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Kamio T, Kono Y, Hirosuna K, Ozato T, Yamamoto H, Hirasawa A, Ennishi D, Tomida S, Toyooka S, Otsuka M. Genomic Differences and Distinct TP53 Mutation Site-Linked Chemosensitivity in Early- and Late-Onset Gastric Cancer. Cancer Med 2025; 14:e70793. [PMID: 40249206 PMCID: PMC12007182 DOI: 10.1002/cam4.70793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 01/16/2025] [Accepted: 03/08/2025] [Indexed: 04/19/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) in younger patients often exhibits aggressive behavior and a poorer prognosis than that in older patients. Although the clinical differences may stem from oncogenic gene variations, it is unclear whether genetic differences exist between these groups. This study compared the genetic profiles of early- and late-onset GC and evaluated their impact on treatment outcomes. METHODS We analyzed genetic data from 1284 patients with GC in the Japanese nationwide Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database, comparing early-onset (≤ 39 years; n = 143) and late-onset (≥ 65 years; n = 1141) groups. The influence of TP53 mutations on the time to treatment failure (TTF) with platinum-based chemotherapy and the sensitivity of cancer cells with different TP53 mutation sites to oxaliplatin were assessed in vitro. RESULTS Early- and late-onset GC showed distinct genetic profiles, with fewer neoantigen-associated genetic changes observed in early-onset cases. In particular, TP53 has distinct mutation sites; R175H and R273 mutations are more frequent in early- and late-onset GC, respectively. The R175H mutation showed higher sensitivity to oxaliplatin in vitro, consistent with the longer TTF in early-onset patients (17.3 vs. 7.0 months, p = 0.013) when focusing on the patients with TP53 mutations. CONCLUSION Genomic differences, particularly in TP53 mutation sites, between early- and late-onset GC support the need for age-specific treatment strategies.
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Affiliation(s)
- Tomohiro Kamio
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Dentistry and Pharmaceutical SciencesOkayama UniversityOkayamaJapan
| | - Yoshiyasu Kono
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Dentistry and Pharmaceutical SciencesOkayama UniversityOkayamaJapan
| | - Kensuke Hirosuna
- Department of Regenerative ScienceOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
| | - Toshiki Ozato
- Department of GastroenterologyOkayama University HospitalOkayamaJapan
| | - Hideki Yamamoto
- Department of Clinical Genomic MedicineOkayama University HospitalOkayamaJapan
| | - Akira Hirasawa
- Department of Clinical Genomic MedicineOkayama University HospitalOkayamaJapan
| | - Daisuke Ennishi
- Center for Comprehensive Genomic MedicineOkayama University HospitalOkayamaJapan
| | - Shuta Tomida
- Center for Comprehensive Genomic MedicineOkayama University HospitalOkayamaJapan
| | - Shinichi Toyooka
- Center for Comprehensive Genomic MedicineOkayama University HospitalOkayamaJapan
- Department of General Thoracic Surgery, Breast and Endocrinological SurgeryFaculty of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
| | - Motoyuki Otsuka
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Dentistry and Pharmaceutical SciencesOkayama UniversityOkayamaJapan
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2
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Kővári B, Carneiro F, Lauwers GY. Epithelial tumours of the stomach. MORSON AND DAWSON'S GASTROINTESTINAL PATHOLOGY 2024:227-286. [DOI: 10.1002/9781119423195.ch13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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3
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Oyama T, Yamamoto T, Nakamura R, Han J, Liu Y, Shioya A, Ooi A, Maeda D, Yamada S. VEGFA locus amplification potentially predicts a favorable prognosis in gastric adenocarcinoma. Pathol Res Pract 2024; 260:155441. [PMID: 38986362 DOI: 10.1016/j.prp.2024.155441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 06/19/2024] [Accepted: 06/28/2024] [Indexed: 07/12/2024]
Abstract
Gastric adenocarcinoma harbors a range of genetic and epigenetic alterations, including alterations in DNA copy number. However, the key genes that promote the development and progression of gastric adenocarcinoma remain unknown. To identify the key genes amplified in gastric adenocarcinoma, we performed array comparative genomic hybridization on formalin-fixed paraffin-embedded samples of surgically resected gastric adenocarcinoma. We detected a relatively wide genomic region of gain containing the vascular endothelial growth factor A (VEGFA) gene locus on chromosome 6p. VEGFA locus amplification in gastric adenocarcinoma was validated by fluorescence in situ hybridization. To assess the frequency of VEGFA locus amplification in gastric adenocarcinoma, we conducted multiplex ligation-dependent probe amplification (MLPA) assays using homemade probes designed to target the VEGFA gene locus. Eleven of 54 (20 %) gastric adenocarcinomas with MLPA values above 1.3 were defined as having VEGFA locus amplification. Next, we investigated the effect of VEGFA locus amplification on the clinicopathological characteristics of gastric adenocarcinomas and patient survival. VEGFA locus amplification demonstrated a significantly close relationship with pathological intestinal type and lower rates of venous invasion Furthermore, a Kaplan-Meier analysis showed that patients with VEGFA locus amplification had significantly better overall survival than those without amplification (p = 0.038), particularly in the long-term follow-up period. In conclusion, VEGFA locus amplification can predict modest aggressiveness and good outcomes, suggesting the possibility that it may predict a favorable prognosis in patients with gastric adenocarcinoma.
