonstrated a more advanced disease stage compared to patients with LOGC. However, patients with EOGC underwent more minimally invasive surgeries, experienced shorter hospital stays, and had lower postoperative morbidity and mortality rates. Conclusion This study proposes an age of ≤50 years as a criterion for defining EOGC and highlights its features compared to LOGC. Further research using this criterion should guide tailored treatment strategies and improve outcomes for young patients with gastric cancer.
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Affiliation(s)
- Seong-A Jeong
- Division of Gastrointestinal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Department of Surgery, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea
| | - Ji Sung Lee
- Department of Clinical Epidemiology and Biostatistics, University of Ulsan College of Medicine, Seoul, Korea
| | - Ba Ool Seong
- Division of Gastrointestinal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Seul-gi Oh
- Department of Surgery, Inha University Hospital, Inha University College of Medicine, Incheon, Korea
| | - Chang Seok Ko
- Division of Gastrointestinal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sa-Hong Min
- Division of Gastrointestinal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chung Sik Gong
- Division of Gastrointestinal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Beom Su Kim
- Division of Gastrointestinal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Moon-Won Yoo
- Division of Gastrointestinal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jeong Hwan Yook
- Division of Gastrointestinal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - In-Seob Lee
- Division of Gastrointestinal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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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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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: 6] [Impact Index Per Article: 6.0] [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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Zhang S, Ren D, Hou H, Yao L, Yuan H. M-CSF secreted by gastric cancer cells exacerbates the progression of gastric cancer by increasing the expression of SHP2 in tumor-associated macrophages. Aging (Albany NY) 2023; 15:15525-15534. [PMID: 38159254 PMCID: PMC10781482 DOI: 10.18632/aging.205390] [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: 06/26/2023] [Accepted: 10/23/2023] [Indexed: 01/03/2024]
Abstract
OBJECTIVE To investigate the effect of Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2) in tumor-associated macrophages (TAMs), which is mediated by macrophage colony-stimulating factor (M-CSF) secreted by gastric cancer cells, on the development of gastric cancer and its molecular mechanism. METHODS The progression of gastric cancer was detected by nude mouse tumor-bearing experiments. Colony formation assay and cell counting kit-8 (CCK8) assay were used to detect the proliferation capacity of gastric cancer cells. The migration capacity of gastric cancer cells was examined by wound healing assay. Transwell migration and invasion assays were performed on gastric cancer cells. Detection of relevant protein expression using western blotting. RESULTS Overexpression of SHP2 could promote the progression of gastric cancer in nude mice. The results of colony formation assay and CCK8 assay showed that overexpression of SHP2 could enhance the proliferation of gastric cancer cells. It was found by wound healing assay and Transwell assay that overexpression of SHP2 could facilitate the migration and invasion of gastric cancer cells. The results of Western blotting revealed that overexpression of SHP2 could increase the expressions of p-STAT3, s-PD-1, p-Src, p-Lyn, p-PI3K, p-AKT, Arginase-1, MMP1 and MMP3 but decrease the expressions of TBK1 and SOCS1 in TAMs, and also increase the expressions of CD9, TSG101 and s-PD-1 in exosomes. CONCLUSION M-CSF secreted by gastric cancer cells can promote the proliferation, invasion and migration of gastric cancer cells by increasing the expression of SHP2 in TAMs.
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Affiliation(s)
- Shaohua Zhang
- Eighth People’s Hospital of Hebei Province, Shijiazhuang 050000, China
| | - Dongfei Ren
- Eighth People’s Hospital of Hebei Province, Shijiazhuang 050000, China
| | - Huiyu Hou
- HeBei General Hospital, Shijiazhuang 050000, China
| | - Li Yao
- Handan Central Hospital, Handan 056000, China
| | - Hufang Yuan
- The Fourth Hospital of Hebei Medical University, Shijiazhuang 050000, China
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Zhang C, Zhu D, Qu Y, Shi M, Ma J, Peng Y, Zhu B, Tao H, Ma T, Hou T. Profiling of the genetic features of Chinese patients with gastric cancer with HRD germline mutations in a large-scale retrospective study. J Med Genet 2023; 60:760-768. [PMID: 36627197 PMCID: PMC10423538 DOI: 10.1136/jmg-2022-108816] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 12/03/2022] [Indexed: 01/11/2023]
Abstract
BACKGROUND Approximately 10% of gastric cancers (GCs) are associated with strong familial clustering and can be attributed to genetic predisposition. Homologous recombination deficiency (HRD) leads to genomic instability and accumulation of genetic variations, playing an important role in the development and progression of cancer. We aimed to delineate the germline mutation characteristics of patients with HRD-mut GC in Chinese. METHODS We retrospectively reviewed the genomic sequencing data of 1135 patients with Chinese GC. Patients harbouring at least one loss of function (LoF) germline mutations in BRCA1, BRCA2, ATM, PALB2, BRIP1, CHEK1, CHEK2, FANCA and FANCL were selected for analysis. RESULTS 89 patients were identified with LoF germline mutations of HRD gene. Germline mutations occurred most commonly in ATM (30.33%), followed by BRIP1 (17.98%), BRCA2 (14.61%), BRCA1 (12.36%), FANCA (10.11%), PALB2 (10.11%), FANCL (6.74%), CHEK1 (3.37%) and CHEK2 (3.37%). 14 out of 89 patients with HRD-mut harboured double mutations in HRD and MMR genes, with the median age of 51.5 years. The decreasing median age would be attributed to five patients with HRD+MMR double-muts harbouring mutations in both HRD and MMR genes. The median age of onset of patients with HRD+MMR double-muts is 47, which is significantly earlier than that of Chinese patients with GC (p=0.0235). CONCLUSION Our data suggest that carrying both HRD and MMR gene LoF germline mutations may cause early-onset GC. Germline mutations in the HRD gene should be of concern in the study of hereditary GC.
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Affiliation(s)
- Chenghai Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital, Beijing, China
| | - Dandan Zhu
- Guangdong Center for Clinical Laboratory, Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Yurong Qu
- Department of Translational Medicine, Hangzhou Jichenjunchuang Medical Laboratory, Co., Ltd, Hangzhou, China
| | - Min Shi
- Department of Translational Medicine, Hangzhou Jichenjunchuang Medical Laboratory, Co., Ltd, Hangzhou, China
| | - Jingjiao Ma
- Department of Bioinformatics, Hangzhou Jichenjunchuang Medical Laboratory, Co., Ltd, Hangzhou, China
| | - Yebo Peng
- Department of Bioinformatics, Hangzhou Jichenjunchuang Medical Laboratory, Co., Ltd, Hangzhou, China
| | - Bowen Zhu
- Department of Translational Medicine, Hangzhou Jichenjunchuang Medical Laboratory, Co., Ltd, Hangzhou, China
| | - Houquan Tao
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China
| | - Tonghui Ma
- Department of Translational Medicine, Hangzhou Jichenjunchuang Medical Laboratory, Co., Ltd, Hangzhou, China
| | - TieYing Hou
- Guangdong Center for Clinical Laboratory, Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
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Lumish MA, Cercek A. Practical Considerations in Diagnosing and Managing Early-Onset GI Cancers. J Clin Oncol 2022; 40:2662-2680. [PMID: 35839438 PMCID: PMC9390825 DOI: 10.1200/jco.21.02708] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 03/12/2022] [Accepted: 04/18/2022] [Indexed: 12/24/2022] Open
Abstract
The incidence of early-onset (EO) GI cancers occurring in individuals younger than age 50 years has been rising at an alarming rate over the past two decades. Although this rise in incidence among young patients correlates with increased rates of obesity, changes in diet, and alterations in the environment, the effects of these environmental factors on carcinogenesis, metastasis, and treatment response are unknown. Although several unique clinical trends exist among EO-GI cancers and their average-onset GI cancer counterparts, GI cancers are molecularly indistinct between younger and older patients, and no data support distinct treatment paradigms for patients with EO disease. The majority of EO-GI cancers are not explained by germline changes. There remains a critical need for further research to understand the pathogenesis and optimal management of EO-GI cancers. In addition, current screening strategies are not adequate to identify EO-GI cancers, and early biomarkers are needed. Specialized centers, with a focus on psychosocial aspects of cancer management, can address the unique care needs of patients with EO-GI cancers.