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Affiliation(s)
- Takeru Oyama
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, School of Medicine, Ishikawa, Japan; Department of Pathology, Kanazawa Medical University Hospital, Ishikawa, Japan.
| | - Toshiyuki Yamamoto
- Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan
| | - Ritsuko Nakamura
- Department of Pathology, School of Medicine, Aichi Medical University, Nagoya, Japan
| | - Jia Han
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, School of Medicine, Ishikawa, Japan
| | - Yao Liu
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, School of Medicine, Ishikawa, Japan; Department of Pathology, Kanazawa Medical University Hospital, Ishikawa, Japan
| | - Akihiro Shioya
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, School of Medicine, Ishikawa, Japan; Department of Pathology, Kanazawa Medical University Hospital, Ishikawa, Japan
| | - Akishi Ooi
- Department of Molecular and Cellular Pathology, Kanazawa University, Grad. School of Medical Science, Ishikawa, Japan
| | - Daichi Maeda
- Department of Molecular and Cellular Pathology, Kanazawa University, Grad. School of Medical Science, Ishikawa, Japan
| | - Sohsuke Yamada
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, School of Medicine, Ishikawa, Japan; Department of Pathology, Kanazawa Medical University Hospital, Ishikawa, Japan
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Liu X, Li X, Zhu C, Ji L. Effective control of postoperative recurrence of pregnancy-related gastric cancer using anti-PD-1 as a monotherapy: a case report. Front Oncol 2024; 14:1321149. [PMID: 38800370 PMCID: PMC11116784 DOI: 10.3389/fonc.2024.1321149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 04/23/2024] [Indexed: 05/29/2024] Open
Abstract
Pregnancy-related gastric cancer is characterized by a refractory nature and poor prognosis; few gastric cancer cases during pregnancy achieved acceptable outcomes by using anti-PD-1 as a monotherapy. A 32-year-old pregnant female patient was admitted to the emergency department of the obstetrics and gynecology department and eventually diagnosed with gastric cancer. Radical surgery for gastric cancer was conducted after the termination of pregnancy. At 1-year postoperative follow-up, tumor recurrence was revealed. This patient has achieved a decrease in tumor burden after receiving anti-PD-1 as a monotherapy. This case documents tumor response to PD-1 monotherapy in pregnancy-related gastric cancer and highlights the potential for future use in specific clinical scenarios.