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Affiliation(s)
- Melissa A. Lumish
- Memorial Sloan Kettering Cancer Center, Department of Medicine, New York, NY
| | - Andrea Cercek
- Memorial Sloan Kettering Cancer Center, Department of Medicine, New York, NY
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7
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Chen YR, Wang MQ, Li YT, Li P, Ouyang SS, Xu HW, Zhu SL. Prognostic performance of different lymph node classification systems in young gastric cancer. J Gastrointest Oncol 2021; 12:1285-1300. [PMID: 34532088 DOI: 10.21037/jgo-21-185] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 06/30/2021] [Indexed: 12/23/2022] Open
Abstract
Background Accurate staging plays a pivotal role in cancer care. The lymph node (LN) ratio (LNR) and the log odds of positive LNs (LODDS) have been suggested as alternatives to the N staging since the TNM system has the risk of stage migration. The prognostic significance of LNR and LODDS in young patients with gastric cancer (GC) has not been reported. This study aims to investigate the correlations between LNR and LODDS and survival of young patients with GC, and compare the predictive performance of these LN staging methods. Methods GC patients before the age of 40 from 2004 to 2016 in the Surveillance, Epidemiology and End Results database were enrolled. The prognostic evaluation of the N factor, LNR and LODDS was compared using the time-dependent receiver operating characteristic (ROC) analysis, area under the curve (AUC), C-index and Akaike information criterion (AIC). Results Multivariate survival analysis identified that the LNR and LODDS were significantly independent prognostic indicators for overall survival (OS) in young patients with GC and in the subgroups comprised of patients with ≤15 LNs examined. The time-dependent ROC curves of the LNR and LODDS were continuously superior to that of the N factor in predicting OS during the observation period. And the AUCs revealed that the predictive accuracy of the LNR and LODDS was remarkably superior to the N factor at 1 and 3 years (P<0.05). The model incorporating LNR or LODDS had higher C-index and lower AIC when comparing to the model incorporating the N factor. Conclusions The LNR and LODDS improve accuracy of survival risk prediction in young patients with GC when comparing to the N factor. These two novel LN classification methods should be considered as alternatives to the N staging for the prognostic prediction of young patients with GC.
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Affiliation(s)
- Yi-Ru Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Mei-Qian Wang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yi-Ting Li
- Department of General Practice, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ping Li
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Su-Shan Ouyang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hui-Wen Xu
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Sen-Lin Zhu
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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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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Puhr HC, Karner A, Taghizadeh H, Jomrich G, Schoppmann SF, Preusser M, Ilhan-Mutlu A. Clinical characteristics and comparison of the outcome in young versus older patients with upper gastrointestinal carcinoma. J Cancer Res Clin Oncol 2020; 146:3313-3322. [PMID: 32617700 PMCID: PMC7679328 DOI: 10.1007/s00432-020-03302-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 06/24/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND The clinical behaviour and outcome of young patients with gastroesophageal tumours (GET) is surmised to differ from older patients, yet data on the comparison of these two patient subgroups is scarce. This study focuses on the investigation of the clinical characteristics and survival outcome of younger-age people with GET, when compared to older patients. METHODS Patients diagnosed with GET at the Medical University of Vienna between 2004 and 2016 were included in this study. Clinical parameters and the overall survival (OS) were compared between young (≤ 45 years) and elderly (≥ 65 years) patients. RESULTS Among 796 patients, who were eligible for this analysis, fifty-eight patients (7%) were ≤ 45 years at the initial onset of the disease. These 58 young patients were then matched to elderly patients based on the gender, tumour stage, histology and tumour location. The number of metastatic lesions was significantly higher among young patients (p < 0.05). In a non-metastatic setting younger patients showed a significant longer OS than older patients (median 1226 versus 801 days, p = 0.028). Furthermore, young patients with extensive metastatic disease (2 or more metastatic site) had a significantly poorer OS than elderly patients (median 450 versus 646 days, p = 0.033). CONCLUSION These results indicate that young patients might be diagnosed very late, which might lead to the development of a more aggressive disease compared to older patients, but a relatively long OS when diagnosed and treated in a non-metastatic setting. Thus, screening methods for younger patients might be considerable to enhance the outcome of young patients with GET.
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Affiliation(s)
- Hannah Christina Puhr
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Upper-GI Tumours Unit, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna, Austria
| | - Alexander Karner
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Upper-GI Tumours Unit, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna, Austria
| | - Hossein Taghizadeh
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Upper-GI Tumours Unit, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna, Austria
| | - Gerd Jomrich
- Department of Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Upper-GI Tumours Unit, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna, Austria
| | - Sebastian Friedrich Schoppmann
- Department of Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Upper-GI Tumours Unit, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna, Austria
| | - Matthias Preusser
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Upper-GI Tumours Unit, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna, Austria
| | - Aysegül Ilhan-Mutlu
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. .,Upper-GI Tumours Unit, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna, Austria.
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10
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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: 820] [Impact Index Per Article: 164.0] [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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11
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Kayamba V, Butt J, Waterboer T, Besa E, Choudhry N, Hamasuku A, Julius P, Heimburger DC, Atadzhanov M, Kelly P. Molecular profiling of gastric cancer in a population with high HIV prevalence reveals a shift to MLH1 loss but not the EBV subtype. Cancer Med 2020; 9:3445-3454. [PMID: 32207245 PMCID: PMC7221426 DOI: 10.1002/cam4.3001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 02/19/2020] [Accepted: 03/01/2020] [Indexed: 12/29/2022] Open
Abstract
The human immunodeficiency virus (HIV) pandemic heavily affects sub-Saharan Africa. It is associated with persistently active Epstein-Barr virus (EBV) infection. To determine if this translates into increased frequency of EBV-associated gastric cancer (EBVaGC), we evaluated molecular profiles of gastric cancer (GC) in Zambia. Patients with GC or premalignant gastric lesions were enrolled in Lusaka, Zambia. We used patients without any of these lesions as a control group. Chromogenic in situ hybridization (CISH) on tumor tissue was used to identify EBVaGC. To identify the microsatellite unstable subtype, immunofluorescence staining for MutL homolog 1 (MLH1) was used. Exposure to EBV and HIV was assessed serologically. We enrolled 369 patients (median age 52 years [IQR 41-65]; 198 (54%) female). Of these, 72 (20%) had GC and 35 (9%) had gastric premalignant lesions (PL). CISH identified EBVaGC in 5/44 (11%) of those with adequate tissue, while MLH1 loss was identified in 29/45 (64%). Both GC and PL were associated with the highest titers of antibodies to Early antigen-diffuse (OR 2.5, 95% CI 1.0-6.1, P = .048 and OR 3.9, 95% CI 1.1-12.9, P = .03, respectively) at high concentrations. Human immunodeficiency virus infection was associated with a range of antibodies to EBV, but not with any cancer subtype. Despite the association of HIV with persistent EBV, the proportion of EBVaGC in Zambia is similar to populations with a low prevalence of HIV infection. The proportion of microsatellite unstable tumors may be higher than other populations.
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Affiliation(s)
- Violet Kayamba
- Tropical Gastroenterology & Nutrition GroupDepartment of Internal MedicineLusakaZambia
- University of Zambia School of MedicineLusakaZambia
| | - Julia Butt
- Cancer Control and Population Sciences ProgramDuke Cancer InstituteDuke UniversityDurhamNCUSA
- Department of Population Health SciencesDuke UniversityDurhamNCUSA
- Infection and Cancer Epidemiology GroupGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Tim Waterboer
- Infection and Cancer Epidemiology GroupGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Ellen Besa
- Tropical Gastroenterology & Nutrition GroupDepartment of Internal MedicineLusakaZambia
| | - Naheed Choudhry
- Blizard InstituteBarts & The London School of Medicine and DentistryQueen Mary University of LondonLondonUK
| | | | - Peter Julius
- University of Zambia School of MedicineLusakaZambia
| | - Douglas C. Heimburger
- Vanderbilt Institute for Global Health and Department of MedicineVanderbilt University Medical CenterNashvilleTNUSA
| | | | - Paul Kelly
- Tropical Gastroenterology & Nutrition GroupDepartment of Internal MedicineLusakaZambia
- University of Zambia School of MedicineLusakaZambia
- Blizard InstituteBarts & The London School of Medicine and DentistryQueen Mary University of LondonLondonUK
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12
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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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13
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Gupta MK, Rajeswari J, Reddy PR, Kumar KS, Chamundeswaramma KV, Vadde R. Genetic Marker Identification for the Detection of Early-Onset Gastric Cancer Through Genome-Wide Association Studies. RECENT ADVANCEMENTS IN BIOMARKERS AND EARLY DETECTION OF GASTROINTESTINAL CANCERS 2020:191-211. [DOI: https:/doi.org/10.1007/978-981-15-4431-6_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/06/2023]
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14
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Gupta MK, Rajeswari J, Reddy PR, Kumar KS, Chamundeswaramma KV, Vadde R. Genetic Marker Identification for the Detection of Early-Onset Gastric Cancer Through Genome-Wide Association Studies. RECENT ADVANCEMENTS IN BIOMARKERS AND EARLY DETECTION OF GASTROINTESTINAL CANCERS 2020:191-211. [DOI: 10.1007/978-981-15-4431-6_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/06/2023]
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15
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Ge Y, Wu Q, Ma G, Shao W, Liu H, Zhang Q, Xin J, Xue Y, Du M, Zhao Q, Wang M, Chu H, Zhang Z. Hypermethylation of EIF4E promoter is associated with early onset of gastric cancer. Carcinogenesis 2018; 39:66-71. [PMID: 29342273 DOI: 10.1093/carcin/bgx110] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 09/29/2017] [Indexed: 12/14/2022] Open
Abstract
Although gastric cancer (GC) in young adults (≤ 45 years) accounts for fewer than 10% of newly diagnosed cases, the young patients are more likely to have advanced disease at presentation compared with elderly patients. Previous studies have identified that the DNA methylation of genomes are different during aging. Our study aimed to explore the association between DNA methylation and the onset of GC. We applied Illumina HumanMethylation450 BeadChip to examine methylation expression profiles and compared methylation expression patterns in five early onset GC patients and seven elderly patients. Additionally, we evaluated the associations of methylation expression with different clinicopathological characteristics of GC. Our results showed that the pattern of genome-wide methylation expression was significantly different between early onset and elderly GC. The top 10 hypomethylation and hypermethylation CpG sites were selected for further analyses in The Cancer Genome Atlas (TCGA) database. We found that the hypermethylation of cg11037477, located at the promoter of EIF4E, was significantly associated with age at diagnosis and the expression of EIF4E. Besides, GC patients with high level of cg11037477 were more likely to have advance disease with T3/T4 invasion and III/IV stage. The cg11037477 hypermethylation and EIF4E down-expression were significantly related to poor survival of GC patients. Our study provides new insights into the molecular mechanism of early onset patients with GC and suggests that methylation of cg11037477 and expression of EIF4E may act as prognostic markers in GC.
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Affiliation(s)
- Yuqiu Ge
- Department of Environmental Genomics, Jiangsu Key Laboratory 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
| | - Qin Wu
- Department of Medical Technology, Yancheng Insititute of Health Sciences, Yancheng, China
| | - Gaoxiang Ma
- Department of Environmental Genomics, Jiangsu Key Laboratory 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
| | - Wei Shao
- Department of Environmental Genomics, Jiangsu Key Laboratory 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
| | - Hanting Liu
- Department of Environmental Genomics, Jiangsu Key Laboratory 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
| | - Qiang Zhang
- Department of Environmental Genomics, Jiangsu Key Laboratory 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 Laboratory 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
| | - Yao Xue
- Department of Hematology and oncology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Mulong Du
- Department of Environmental Genomics, Jiangsu Key Laboratory 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
| | - Qinghong Zhao
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Meilin Wang
- Department of Environmental Genomics, Jiangsu Key Laboratory 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 Laboratory 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
| | - Zhengdong Zhang
- Department of Environmental Genomics, Jiangsu Key Laboratory 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
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16
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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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17
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Clinicopathologic Characteristics of Microsatellite Instable Gastric Carcinomas Revisited: Urgent Need for Standardization. Appl Immunohistochem Mol Morphol 2017; 25:12-24. [PMID: 26371427 PMCID: PMC5147042 DOI: 10.1097/pai.0000000000000264] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Microsatellite instable gastric cancer (MSI-GC) is a specific molecular subtype of GC. We studied the phenotypes, genotypes, and clinicopathologic characteristics of MSI-GC in a white GC cohort and compared our findings with an extended literature review. The study cohort consisted of 482 patients. Specimens were available from 452 cases and were used for immunostaining (MLH1, PMS2, MSH2, MSH6) and molecular biological analyses (BAT-25, BAT-26, NR-21, NR-24, NR-27; Epstein-Barr virus in situ hybridization). Thirty-four (7.5%) GCs were MSI. Loss of MLH1 and/or PMS2 was found in 30 (88%) MSI-GC, 3 (9%) showed loss of MSH2 and/or MSH6. One (3%) MSI-GC was identified only by molecular biological testing. A single case was heterogeneous and contained microsatellite-stable and instable tumor areas. Twenty-one (62%) MSI-GCs showed unusual histologic features. MSI-GC was not found in diffuse-type or Epstein-Barr virus-positive GC. MSI-GC was significantly more prevalent in elderly patients, distal stomach, and was associated with a significantly lower number of lymph node metastases and a significantly better overall and tumor-specific survival. MSI-GC constitutes a small but relevant subgroup of GC with distinct clinicopathologic characteristics. Our literature review illustrates the shortcomings of missing standardized testing algorithms with prevalences of MSI-GC ranging from 0% to 44.5%. Future studies should test the hypothesis that patients with MSI-GCs may not need adjuvant/perioperative chemotherapy. However, this will require a standardized, quality-controlled diagnostic algorithm of MSI for GC.
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18
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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: 98] [Impact Index Per Article: 12.3] [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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19
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Geramizadeh B, Adeli OA, Rahsaz M, Mokhtari M, Sefidbakht S. Comparison of the Expression of Cell Adhesion Molecule Markers (E-Cadherin and Syndecan-1) between Young and Older Age Patients with Gastric Carcinoma. J Gastrointest Cancer 2016; 41:193-6. [PMID: 20393887 DOI: 10.1007/s12029-010-9149-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
AIM The aim of this study was to evaluate the relationship between age and cell adhesion molecule markers (E-cadherin and syndecan-1). MATERIALS AND METHODS Forty-three cases of gastric carcinoma below the age of 50 were referred to our center in the period of 5 years (2003–2008). Forty-three gastric carcinoma above the age of 50 years were sex-matched with the first group. Expression of syndecan-1 and E-cadherin were evaluated by immunohistochemistry in a total of 86 gastric carcinomas accompanying with all the clinicopathological findings in each case. RESULTS The expression of syndecan-1 and E-cadherin did not show significant difference between two age groups; in addition, there were no significant differences in all the clinicopathological findings in these two age groups. DISCUSSION Gastric carcinoma in young and old age adults showed no significant difference in respect of the expression of cell adhesion molecule markers. Our result shows that young age alone cannot be predictive of more metastasis and invasion potential.
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Affiliation(s)
- Bita Geramizadeh
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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20
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Lee J, Lee MA, Kim IH, Roh SY. Clinical characteristics of young-age onset gastric cancer in Korea. BMC Gastroenterol 2016; 16:110. [PMID: 27600152 PMCID: PMC5011834 DOI: 10.1186/s12876-016-0528-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 08/23/2016] [Indexed: 12/23/2022] Open
Abstract
Background Gastric cancer is the fourth most common cancer worldwide and more frequently detected in Asian countries including Korea and Japan. The incidence of young-age gastric cancer (GC) is increasing worldwide, but clinical behavior of young-age GC patients is not well established. We retrospectively analyzed the clinical features and outcomes of GC diagnosed at young-age population. Methods Between Jan. 2009 to Jan. 2015, 163 patients diagnosed as early, advanced, recurrent, or metastatic GC at ages between 22 ~ 39 years were analyzed. Based on medical records, authors analyzed the clinicopathologic characteristics and survival outcomes including overall survival (OS), disease free survival (DFS), and progression free survival (PFS). Results One-hundred and four patients (82.8 %) were diagnosed as GC at their thirties; especially 81 patients (31.2 %) patients were diagnosed over 35 years of age. The ratio of early GC and advanced GC were relatively similar (47.2 % vs. 52.8 %, respectively). Among stage II and III patients, 45 patients received 5-FU based adjuvant chemotherapy and recurrence rate was 48.9 %. Among patients diagnosed as recurrent or metastatic GC, recurrent GC patients showed relatively superior PFS and OS after cancer recurrence, compared to metastatic GC patients, but without statistical significance. Among metastatic GC patients, patients receiving palliative debulking surgery for ovary metastases showed superior PFS compared to patients who only received palliative systemic chemotherapy (P = 0.021, PFS 7.7 vs. 3.37 months, respectively). Conclusions Young age GC were commonly diagnosed at their thirties, without sexual predominance. The incidence of advanced GC in young age patients were higher compared to general patient population. Among recurrent GC patients, palliative debulking surgery might have role for superior survival outcomes. Considering relatively higher incidence for advanced GC, active surveillance for gastric cancer is warranted.
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Affiliation(s)
- Jieun Lee
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea
| | - Myung Ah Lee
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea.,Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - In-Ho Kim
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea
| | - Sang-Young Roh
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea.