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Affiliation(s)
| | | | | | - Linhua Ji
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Krishnamoorthi N, Charles L, Nisha Y, Dubashi B, Ganesan P, Kayal S, Penumadu P, Nelamangala Ramakrishnaiah VP, Ganesh RN. Aggressive Histology and Extensive Metastasis Characteristic of Very Young Gastric Cancer (Less Than 30 Years): A Retrospective Clinical Audit. South Asian J Cancer 2023; 12:326-333. [PMID: 38130279 PMCID: PMC10733067 DOI: 10.1055/s-0043-1761284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2023] Open
Abstract
Narendran KrishnamoorthiObjectives Gastric cancer (GC) is an aggressive disease and remains one of the most common causes of cancer-related mortality worldwide. Incidence of gastric cancer in young (GCY) varies between 2 and 8%. GCY faces unique challenges such as biological variation, diagnosis at an advanced stage, issues related to fertility preservation, and psychosocial considerations. This study aimed to find the differences in clinical characteristics and treatment outcomes of GCY compared to gastric cancer in older adults (GCO). Material and Methods This is a retrospective study from a tertiary care center. We screened records from 2015 to 2020, identified 33 records of GCY (less than 30 years), and compared the data with GCO (greater than 30 years) during 2015 and 2018. Results We identified 33 patients with GCY with a median age of 28 years (21-30) and a female to male ratio of 2:1. In GCY, 60% of patients presented with metastatic disease. Diffuse-type histology was more common in the GCY than in GCO (66.7% vs. 41.7%, p = 0.001). In patients with metastasis, multiple metastases were common in GCY compared to GCO (45% vs. 15%, p = 0.003). The median duration of follow-up for all patients was 27 (24-29) months. In GCY, the median OS was not reached for patients treated with curative intent, and it was 13 months for those treated with palliative intent. Conclusion The incidence of GCY in our study was like the western literature. Female patients with aggressive diffuse histology and multiple extensive metastases were characteristic of GCY. The survival outcomes were identical to GCO.
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Affiliation(s)
- Narendran Krishnamoorthi
- Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantari Nagar, Pondicherry, India
| | - Lourdhusamy Charles
- Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantari Nagar, Pondicherry, India
| | - Yadav Nisha
- Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantari Nagar, Pondicherry, India
| | - Biswajit Dubashi
- Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantari Nagar, Pondicherry, India
| | - Prasanth Ganesan
- Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantari Nagar, Pondicherry, India
| | - Smita Kayal
- Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantari Nagar, Pondicherry, India
| | - Prasanth Penumadu
- Department of Surgical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantari Nagar, Pondicherry, India
| | | | - Rajesh Nachiappa Ganesh
- Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantari Nagar, Pondicherry, India
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Constantin A, Constantin R, Achim F, Socea B, Predescu D. Pregnancy and Gastric Cancer: A Narrative Review. Diagnostics (Basel) 2023; 13:1909. [PMID: 37296761 PMCID: PMC10252424 DOI: 10.3390/diagnostics13111909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 05/22/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Cases of digestive cancers diagnosed during pregnancy are rare. The increasing prevalence of pregnancy in women aged 30-39 years (and not exceptionally 40-49 years) could explain the frequent co-occurrence of cancers and pregnancy. The diagnosis of digestive cancers in pregnancy is difficult due to the overlap between neoplasm symptomatology and the clinical picture of pregnancy. A paraclinical evaluation may also be difficult depending on the trimester of the pregnancy. Diagnosis is also delayed by practitioners' hesitation to use invasive investigations (imaging, endoscopy, etc.) due to fetal safety concerns. Therefore, digestive cancers are often diagnosed during pregnancy in advanced stages, where complications such as occlusions, perforations, and cachexia have already arisen. In this review, we highlight the epidemiology, clinical aspects, paraclinical evaluation, and particularities of the diagnosis and treatment of gastric cancer during pregnancy.
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Affiliation(s)
- Adrian Constantin
- Department of Esophageal and General Surgery, Sf. Maria Clinical Hospital Bucharest, 011192 Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy Bucharest, 050474 Bucharest, Romania
| | - Roxana Constantin
- Department of Obstetrics and Gynecology, Sanador Hospital, 010991 Bucharest, Romania
| | - Florin Achim
- Department of Esophageal and General Surgery, Sf. Maria Clinical Hospital Bucharest, 011192 Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy Bucharest, 050474 Bucharest, Romania
| | - Bogdan Socea
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy Bucharest, 050474 Bucharest, Romania
- Department of Surgery, Sf. Pantelimon Emergency Clinical Hospital, 021659 Bucharest, Romania
| | - Dragos Predescu
- Department of Esophageal and General Surgery, Sf. Maria Clinical Hospital Bucharest, 011192 Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy Bucharest, 050474 Bucharest, Romania
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Li L, Li Y, Lin L, Liu Y, Duan L, Wang D, Cheng S, Liu G. Mutational characteristics of young and elderly gastric cancer: a comparative study. J Gastrointest Oncol 2022; 13:77-83. [PMID: 35284122 PMCID: PMC8899741 DOI: 10.21037/jgo-21-934] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 02/21/2022] [Indexed: 08/30/2023] Open
Abstract
BACKGROUND Young gastric cancer (YGC) has been indicated as having a worse prognosis than in elderly gastric cancer (EGC). It has been reported that YGC and EGC patients show different genomic profiles; however, there has been no comparative study conducted to reveal their mutational characteristics. METHODS Firstly, we divided and analyzed the mutational landscape and 50 cancer-related genes characters of YGC (n=18) and EGC (n=18) patients from The Cancer Genome Atlas-Stomach Adenocarcinoma (TCGA-STAD). A total of 8 gastric cancer samples including 4 YGC and 4 EGC patients were collected to detect 50 cancer-related genes by multiplex polymerase chain reaction (PCR) next generation sequencing. The R/maftools package was used to describe the mutational characteristics. RESULTS Our results showed that the EGC group harbored more mutations than the YGC group. In 50 cancer-related genes in our cohort, the YGC group tended to be different from the EGC group using multiplex PCR next generation sequencing. In the YGC group, candidate mutations were identified within the following genes: IDH2, PDGFRA, KRAS, FLT3, FGFR2, and FGFR3. The YGC group showed less tumor mutational burden (TMB) level then EGC. CONCLUSIONS The YGC group tended to be more sensitive to molecularly targeted therapy because of it having more somatic mutations in 50 cancer-related genes using targeted next-generation sequencing.
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Affiliation(s)
- Long Li
- Medical College of Xiamen University, Xiamen University, Xiamen, China
| | - Yin Li
- Xiamen International Travel Healthcare Center, Xiamen, China
| | - Li Lin
- Department of Gastrointestinal Surgery and Xiamen City Key Laboratory of Gastrointestinal Cancer, Zhongshan Hospital, Xiamen University, China
| | - Yanling Liu
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Linshan Duan
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Dan Wang
- Medical College of Xiamen University, Xiamen University, Xiamen, China
| | - Shuyu Cheng
- Medical College of Xiamen University, Xiamen University, Xiamen, China
| | - Guoyan Liu
- Medical College of Xiamen University, Xiamen University, Xiamen, China
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China
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8
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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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Moon HH, Kang HW, Koh SJ, Kim JW, Shin CM. Clinicopathological Characteristics of Asymptomatic Young Patients with Gastric Cancer Detected during a Health Checkup. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2019; 74:281-290. [PMID: 31765556 DOI: 10.4166/kjg.2019.74.5.281] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 10/10/2019] [Accepted: 10/10/2019] [Indexed: 12/09/2022]
Abstract
Background/Aims The Korean National Cancer Screening Program recommends biennial gastric cancer screening for patients aged ≥40 years. This study compared the characteristics of asymptomatic young gastric cancer patients aged <40 years, whose cancer was detected during a health checkup (screening group), with those whose disease was detected because of symptoms (diagnostic group). Methods Data were collected retrospectively from 84 subjects who underwent a gastroduodenoscopy before the age of 40 years and who were diagnosed with gastric cancer from January 2006 to February 2017 in three tertiary centers in Korea. The clinicopathological characteristics, including age, sex, stage, location, pathology, and survival, were compared according to the purpose of endoscopy (screening group, n=23 vs. diagnostic group, n=61). Results The median age of the screening group was higher than that of the diagnostic group (37 vs. 35 years, p=0.027), as was the proportion of early gastric cancer cases (78.3% vs. 29.5%, p<0.01), curative endoscopic treatment or operation rate (95.7% vs. 52.5%, p<0.01), and the overall survival (p<0.01). Poorly differentiated or signet ring cell carcinoma was less common in the screening group than in the diagnostic group (56.5% vs. 83.6%, p=0.006). The sex ratio, smoking status, family history of gastric cancer, Helicobacter pylori infection status, and tumor location were similar in the two groups. Conclusions Screening gastroduodenoscopy may enable the early detection of gastric cancer and prolong survival in patients <40 years of age.