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21
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Park CH, Kim EH, Chung H, Park JC, Shin SK, Lee YC, An JY, Kim HI, Cheong JH, Hyung WJ, Noh SH, Kim CB, Lee SK. Periodic Endoscopies Might Not Increase the Detection of Early Gastric Cancer in a Young Population. PLoS One 2016; 11:e0159759. [PMID: 27448311 PMCID: PMC4957784 DOI: 10.1371/journal.pone.0159759] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 07/07/2016] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Screening endoscopies in individuals 40 years or older in regions where gastric cancer is prevalent increase the diagnosis of gastric cancer at an early stage. However, the benefits of screening endoscopies in a young population (<40 years) have not been evaluated. METHODS We reviewed data from patients less than 40 years old who underwent endoscopic submucosal dissection or surgery for initial-onset gastric cancer. We also administered a questionnaire to gather information concerning periodic endoscopic inspections and the period from the penultimate endoscopy to diagnosis. RESULTS Of the 564 patients in this study, 101 (17.9%) patients underwent screening endoscopy within 24 months of their gastric cancer diagnosis. Lesion size was significantly smaller in the ≤24 months group than in the >24 month group (23.8 mm [standard deviation, 22.2 mm] vs. 30.5 mm [standard deviation, 23.1 mm], P = 0.008). However, the proportion of patients with early gastric cancer did not differ between the two groups (≤24 months vs. >24 months group; 67.6% vs. 65.7%, P = 0.712). On multivariable analysis, periodic endoscopies did not influence the early diagnosis of gastric cancer (with >24 months as the reference group: ≤24 months, odds ratio = 0.939, 95% confidence interval = 0.583-1.513). CONCLUSION Although periodic endoscopies aided in the detection of gastric cancer when lesions were smaller in size, they seemed not to increase the proportion of patients with early gastric cancer in young patients diagnosed with resectable gastric cancer.
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Affiliation(s)
- Chan Hyuk Park
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Eun Hye Kim
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Hyunsoo Chung
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Jun Chul Park
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Kwan Shin
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Yong Chan Lee
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Ji Yeong An
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hyoung-Il Kim
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jae-Ho Cheong
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Woo Jin Hyung
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Hoon Noh
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Choong Bae Kim
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Kil Lee
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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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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Bautista MC, Jiang SF, Armstrong MA, Postlethwaite D, Li D. Impact of age on clinicopathological features and survival of patients with noncardia gastric adenocarcinoma. J Gastric Cancer 2014; 14:238-45. [PMID: 25580355 PMCID: PMC4286902 DOI: 10.5230/jgc.2014.14.4.238] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 10/12/2014] [Accepted: 10/16/2014] [Indexed: 12/12/2022] Open
Abstract
Purpose Gastric cancer often occurs in the elderly but is uncommon in young individuals. Whether young patients have different clinical behaviors and outcomes from those of older patients remain unclear. Materials and Methods We identified 1,366 cases of newly diagnosed noncardia gastric adenocarcinoma from the Kaiser Permanente Northern California Cancer Registry between 2000 and 2010. We then compared the clinicopathological features and survival among the different age groups. Results The male : female ratio differed significantly between the younger and older patient groups (0.84 in age <50 years vs. 1.52>60 years, P<0.01). More younger patients were Hispanic (54% patients <40 years vs. 19% patients ≥70 years, P<0.0001), while more older patients were Caucasian (49% patients ≥70 years vs. 15% patients <40 years; P<0.0001). The diffuse/mixed histological type was more prevalent in younger patients (70% patients <40 years vs. 27% patients ≥70 years; P<0.0001), whereas the intestinal type was more frequent in older patients (71% in patients ≥70 years vs. 30% in patients <40 years; P<0.0001). Poorly differentiated adenocarcinoma was more common in the younger patients (80% in patients <40 years vs. 60% in patients ≥70 years; P=0.016). Survival rates at 1, 2, and 5 years gradually declined with increasing age (overall P=0.0002). Conclusions Young patients with gastric cancer had more aggressive disease but higher overall survival rates than older patients. Younger Hispanic patients and older Caucasian patients were more likely to be diagnosed with gastric cancer. These differences may be due to biological predisposition and/or environmental exposure.
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Affiliation(s)
- Marita C Bautista
- Department of Gastroenterology, Kaiser Permanente Northern California, Santa Clara, CA, USA
| | - Sheng-Fang Jiang
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Mary Anne Armstrong
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | | | - Dan Li
- Department of Gastroenterology, Kaiser Permanente Northern California, Santa Clara, CA, USA
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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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Luis M, Tavares A, Carvalho LS, Lara-Santos L, Araújo A, Mello RAD. Personalizing therapies for gastric cancer: molecular mechanisms and novel targeted therapies. World J Gastroenterol 2013; 19:6383-6397. [PMID: 24151357 PMCID: PMC3801309 DOI: 10.3748/wjg.v19.i38.6383] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 07/24/2013] [Accepted: 08/05/2013] [Indexed: 02/06/2023] Open
Abstract
Globally, gastric cancer is the 4(th) most frequently diagnosed cancer and the 2(nd) leading cause of death from cancer, with an estimated 990000 new cases and 738000 deaths registered in 2008. In the advanced setting, standard chemotherapies protocols acquired an important role since last decades in prolong survival. Moreover, recent advances in molecular therapies provided a new interesting weapon to treat advanced gastric cancer through anti-human epidermal growth factor receptor 2 (HER2) therapies. Trastuzumab, an anti-HER2 monoclonal antibody, was the first target drug in the metastatic setting that showed benefit in overall survival when in association with platinum-5-fluorouracil based chemotherapy. Further, HER2 overexpression analysis acquired a main role in predict response for trastuzumab in this field. Thus, we conducted a review that will discuss the main points concerning trastuzumab and HER2 in gastric cancer, providing a comprehensive overview of molecular mechanisms and novel trials involved.
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Leal MF, Calcagno DQ, Demachki S, Assumpção PP, Chammas R, Burbano RR, Smith MDAC. Clinical implication of 14-3-3 epsilon expression in gastric cancer. World J Gastroenterol 2012; 18:1531-7. [PMID: 22509086 PMCID: PMC3319950 DOI: 10.3748/wjg.v18.i13.1531] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2011] [Revised: 12/23/2011] [Accepted: 12/31/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate for the first time the protein and mRNA expression of 14-3-3ε in gastric carcinogenesis.
METHODS: 14-3-3ε protein expression was determined by western blotting, and mRNA expression was examined by real-time quantitative RT-PCR in gastric tumors and their matched non-neoplastic gastric tissue samples.
RESULTS: Authors observed a significant reduction of 14-3-3ε protein expression in gastric cancer (GC) samples compared to their matched non-neoplastic tissue. Reduced levels of 14-3-3ε were also associated with diffuse-type GC and early-onset of this pathology. Our data suggest that reduced 14-3-3ε may have a role in gastric carcinogenesis process.
CONCLUSION: Our results reveal that the reduced 14-3-3ε expression in GC and investigation of 14-3-3ε interaction partners may help to elucidate the carcinogenesis process.
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Dittmar Y, Rauchfuss F, Götz M, Scheuerlein H, Jandt K, Settmacher U. Impact of clinical and pathohistological characteristics on the incidence of recurrence and survival in elderly patients with gastric cancer. World J Surg 2012; 36:338-345. [PMID: 22205105 DOI: 10.1007/s00268-011-1395-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Gastric cancer is one of the most frequent malignant tumors worldwide. Despite improvements in diagnostic procedures, as well as the introduction of multimodal treatment strategies, the overall prognosis remains poor. The role of gastric resection in elderly patients with gastric cancer has not been clearly defined as yet. The goal of the present study was to assess whether specific pathohistological features result in different outcomes for younger patients and elderly patients. METHODS A total of 272 patients with advanced gastric cancer treated surgically in our hospital between 1998 and 2009 were included in the study. Data were analyzed from a prospectively maintained database. RESULTS Median overall survival was 84 months in the younger subgroup and 37 months in the elderly subgroup (P = 0.038), whereas local recurrence occurred more frequently in younger patients (33% vs. 23%). We identified positive lymph nodes at the contralateral curvature, perilymphonodular tumor cells, and positive lymph node conglomerates as strong negative prognostic factors. There were few pathohistological characteristics that affected survival and the incidence of tumor recurrence differently in elderly and younger patients. Although only a few elderly patients underwent chemotherapy plus gastric resection (7% vs. 28% of the younger patients), there was a trend toward longer survival for those who received multimodal treatment. CONCLUSIONS Our results suggest that there is no tumor-related prognostic difference between young and elderly patients that would preclude radical surgery in elderly patients, as long as they are generally fit for surgery.
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Affiliation(s)
- Yves Dittmar
- Department of General, Visceral and Vascular Surgery, University of Jena, Erlanger Allee 101, 07740, Jena, Germany.