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Affiliation(s)
- Hyoung Ho Moon
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea
| | - Hyoun Woo Kang
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea
| | - Seong-Joon Koh
- Department of Internal Medicine, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Ji Won Kim
- Department of Internal Medicine, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
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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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Cho SY, Park JW, Liu Y, Park YS, Kim JH, Yang H, Um H, Ko WR, Lee BI, Kwon SY, Ryu SW, Kwon CH, Park DY, Lee JH, Lee SI, Song KS, Hur H, Han SU, Chang H, Kim SJ, Kim BS, Yook JH, Yoo MW, Kim BS, Lee IS, Kook MC, Thiessen N, He A, Stewart C, Dunford A, Kim J, Shih J, Saksena G, Cherniack AD, Schumacher S, Weiner AT, Rosenberg M, Getz G, Yang EG, Ryu MH, Bass AJ, Kim HK. Sporadic Early-Onset Diffuse Gastric Cancers Have High Frequency of Somatic CDH1 Alterations, but Low Frequency of Somatic RHOA Mutations Compared With Late-Onset Cancers. Gastroenterology 2017; 153:536-549.e26. [PMID: 28522256 PMCID: PMC6863080 DOI: 10.1053/j.gastro.2017.05.012] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 05/08/2017] [Accepted: 05/08/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Early-onset gastric cancer, which develops in patients younger than most gastric cancers, is usually detected at advanced stages, has diffuse histologic features, and occurs more frequently in women. We investigated somatic genomic alterations associated with the unique characteristics of sporadic diffuse gastric cancers (DGCs) from younger patients. METHODS We conducted whole exome and RNA sequence analyses of 80 resected DGC samples from patients 45 years old or younger in Korea. Patients with pathogenic germline mutations in CDH1, TP53, and ATM were excluded from the onset of this analysis, given our focus on somatic alterations. We used MutSig2CV to evaluate the significance of mutated genes. We recruited 29 additional early-onset Korean DGC samples and performed SNP6.0 array and targeted sequencing analyses of these 109 early-onset DGC samples (54.1% female, median age, 38 years). We compared the SNP6.0 array and targeted sequencing data of the 109 early-onset DGC samples with those from diffuse-type stomach tumor samples collected from 115 patients in Korea who were 46 years or older (late onset) at the time of diagnosis (controls; 29.6% female, median age, 67 years). We compared patient survival times among tumors from different subgroups and with different somatic mutations. We performed gene silencing of RHOA or CDH1 in DGC cells with small interfering RNAs for cell-based assays. RESULTS We identified somatic mutations in the following genes in a significant number of early-onset DGCs: the cadherin 1 gene (CDH1), TP53, ARID1A, KRAS, PIK3CA, ERBB3, TGFBR1, FBXW7, RHOA, and MAP2K1. None of 109 early-onset DGC cases had pathogenic germline CDH1 mutations. A higher proportion of early-onset DGCs had mutations in CDH1 (42.2%) or TGFBR1 (7.3%) compared with control DGCs (17.4% and 0.9%, respectively) (P < .001 and P = .014 for CDH1 and TGFBR1, respectively). In contrast, a smaller proportion of early-onset DGCs contained mutations in RHOA (9.2%) than control DGCs (19.1%) (P = .033). Late-onset DGCs in The Cancer Genome Atlas also contained less frequent mutations in CDH1 and TGFBR1 and more frequent RHOA mutations, compared with early-onset DGCs. Early-onset DGCs from women contained significantly more mutations in CDH1 or TGFBR1 than early-onset DGCs from men. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times in patients with early-onset DGCs (hazard ratio, 3.4; 95% confidence interval, 1.5-7.7). RHOA activity was reduced by an R5W substitution-the RHOA mutation most frequently detected in early-onset DGCs. Silencing of CDH1, but not RHOA, increased migratory activity of DGC cells. CONCLUSIONS In an integrative genomic analysis, we found higher proportions of early-onset DGCs to contain somatic mutations in CDH1 or TGFBR1 compared with late-onset DGCs. However, a smaller proportion of early-onset DGCs contained somatic mutations in RHOA than late-onset DGCs. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times of patients, which might account for the aggressive clinical course of early-onset gastric cancer. Female predominance in early-onset gastric cancer may be related to relatively high rates of somatic CDH1 and TGFBR1 mutations in this population.