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Yonezawa S, Kitajima S, Higashi M, Osako M, Horinouchi M, Yokoyama S, Kitamoto S, Yamada N, Tamura Y, Shimizu T, Tabata M, Goto M. A novel anti-MUC1 antibody against the MUC1 cytoplasmic tail domain: use in sensitive identification of poorly differentiated cells in adenocarcinoma of the stomach. Gastric Cancer 2012; 15:370-81. [PMID: 22237656 PMCID: PMC3477479 DOI: 10.1007/s10120-011-0125-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2011] [Accepted: 11/26/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND Isolated cancer cells of non-solid type poorly differentiated adenocarcinoma (por2) or signet-ring cell carcinoma (sig) are frequently seen in scirrhous gastric cancers with a very poor prognosis. These cells are often scattered in granulation tissue or desmoplastic fibrotic tissue and tend to be overlooked in routine pathological examination. We aimed to raise a novel antibody that can identify the isolated cancer cells easily. METHODS Because the MUC1 cytoplasmic tail domain (CTD) has many biological roles including tumor progression and cell adhesion disturbance and is expected to be expressed in isolated cancer cells, we raised a novel monoclonal antibody (MAb) MUC1-014E against an intracellular nonrepeating 19-amino-acid sequence (RYVPPSSTDRSPYEKVSAG: N-1217-1235-C) of the MUC1 CTD, using a synthetic peptide including the 7-amino-acid epitope (STDRSPY: N-1223-1229-C). RESULTS In the immunohistochemical staining of 107 gastrectomy specimens including 48 por2 and 31 sig lesions, the MAb MUC1-014E showed high rates of positive staining (≥5% of carcinoma cells stained) for por2 (100%) and sig (97%), and of the highest intensity staining (4+, ≥75% of carcinoma cells stained) for por2 (100%) and sig (90%). In the 89 biopsy specimens including 82 por2 and 38 sig lesions, the MAb MUC1-014E showed high rates of positive staining for por2 (100%) and sig (100%) and of 4+ staining for por2 (87%) and sig (84%). All the rates were significantly higher than those with cytokeratins (AE1/AE3 or CAM5.2). CONCLUSIONS The MAb MUC1-014E is very useful for accurate detection of isolated cancer cells in scirrhous gastric cancers.
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Affiliation(s)
- Suguru Yonezawa
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
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Choi JY, Shim KN, Roh SH, Tae CH, Kim SE, Jung HK, Kim TH, Jung SA, Yoo K, Moon IW. [Clinicopathological characteristics of gastric cancer and survival improvement by surgical treatment in the elderly]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2011; 58:9-19. [PMID: 21778798 DOI: 10.4166/kjg.2011.58.1.9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
BACKGROUND/AIMS It has been known that elderly patients with gastric cancer show worse general condition and higher comorbidities. Therefore, few elderly patients undergo surgery. This study was designed to determine clinicopathological characteristics of gastric cancer in elderly patients and evaluate their survival improvements by the surgical treatment. METHODS Gastric cancer patients, diagnosed at Ewha Womans University Mokdong Hospital between 2000 to 2004, were divided into two groups those aged ≥65 years vs. <65 years. Clinicopathological characteristics, incidence of postoperative complications, and survival time of patients in each group were analyzed. RESULTS Total 370 patients were subjected and divided into the elderly and the younger group (55.4% vs. 44.6%). The elderly group showed higher incidences of hypertension and cardiovascular disease. Well differentiated adenocarcinoma was more frequently found in the elderly group (19.0% vs. 10.0%, p=0.025). There were no differences of operation time (242.6±70.7 vs. 257.3±83.8 min, p=0.115), postoperative hospital stays (15.8±10.6 vs. 14.7±9.8 days, p=0.361), and incidence of any complications (6.7% vs. 9.9%, p=0.309) between the two subgroups. The significant factors related with the elderly patient's survival were the tumor-node-metastasis (TNM) stage (stage I, hazard ratio [HR] 1.00; stage II, HR 1.28, 95% confidence interval [CI] 0.44-3.72; stage III, HR 4.06, 95% CI 2.08-7.92, stage IV, HR 9.78, 95% CI 4.97-19.26; p<0.001) and the treatment modality (laparoscopy, HR 1.00; open surgery, HR 3.90, 95% CI 2.43-6.26; p<0.001). The elderly patients who underwent gastric cancer surgery showed prolonged survival on TNM stage I, II, and III than those who were treated conservatively. CONCLUSIONS In the elderly patients with gastric cancer, those who had received surgical treatments showed significantly higher survival rate than those who had treated conservatively. Therefore, aggressive surgical treatments should be seriously considered even for the elderly patients with gastric cancer.
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Affiliation(s)
- Ju Young Choi
- Department of Internal Medicine, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
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Moelans CB, Milne AN, Morsink FH, Offerhaus GJA, van Diest PJ. Low frequency of HER2 amplification and overexpression in early onset gastric cancer. Cell Oncol (Dordr) 2011; 34:89-95. [PMID: 21394646 PMCID: PMC3063579 DOI: 10.1007/s13402-011-0021-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2011] [Indexed: 12/14/2022] Open
Abstract
Background The recent ToGA trial results indicated that trastuzumab is a new, effective, and well-tolerated treatment for HER2-positive gastric cancer (GC). Although GC mainly affects older patients, fewer than 10% of GC patients are considered early-onset (EOGC) (presenting at the age of 45 years or younger). These EOGC show different clinicopathological and molecular profiles compared to late onset GC suggesting that they represent a separate entity within gastric carcinogenesis. In light of potential trastuzumab benefit, subpopulations of GC such as EOGC (versus late onset) should be evaluated for their frequency of amplification and overexpression using currently available techniques. Methods Tissue microarray (TMA) blocks of 108 early onset GC and 91 late onset GC were stained by immunohistochemistry (IHC, Hercep test, DAKO) and chromogenic in situ hybridization (CISH, SPoT-Light, Invitrogen). Results Overall, we found only 5% HER2 high level amplification and 3% HER2 3+ overexpression (6/199). In addition, 8 patients (4%) showed a low level CISH amplification and 9 patients (4.5%) showed a 2+ IHC score. IHC and CISH showed 92% concordance and CISH showed less heterogeneity than IHC. In 2/199 cases (1%), IHC showed clinically relevant heterogeneity between TMA cores, but all cases with focal IHC 3+ expression were uniformly CISH high level amplified. Early onset GCs showed a significantly lower frequency of HER2 amplification (2%) and overexpression (0%) than late onset GCs (8% and 7% respectively) (p = 0.085 and p = 0.008 respectively). Proximal GC had more HER2 amplification (9% versus 3%) and overexpression (7% versus 2%) than distal tumours although this difference was not significant (p = 0.181 and p = 0.182 respectively). HER2 CISH showed more high level amplification in the intestinal type (7%, 16% if low-level included) compared to the mixed (5%, 5% if low-level included) and diffuse type (3%, 4% if low-level included) GCs (p = 0.029). A similar association was seen for HER2 IHC and histologic type (p = 0.008). Logistic regression indicated a significant association between HER2 expression and age, which remained significant when adjusted for both location and histological type. Conclusions Even focal HER2 overexpression in GC points to uniform HER2 amplification by CISH. We show for the first time that early onset GC has a lower frequency of HER2 amplification and overexpression than late onset GC, and confirm that intestinal type GC shows the highest rate of HER2 amplification and overexpression.
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Affiliation(s)
- Cathy B Moelans
- Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, 3508GA, Utrecht, The Netherlands.
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Moelans CB, van Diest PJ, Milne ANA, Offerhaus GJA. Her-2/neu testing and therapy in gastroesophageal adenocarcinoma. PATHOLOGY RESEARCH INTERNATIONAL 2010; 2011:674182. [PMID: 21188213 PMCID: PMC3005843 DOI: 10.4061/2011/674182] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2010] [Accepted: 10/25/2010] [Indexed: 12/12/2022]
Abstract
Despite ongoing advances in the treatment of gastroesophageal cancer, prognosis remains poor. The best promise to improve this poor survival is provided by new targeted agents. Of these, human epidermal growth factor receptor 2 (HER2) is currently in the spotlight. In this review, we provide an overview of recent developments in HER2 testing and results of clinical trials targeting HER2 in gastroesophageal adenocarcinoma. Based on the encouraging ToGA trial findings it is now expected that routine HER2 testing will be included in the diagnostic work-up of patients with advanced gastric cancer. With regard to this testing, overexpression of the HER2 protein seems to possess the best predictive properties. However, HER2 immunohistochemistry (IHC) is subject to assay and interobserver variability, so standardization and internal and external proficiency testing is an absolute prerequisite, especially as the IHC scoring system in gastric cancer is different from that of breast cancer. Further study is needed to investigate the clinical meaning of the significant heterogeneity observed in both gene amplification and protein overexpression in gastroesophageal cancer. Highly effective therapies for gastroesophageal cancer can only be accomplished by a multi-targeted approach, considering crosstalk between pathways and continuing to optimize chemotherapy.