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Affiliation(s)
- Soo Young Cho
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Jun Won Park
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Yang Liu
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Young Soo Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ju Hee Kim
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Hanna Yang
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Hyejin Um
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Woo Ri Ko
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Byung Il Lee
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea
| | - Sun Young Kwon
- Department of Pathology, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Seung Wan Ryu
- Department of Surgery, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Chae Hwa Kwon
- Department of Pathology and BioMedical Research Institute, Pusan National University Hospital and Pusan National University School of Medicine, Busan, Republic of Korea
| | - Do Youn Park
- Department of Pathology and BioMedical Research Institute, Pusan National University Hospital and Pusan National University School of Medicine, Busan, Republic of Korea
| | - Jae-Hyuk Lee
- Department of Pathology, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Sang Il Lee
- Department of Surgery, School of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Kyu Sang Song
- Department of Pathology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Hoon Hur
- Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Sang-Uk Han
- Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Heekyung Chang
- Department of Pathology, Kosin University College of Medicine, Busan, Republic of Korea
| | - Su-Jin Kim
- Department of Pathology, Dong-A University College of Medicine, Busan, Republic of Korea
| | - Byung-Sik Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jeong-Hwan Yook
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Moon-Won Yoo
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Beom-Su Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - In-Seob Lee
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | | | - Nina Thiessen
- British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - An He
- British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - Chip Stewart
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Andrew Dunford
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Jaegil Kim
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Juliann Shih
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Gordon Saksena
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Andrew D Cherniack
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Steven Schumacher
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Amaro-Taylor Weiner
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Mara Rosenberg
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Gad Getz
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Eun Gyeong Yang
- Korea Institute of Science and Technology, Seoul, Republic of Korea
| | - Min-Hee Ryu
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Adam J Bass
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
| | - Hark Kyun Kim
- National Cancer Center, Goyang, Gyeonggi, Republic of Korea; National Cancer Center Graduate School of Cancer Science and Policy, Goyang, Gyeonggi, Republic of Korea.
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Merchant SJ, Kim J, Choi AH, Sun V, Chao J, Nelson R. A rising trend in the incidence of advanced gastric cancer in young Hispanic men. Gastric Cancer 2017; 20:226-234. [PMID: 26924751 PMCID: PMC5630456 DOI: 10.1007/s10120-016-0603-7] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 02/17/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although the incidence of gastric cancer has been decreasing, recent reports suggest an increased rate in select populations. We sought to evaluate trends in gastric cancer incidence to identify high-risk populations. METHODS Gastric cancer incidence rates from 1992 to 2011 were computed with use of the Surveillance, Epidemiology, and End Results (SEER) registry. We evaluated trends in incidence rates by calculating the annual percent change (APC) across three age groups (20-49 years, 50-64 years, and 65 years or older) and four racial/ethnic groups (Hispanics, non-Hispanic whites, blacks, and Asian/Pacific Islanders). RESULTS We identified 41,428 patients with gastric cancer. For the entire cohort during the study period, the APC was decreased. When patients were grouped according to sex, the APC was flat or decreased in women regardless of age or race/ethnicity. The APC was also flat or decreased for all men except young Hispanic men (20-49 years), who had an increased APC of nearly 1.6 % (1.55 %, 95 % confidence interval 0.26-2.86 %). Furthermore, young Hispanic men were the only group to have increased incidence of stage IV disease (APC 4.34 %, 95 % confidence interval 2.76-5.94 %) and poorly differentiated tumors (APC 2.08 %, 95 % confidence interval 0.48-3.70 %). CONCLUSIONS The APC of the incidence of gastric cancer in young Hispanic men places it among the top cancers with rising incidence in the USA. This is concomitant with increased incidence of advanced disease at presentation. This major public health concern warrants additional research to determine the cause of the increasing incidence in this group.
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Affiliation(s)
- Shaila J Merchant
- Division of Surgical Oncology, Queen's University, Kingston, ON, Canada
| | - Joseph Kim
- Division of Surgical Oncology, Stony Brook Medicine, Stony Brook, NY, USA
| | - Audrey H Choi
- Divisions of Surgical Oncology, City of Hope, Duarte, CA, USA
| | - Virginia Sun
- Nursing Research and Education, City of Hope, Duarte, CA, USA
| | - Joseph Chao
- Medical Oncology, City of Hope, Duarte, CA, USA
| | - Rebecca Nelson
- Department of Biostatistics, City of Hope, 1500 East Duarte Rd, Duarte, CA, 91010, USA.