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Affiliation(s)
- Cathy B Moelans
- Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, P.O. Box 85500, 3508 GA Utrecht, The Netherlands
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Corso G, Pedrazzani C, Pinheiro H, Fernandes E, Marrelli D, Rinnovati A, Pascale V, Seruca R, Oliveira C, Roviello F. E-cadherin genetic screening and clinico-pathologic characteristics of early onset gastric cancer. Eur J Cancer 2010; 47:631-9. [PMID: 21106365 DOI: 10.1016/j.ejca.2010.10.011] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2010] [Revised: 10/12/2010] [Accepted: 10/13/2010] [Indexed: 01/05/2023]
Abstract
AIM CDH1 germline alterations occur in about 40% of hereditary diffuse gastric cancer (HDGC) families. CDH1 germline mutations are also documented in few early onset diffuse gastric cancer patients (EODGC) without family history, but the real frequency in this setting in unknown. In these patients, the advanced stage at the time of diagnosis remains a clinical burden due to the poor long term survival. METHODS The entire coding region and exon flanking sequences of the CDH1 gene was analysed by direct sequencing in 21 EODGC patients aged ≤50 years. The potential deleterious nature for a new CDH1 missense variant was assessed by cell-cell aggregation and invasion assays. Somatic CDH1 mutation, loss of heterozygosity (LOH) and promoter hypermethylation was explored in the tumour from one CDH1 germline mutation carrier. RESULTS Two novel CDH1 germline variants were identified in 21 EODGC cases, c.670C>T and -63C>A. Functional analysis of the c.670C>T missense variant classified this mutation as non-pathogenic. The analysis of CDH1 somatic second hits failed to demonstrate E-cadherin structural and epigenetic alterations in the tumour sample. CONCLUSION Data from the present work and a systematic review of the literature revealed that CDH1 germline mutations occurred in 7.2% of EOGC patients invariably with diffuse of mixed histology. From these, proved CDH1 mutation pathogenicity has been assigned only to 2.3% of the cases who were recurrently diagnosed before 35 years old. Germline CDH1 mutation remain the only germline genetic defect described in this type of patients and CDH1 mutation screening should be recommended for patients with these characteristics.
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Affiliation(s)
- Giovanni Corso
- Department of Human Pathology and Oncology, Unit of Surgical Oncology, University of Siena and Istituto Toscano Tumori, Italy
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Langeveld D, van Hattem WA, de Leng WWJ, Morsink FH, ten Kate FJW, Giardiello FM, Offerhaus GJA, Brosens LAA. SMAD4 immunohistochemistry reflects genetic status in juvenile polyposis syndrome. Clin Cancer Res 2010; 16:4126-34. [PMID: 20682711 PMCID: PMC2921472 DOI: 10.1158/1078-0432.ccr-10-0168] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE Juvenile polyposis syndrome (JPS) can be caused by a germline defect of the SMAD4 gene. Somatic inactivation of SMAD4 occurs in pancreatic and colorectal cancers and is reflected by loss of SMAD4 immunohistochemistry. Here, SMAD4 immunohistochemistry as a marker of SMAD4 gene status and the role of SMAD4 in the adenoma-carcinoma sequence in neoplastic progression in JPS are studied. EXPERIMENTAL DESIGN Twenty polyps with a SMAD4 germline defect and 38 control polyps were studied by SMAD4 immunohistochemistry. Inactivation of the SMAD4 wild-type allele was studied in dysplastic epithelium and in areas with aberrant SMAD4 expression. APC, beta-catenin, p53, and K-ras were studied to evaluate the adenoma-carcinoma sequence. RESULTS Nine of 20 polyps with a SMAD4 germline defect showed loss of epithelial SMAD4 expression. Loss of heterozygosity of SMAD4 was found in five polyps and a somatic stop codon mutation was found in two polyps without loss of heterozygosity. Remarkably, somatic inactivation of epithelial SMAD4 did not always coincide with dysplasia and aberrant p53 staining was found in four of six dysplastic polyps with normal SMAD4 staining. One K-ras mutation was found in nine juvenile polyps with dysplasia. No evidence for Wnt activation was found. CONCLUSIONS SMAD4 immunohistochemistry mirrors genetic status and provides a specific adjunct in the molecular diagnosis of JPS. However, epithelial SMAD4 inactivation is not required for polyp formation and is not obligatory for neoplastic progression in JPS. Instead, different routes to neoplasia in JPS caused by germline SMAD4 mutation seem to be operative, including somatic loss of SMAD4 and p53 inactivation without somatic loss of SMAD4.
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Affiliation(s)
- Danielle Langeveld
- Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands
- Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands
| | - W. Arnout van Hattem
- Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands
- Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands
| | - Wendy W. J. de Leng
- Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Folkert H. Morsink
- Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Fiebo J. W. ten Kate
- Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Francis M. Giardiello
- Department of Medicine, Division of Gastroenterology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - G. Johan A. Offerhaus
- Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands
- Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands
- Department of Medicine, Division of Gastroenterology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Milne AN, Offerhaus GJA. Early-onset gastric cancer: Learning lessons from the young. World J Gastrointest Oncol 2010; 2:59-64. [PMID: 21160922 PMCID: PMC2998932 DOI: 10.4251/wjgo.v2.i2.59] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2009] [Revised: 07/27/2009] [Accepted: 08/03/2009] [Indexed: 02/05/2023] Open
Abstract
There is by no means a clear-cut pattern of mutations contributing to gastric cancers, and gastric cancer research can be hampered by the diversity of factors that can induce gastric cancer, such as Helicobacter pylori infection, diet, ageing and other environmental factors. Tumours are unquestionably riddled with genetic changes yet we are faced with an unsolvable puzzle with respect to a temporal relationship. It is postulated that inherited genetic factors may be more important in early-onset gastric cancer (EOGC) than in gastric cancers found in older patients as they have less exposure to environmental carcinogens. EOGC, therefore, could provide a key to unravelling the genetic changes in gastric carcinogenesis. Gastric cancers occurring in young patients provide an ideal background on which to try and uncover the initiating stages of gastric carcinogenesis. This review summarizes the literature regarding EOGC and also presents evidence that these cancers have a unique molecular-genetic phenotype, distinct from conventional gastric cancer.
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Affiliation(s)
- Anya N Milne
- Anya N Milne, Department of Pathology, University Medical Centre Utrecht, Postbus 85500, 3508 GA, Utrecht, The Netherlands
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Chung HW, Noh SH, Lim JB. Analysis of demographic characteristics in 3242 young age gastric cancer patients in Korea. World J Gastroenterol 2010; 16:256-63. [PMID: 20066747 PMCID: PMC2806566 DOI: 10.3748/wjg.v16.i2.256] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the epidemiologic features of young age gastric cancer (GC).
METHODS: Retrospectively, a total of 3242 patients with GC between 18 and 45 years of age and 3000 sex- and age-matched controls were reviewed. All subjects were stratified into 3 groups based on age (A, 18-30 years; B, 31-40 years; C, 41-45 years). Epidemiologic characteristics and risk factors were investigated with reference to their age and gender.
RESULTS: Compared to controls, more frequent intake of high risk diet (P = 0.00075), history of heavy smoking (P = 0.00087), intake of heavy alcohol (P = 0.00091), lower social economic status (P = 0.00083), body mass index > 30 (P = 0.00097), urban residence (P = 0.00065), and more frequent exposure to harmful occupational environments (P = 0.00072) were observed in all age groups and both genders in young age GC. These relationships were weaker in females compared to males of the same age, and were stronger as the age of patients increased. However, in group C of young age GC patients, environmental factors played important roles in females and males with a similar body weight. In females, older age at first delivery (> 35 years), lack of lactation history, nulliparity, and poor nutritional status during pregnancy were significantly associated with an increased risk of GC (P = 0.00034). In this study, 252 patients (7.8%) had a family history of GC with high odds ratio (OR) (3.22-4.21). In particular, family history was more closely associated with GC in males (OR, 4.21 in male vs 3.46 in female) and more advanced cases (P = 0.00051).
CONCLUSION: Hormonal associated factors were more commonly associated with females whereas environmental factors were more commonly associated with males in young age GC patients.