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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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Mello AA, Leal MF, Rey JA, Pinto GR, Lamarão LM, Montenegro RC, Alves APNN, Assumpção PP, Borges BDN, Smith MC, Burbano RR. Deregulated Expression of SRC, LYN and CKB Kinases by DNA Methylation and Its Potential Role in Gastric Cancer Invasiveness and Metastasis. PLoS One 2015; 10:e0140492. [PMID: 26460485 PMCID: PMC4604160 DOI: 10.1371/journal.pone.0140492] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Accepted: 09/25/2015] [Indexed: 12/29/2022] Open
Abstract
Kinases are downstream modulators and effectors of several cellular signaling cascades and play key roles in the development of neoplastic disease. In this study, we aimed to evaluate SRC, LYN and CKB protein and mRNA expression, as well as their promoter methylation, in gastric cancer. We found elevated expression of SRC and LYN kinase mRNA and protein but decreased levels of CKB kinase, alterations that may have a role in the invasiveness and metastasis of gastric tumors. Expression of the three studied kinases was also associated with MYC oncogene expression, a possible biomarker for gastric cancer. To understand the mechanisms that regulate the expression of these genes, we evaluated the DNA promoter methylation of the three kinases. We found that reduced SRC and LYN methylation and increased CKB methylation was associated with gastric cancer. The reduced SRC and LYN methylation was associated with increased levels of mRNA and protein expression, suggesting that DNA methylation is involved in regulating the expression of these kinases. Conversely, reduced CKB methylation was observed in samples with reduced mRNA and protein expression, suggesting CKB expression was found to be only partly regulated by DNA methylation. Additionally, we found that alterations in the DNA methylation pattern of the three studied kinases were also associated with the gastric cancer onset, advanced gastric cancer, deeper tumor invasion and the presence of metastasis. Therefore, SRC, LYN and CKB expression or DNA methylation could be useful markers for predicting tumor progression and targeting in anti-cancer strategies.
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Affiliation(s)
- Adriano Azevedo Mello
- Centro de Ciências Biológicas e da Saúde, Universidade Federal de Campina Grande, Campina Grande, PB, Brazil
| | - Mariana Ferreira Leal
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- * E-mail:
| | - Juan Antonio Rey
- Laboratorio de Oncogenética Molecular, Hospital Universitario La Paz, Madrid, Madrid, Spain
| | | | - Leticia Martins Lamarão
- Laboratório de Testes de Ácidos Nucleicos, Fundação Centro de Hemoterapia e Hematologia do Pará, Belém, PA, Brazil
- Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
| | | | | | - Paulo Pimentel Assumpção
- Núcleo de Pesquisa em Oncologia, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, PA, Brazil
| | - Barbara do Nascimento Borges
- Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
- Centro de Tecnologia Agropecuária, Instituto Socioambiental e dos Recursos Hídricos, Universidade Federal Rural da Amazônia, Belém, PA, Brazil
| | - Marília Cardoso Smith
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Rommel Rodriguez Burbano
- Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
- Núcleo de Pesquisa em Oncologia, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, PA, Brazil
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15
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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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Leal MF, Cirilo PDR, Mazzotti TKF, Calcagno DQ, Wisnieski F, Demachki S, Martinez MC, Assumpção PP, Chammas R, Burbano RR, Smith MC. Prohibitin expression deregulation in gastric cancer is associated with the 3' untranslated region 1630 C>T polymorphism and copy number variation. PLoS One 2014; 9:e98583. [PMID: 24879411 PMCID: PMC4039508 DOI: 10.1371/journal.pone.0098583] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Accepted: 05/05/2014] [Indexed: 01/03/2023] Open
Abstract
PHB is a reported oncogene and tumor suppressor in gastric cancer. Here, we evaluated whether the PHB copy number and the rs6917 polymorphism affect its expression in gastric cancer. Down-regulation and up-regulation of PHB were observed in the evaluated tumors. Reduced expression was associated with tumor dedifferentiation and cancer initiation. The T allele of the rs6917 polymorphism was associated with reduced PHB mRNA levels. Moreover, the up-regulation of PHB appeared to be regulated by the gain of additional gene copies. Thus, PHB copy number variation and differential expression of the rs6917 polymorphism may play a role in PHB transcriptional regulation.