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Silva EM, Begnami MD, Fregnani JHTG, Pelosof AG, Zitron C, Montagnini AL, Soares FA. Cadherin-catenin adhesion system and mucin expression: a comparison between young and older patients with gastric carcinoma. Gastric Cancer 2009; 11:149-59. [PMID: 18825309 DOI: 10.1007/s10120-008-0468-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2007] [Accepted: 05/05/2008] [Indexed: 02/07/2023]
Abstract
BACKGROUND Young patients are thought to develop gastric carcinomas with a molecular genetic profile that is distinct from that of gastric carcinomas occurring at a later age. The aim of this study was to compare the clinicopathological features and expression patterns of the markers E-cadherin and beta-catenin, and mucins (MUC1, MUC2, MUC5AC, and MUC6) in young and older patients. METHODS The clinicopathological features and overall survival data of 62 young patients (age <or=40 years) with gastric cancer were retrospectively reviewed from hospital records and compared with the data for 453 older patients (age >40 years). A tissue microarray method and immunohistochemistry were used in order to analyze marker expression in paraffin-embedded tissue blocks obtained from both groups. RESULTS The young group presented a higher percentage of diffuse-type tumors in comparison to the older group (P<0.01). The rates of positivity for E-cadherin and beta-catenin membranous expression patterns and mucin (MUC2, MUC5AC and MUC6) positivity were higher in the young group (P<0.01). Although young patients showed a lower frequency of alterations in marker expression and had significantly better survival rates than the older patients, neither age nor the marker expression pattern were found to be independent prognostic factors of survival. Only stage, tumor size, and tumor location persisted as prognostic factors for patients with gastric cancer. CONCLUSION Biological markers of cellular adhesion and gastric differentiation were differently expressed in young and older patients. Our findings support the hypothesis that young patients develop carcinomas with a different genetic pathway compared to the pathway of tumors occurring at a later age, and we suggest further investigations to assess the prognostic relevance of the markers to specific subgroups.
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Affiliation(s)
- Edaise M Silva
- Department of Anatomic Pathology, Hospital AC Camargo, Rua Antonio Prudente, 109-1o Andar, São Paulo 01509-010, Brazil
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Sitarz R, de Leng WWJ, Polak M, Morsink FHM, Bakker O, Polkowski WP, Maciejewski R, Offerhaus GJA, Milne AN. IL-1B -31T>C promoter polymorphism is associated with gastric stump cancer but not with early onset or conventional gastric cancers. Virchows Arch 2008; 453:249-255. [PMID: 18688641 DOI: 10.1007/s00428-008-0642-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2008] [Revised: 06/04/2008] [Accepted: 07/03/2008] [Indexed: 02/05/2023]
Abstract
It has been reported that interleukin-1beta (IL-1B) genes play a crucial role in the genetic predisposition to gastric cancer although there is no information about their role in different subtypes of gastric cancer. We performed single nucleotide polymorphism analysis of IL-1B in 241 gastric cancers including early onset gastric cancers (EOGC), conventional gastric cancers, and gastric stump cancers (GSCs) as well as 100 control patients, using real-time polymerase chain reaction and sequence analysis. The C allele was present in 60% of EOGCs, 59% of conventional gastric cancers, and 90% of GSCs, compared to 62% in the control group. Interestingly, there was no difference between early onset and conventional gastric cancer with respect to the IL-1B -31T>C polymorphism distribution. A statistically significant difference in the presence of the C allele compared to the control group was found in patients with gastric stump cancer (p = 0.008) with the T allele conferring protection against gastric stump cancer. In summary, we have shown that the IL-1B -31C allele promoter polymorphism is significantly associated with gastric stump cancer compared to the control group. Although several molecular differences have been identified between conventional gastric cancer and early onset gastric cancer, the IL-1B -31 allele distribution is similar between these two groups.
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Affiliation(s)
- R Sitarz
- Department of Pathology, H04-312, University Medical Center Utrecht, Postbox 85500, 3508 GA Utrecht, The Netherlands
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Pedrazzani C, Corso G, Marrelli D, Roviello F. E-cadherin and hereditary diffuse gastric cancer. Surgery 2007; 142:645-57. [PMID: 17981184 DOI: 10.1016/j.surg.2007.06.006] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2007] [Revised: 05/28/2007] [Accepted: 06/01/2007] [Indexed: 02/06/2023]
Affiliation(s)
- Corrado Pedrazzani
- Department of Human Pathology and Oncology, Unit of Surgical Oncology, University of Siena, Italy
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Tanaka Y, Imamura J, Kanai F, Ichimura T, Isobe T, Koike M, Kudo Y, Tateishi K, Ikenoue T, Ijichi H, Yamaji Y, Yoshida H, Kawabe T, Omata M. Runx3 interacts with DNA repair protein Ku70. Exp Cell Res 2007; 313:3251-3260. [PMID: 17662272 DOI: 10.1016/j.yexcr.2007.06.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2006] [Revised: 05/20/2007] [Accepted: 06/25/2007] [Indexed: 11/25/2022]
Abstract
Recent studies have suggested that Runt-related transcription factor 3 (Runx3) is associated with genesis and progression of gastric carcinoma. A proteomic approach was used to search for Runx3-interacting proteins to elucidate the molecular mechanisms of gastric carcinogenesis. Runx3 bound with myc and flag tags (MEF tags) is expressed in HEK293T cells, and the protein complex formed with Runx3 was purified and identified by mass spectrometry. Ku70 and Ku80, members of the DNA repair protein complex, were identified as Runx3-interacting proteins. Runx3, Ku70, and Ku80 associate in vivo, and in vitro interaction between Runx3 and Ku70 was confirmed via His-tag pull-down assay. The amino acids 241-322 of Runx3, which correspond to the transcriptional activation domain, and the amino acids 1-116 of Ku70 were necessary for binding with each other, and immunocytochemistry under confocal laser microscopy demonstrated that Runx3 and Ku70 localized throughout the nucleus excluding the nucleoli. Furthermore, Runx3 highly activated the transcription of p21, the target gene of Runx3, in Ku70 knockdown cells. These results suggest a possible link between a tumor suppressor function and DNA repair.
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Affiliation(s)
- Yasuo Tanaka
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, and Department of Clinical Drug Evaluation, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Carvalho R, Milne ANA, Polak M, Offerhaus GJA, Weterman MAJ. A novel region of amplification at 11p12-13 in gastric cancer, revealed by representational difference analysis, is associated with overexpression of CD44v6, especially in early-onset gastric carcinomas. Genes Chromosomes Cancer 2006; 45:967-75. [PMID: 16868940 DOI: 10.1002/gcc.20360] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Diffuse-type gastric carcinomas (GCs) are often difficult to characterize because of contamination of tumor samples by surrounding normal tissue. As such, information regarding chromosomal aberrations in this subtype of GCs is limited. In this study, we used representational difference analysis to pinpoint genomic amplifications occurring in diffuse-type GCs. We found nine differential products from two novel regions of amplification in two tumors: one product mapped to 19p13.1 and eight mapped to a 1.8-Mb region in chromosomal segment 11p12-13. These amplifications were confirmed using Southern blot analysis and occurred in 3/16 and 6/15 diffuse-type GCs, respectively. CD44, a well characterized cellular adhesion molecule involved in several human malignancies, is encoded by a gene located within 200 kb of the 11p12-13 amplification fragments. We confirmed that overexpression of isoform CD44v6 was correlated with amplification at 11p12-13 in 11/12 diffuse-type GCs. Since diffuse-type GCs occur more frequently in early-onset gastric carcinomas (EOGCs, presented at 45 years of age or younger) than in "conventional" GCs, and the tumors carrying the original amplifications were EOGCs, we investigated overexpression of CD44v6 in 107 EOGCs and 88 conventional GCs using tissue microarrays. We found frequent CD44v6 overexpression in both tumor groups (76% and 57% respectively) and, interestingly, significantly more cases with overexpression of CD44v6 in EOGCs than in conventional GCs (P = 0.005), irrespective of histology. These findings provide further evidence for both the relevance of CD44 in GC and for distinct molecular characteristics of EOGCs when compared with those of GCs occurring at a later age.
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Affiliation(s)
- Ralph Carvalho
- Department of Pathology, Academisch Medisch Centrum, Amsterdam, The Netherlands.
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Hussain SZ, Jaiswal A, Bader AA, Mohan P, Markle BM, Minnitti C, Przygodzki R, Kerzner B, Kaufman SS. Fatal acute liver failure in a child with metastatic gastric adenocarcinoma. J Pediatr Gastroenterol Nutr 2006; 43:116-8. [PMID: 16819388 DOI: 10.1097/01.mpg.0000189365.91792.bf] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Affiliation(s)
- Sunny Zaheed Hussain
- Department of Gastroenterology and Nutrition, Children's National Medical Center, Washington, DC 20010, USA
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Bacani JT, Soares M, Zwingerman R, di Nicola N, Senz J, Riddell R, Huntsman DG, Gallinger S. CDH1/E-cadherin germline mutations in early-onset gastric cancer. J Med Genet 2006; 43:867-72. [PMID: 16801346 PMCID: PMC2563190 DOI: 10.1136/jmg.2006.043133] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Gastric cancer remains a leading cause of cancer deaths worldwide. Genetic factors, including germline mutations in E-cadherin (CDH1, MIM#192090) in hereditary diffuse gastric cancer (HDGC, MIM#137215), are implicated in this disease. Family studies have reported CDH1 germline mutations in HDGC but the role of CDH1 germline mutations in the general population remains unclear. AIMS To examine the frequency of CDH1 germline mutations in a population-based series of early-onset gastric cancer (EOGC <50 years old). METHODS 211 cases of EOGC were identified in Central-East Ontario region from 1989 to 1993, with archival material and histological confirmation of non-intestinal type gastric cancer available for 81 subjects. Eligible cases were analysed for CDH1 germline mutations by single-strand conformation polymorphism, variants were sequenced, and tumours from cases with functional mutations were stained for E-cadherin (HECD-1) using immunohistochemistry. RESULTS 1155 (89%) of 1296 polymerase chain reactions amplified successfully. One new germline deletion (nt41delT) was identified in a 30-year-old patient with isolated cell gastric cancer. The overall frequency of germline CDH1 mutations was 1.3% (1/81) for EOGC and 2.8% (1/36) for early-onset isolated cell gastric cancer. CONCLUSION This is the first population-based study, in a low-incidence region, of genetic predisposition to gastric cancer. Combined with our previous report of germline hMLH1 mutations in two other subjects from this series, it is suggested that 2-3% of EOCG cases in North Americans may be owing to high-risk genetic mutations. These data should inform cancer geneticists on the utility of searching for specific genetic mutations in EOGC.
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Gallego Melcón S. Older adolescents and young adults with cancer: a different subset of patients? Clin Transl Oncol 2006; 8:383-4. [PMID: 16790388 DOI: 10.1007/s12094-006-0189-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Milne ANA, Carvalho R, Morsink FM, Musler AR, de Leng WWJ, Ristimäki A, Offerhaus GJA. Early-onset gastric cancers have a different molecular expression profile than conventional gastric cancers. Mod Pathol 2006; 19:564-72. [PMID: 16474375 DOI: 10.1038/modpathol.3800563] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Many studies examine the molecular genetics of gastric cancer, but few look at young patients in particular and there is no comparison of molecular expression between early-onset gastric cancer (< or = 45 years old) and conventional gastric cancers. Expression of cycloxygenase-2 (COX-2) is elevated in gastric adenocarcinomas compared to non-neoplastic mucosa, and in light of studies showing reduced risk of gastric cancer in nonsteroidal anti-inflammatory drug users, we have chosen to investigate the expression of COX-2 and related molecules in 113 early-onset gastric cancers and compare it with 91 conventional gastric cancers, using tissue microarrays. These markers include molecules known to be important in conventional gastric carcinogenesis, such as E-Cadherin, p53, COX-2, Trefoil Factor-1 (TFF1), beta-catenin, p16 and c-myc; as well as molecules not yet described as being important in gastric cancer, such as the transcription factor c-jun, the COX-2 mRNA stabilizer HuR, and C/EBP-beta, a transcription factor for COX-2. All markers showed a statistically significant difference between early-onset gastric cancers and conventional gastric cancers, using a chi2 test. In particular, early-onset gastric cancers displayed a COX-2 Low, TFF1-expressing phenotype, whereas COX-2 overexpression and loss of TFF1 was found in conventional cancers, and this difference between early-onset gastric cancers and conventional cancers remained statistically significant when adjusted for location and histology (P<0.0001 and P = 0.002 respectively). We found that COX-2 overexpression correlates significantly with loss of TFF1 (P = 0.001), overexpression of C/EBP-beta (P<0.001) and cytoplasmic HuR (P = 0.016). COX-2 was significantly associated with p53 positivity (P = 0.003). Abnormalities in E-Cadherin correlated significantly with diffuse phenotype, whereas high expression of COX-2, loss of TFF1 and overexpression of C/EBP-beta correlated with the intestinal phenotype. Our results provide further evidence that early-onset gastric cancer exhibits a distinctive expression profile that may have practical implications.
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Affiliation(s)
- Anya N A Milne
- Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
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Carvalho R, Milne ANA, Polak M, Corver WE, Offerhaus GJA, Weterman MAJ. Exclusion of RUNX3 as a tumour-suppressor gene in early-onset gastric carcinomas. Oncogene 2006; 24:8252-8. [PMID: 16091737 DOI: 10.1038/sj.onc.1208963] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Recent studies claim a critical role for RUNX3 in gastric epithelial homeostasis. However, conflicting results exist regarding RUNX3 expression in the stomach and its potential role as a tumour-suppressor gene (TSG) in gastric carcinogenesis. Our aim was to evaluate the role of RUNX3 in early-onset gastric carcinomas (EOGCs). We analysed 41 EOGCs for RUNX3 aberrations using loss of heterozygosity (LOH), fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) analyses. LOH of markers flanking RUNX3 was relatively common, indicating that loss of the gene may play a role in gastric carcinogenesis. However, FISH analysis of selected cases and a panel of 14 gastric carcinoma-derived cell lines showed widespread presence of multiple copies of centromere 1. While RUNX3 copy numbers were generally equal to or fewer than those of centromere 1, at least two copies were present in almost all cells analysed. Accordingly, a subpopulation of tumour cells in 12/37 cases showed RUNX3 protein expression. However, expression was not detected in the adjacent nontumorous mucosa of any case. Together, these observations indicate that chromosome 1 aberrations occur frequently in EOGCs and are reflected in the LOH and IHC patterns found. Our findings refute a role for RUNX3 as a TSG in EOGCs.
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Affiliation(s)
- Ralph Carvalho
- Department of Pathology, Academisch Medisch Centrum, Amsterdam, The Netherlands.
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Abstract
Several attempts to classify gastric cancer (GCA) have been made over the past decades. Most successful, and widely used, is the classification by Laurén, which distinguishes, by microscopical morphology alone, two main cancer pathogeneses, diffuse (DGCA) and intestinal (IGCA) subtypes, which appear clearly as dissimilar clinical and epidemiological entities. Here we review the main differences in epidemiology, histopathology, and molecular pathology of the two main subtypes of gastric carcinomas based on Laurén classification. In clinical practice, however, clinical staging, particularly in predicting the survival, still remains superior to all classifications of gastric cancer independent of cancer type. The existence of local precursor lesions or conditions of IGCA tumours, i.e. Helicobacter pylori gastritis, atrophic gastritis (AG), intestinal metaplasia (IM), adenoma, dysplasia, and intramucosal neoplasia, is firmly established. The links of DGCA with intestinal-type epithelium, AG or IM are poor, or do not exist. So far, H. pylori gastritis is the only universal precursor condition for DGCA. It implies that AG and achlorhydria are of minor significance and infrequent in the development of DGCA but are important steps in that of IGCA. Despite an increasing body of data, the overall view on molecular pathology of GCA remains fragmentary. No consistent differences in the molecular pathology of GCA subtypes to meet the Laurén classification have been established. With the exception of TP53, no gene mutation occurring regularly in both histological types of GCA has been reported. Chromosomal aberrations and loss of heterozygosity seem to be non-specific and do not follow any consistent route in the progression of GCA. Microsatellite instability is more commonly found in IGCA than in DGCA. The present epigenetic data suggest that most of the decrease (or loss) of gene expression may be explained by promoter hypermethylation which is more often found in IGCA. In DGCA specific genes such as CDH1 are more often hypermethylated. Compared with GCA, in premalignant condition lesions gene mutations and chromosomal aberrations are infrequent. Epigenetic dysregulation might also represent a major mechanism for altered gene expression in premalignant stages in gastric carcinogenesis.
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Affiliation(s)
- Matti Vauhkonen
- Department of Medicine, Helsinki University Central Hospital (HUCH), Jorvi Hospital, Espoo, Finland
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Bacani J, Zwingerman R, Di Nicola N, Spencer S, Wegrynowski T, Mitchell K, Hay K, Redston M, Holowaty E, Huntsman D, Pollett A, Riddell R, Gallinger S. Tumor microsatellite instability in early onset gastric cancer. J Mol Diagn 2005; 7:465-77. [PMID: 16237216 PMCID: PMC1888489 DOI: 10.1016/s1525-1578(10)60577-6] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/31/2005] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer (GC) remains a leading cause of cancer mortality worldwide. Genetic factors are implicated, including DNA mismatch repair (MMR) deficiency manifested as tumor microsatellite instability (MSI). However, a standardized panel of markers and a definition of low-versus-high level MSI in GC are lacking. We examined a population-based cohort of early onset (or=3 markers MSI+/MSI-high) demonstrated MMR protein deficiency. Three novel hMLH1 mutations (two germline frameshift and one somatic nonsense) were also found. The only significant clinicopathological associations were increased tumor size in MSI+ cases (P=0.04) and Lauren histotype (P=0.006) and tumor grade (P=0.007) in MSI-high cases. Tumor size, location, depth, nodal status, and Ming subtype were significant prognostic variables. Therefore, we propose a new definition of high-level MSI based on unifying characteristics of instability of more than or equal to three of six mononucleotide markers and loss of MMR protein expression.
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Affiliation(s)
- Julinor Bacani
- Center for Cancer gEnetics-Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5
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