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Affiliation(s)
- Mariana Ferreira Leal
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- * E-mail:
| | - Priscila Daniele Ramos Cirilo
- Laboratório de Oncologia Experimental, Departamento de Radiologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
- Centro de Investigação Translacional em Oncologia, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brazil
| | - Tatiane Katsue Furuya Mazzotti
- Laboratório de Oncologia Experimental, Departamento de Radiologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
- Centro de Investigação Translacional em Oncologia, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brazil
| | - Danielle Queiroz Calcagno
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- Núcleo de Pesquisa em Oncologia, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, PA, Brazil
| | - Fernanda Wisnieski
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Samia Demachki
- Núcleo de Pesquisa em Oncologia, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, PA, Brazil
| | - Margarita Cortes Martinez
- Laboratório de Oncologia Experimental, Departamento de Radiologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
- Centro de Investigação Translacional em Oncologia, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brazil
| | - Paulo Pimentel Assumpção
- Núcleo de Pesquisa em Oncologia, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, PA, Brazil
| | - Roger Chammas
- Laboratório de Oncologia Experimental, Departamento de Radiologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
- Centro de Investigação Translacional em Oncologia, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brazil
| | - Rommel Rodríguez Burbano
- Laboratório de Citogenética Humana, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
| | - Marília Cardoso Smith
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil
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Abstract
The development of gastric adenocarcinoma is a complex multistep process involving multiple genetic alterations. Based on pathology, four different macroscopic types and at least two major histological types, intestinal and diffuse, have been described. Most gastric cancer (GC) show genetic instability, either microsatellite instability or chromosomal instability, which is considered an early event in gastric carcinogenesis. Molecular studies of alterations of single genes have provided evidence that intestinal and diffuse type GC evolve via different genetic pathways. Recent results from high-throughput whole-genome expression or copy number studies have demonstrated extensive genetic diversity between cases and within individual GC. Sets of commonly up- or downregulated microRNAs have been identified in GC and might be useful in the near future to identify pathways of GC progression. Results from detailed molecular and/or pathological GC studies, although promising, still have limited clinical utility in predicting survival and stratifying GC patients for appropriate treatment.
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Affiliation(s)
- Heike I Grabsch
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK.
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18
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López-Basave HN, Morales-Vásquez F, Ruiz-Molina JM, Namendys-Silva SA, Vela-Sarmiento I, Ruan JM, Rosciano AEP, Calderillo-Ruiz G, Díaz-Romero C, Herrera-Gómez A, Meneses-García AA. Gastric cancer in young people under 30 years of age: worse prognosis, or delay in diagnosis? Cancer Manag Res 2013; 5:31-6. [PMID: 23580357 PMCID: PMC3621605 DOI: 10.2147/cmar.s40377] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background Gastric cancer is an aggressive disease with nonspecific early symptoms. Its incidence and prognosis in young patients has shown considerable variability. Purpose of the study Our objective was to retrospectively study patients from our institution aged <30 years with gastric carcinoma. The study was undertaken to describe the experience of gastric cancer in this population, and to demonstrate its specific clinical and pathological characteristics. Materials and methods We reviewed the cases of histologically confirmed gastric cancer between 1985 and 2006 at the Instituto Nacional de Cancerología of Mexico (INCan); emphasis in our review was placed on clinical presentation, diagnostic and therapeutic intervention, pathology, and the results. Results Thirty cases of gastric carcinoma were reviewed. The patients’ median age was 27 years (range, 18–30 years) and the male:female ratio was 1:1. Conclusion Gastric cancer exhibits different behavior in patients aged, 30 years, but delay in diagnosis and the tumor’s behavior appear to be the most important factors in prognosis of the disease.
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Affiliation(s)
- Horacio Noé López-Basave
- Departamento de Cirugía Oncológica, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico
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19
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Carneiro F, Lauwers GY. Epithelial Tumours of the Stomach. MORSON AND DAWSON'S GASTROINTESTINAL PATHOLOGY 2013:180-222. [DOI: 10.1002/9781118399668.ch13] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Nagini S. Carcinoma of the stomach: A review of epidemiology, pathogenesis, molecular genetics and chemoprevention. World J Gastrointest Oncol 2012; 4:156-69. [PMID: 22844547 PMCID: PMC3406280 DOI: 10.4251/wjgo.v4.i7.156] [Citation(s) in RCA: 327] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2011] [Revised: 06/04/2012] [Accepted: 06/12/2012] [Indexed: 02/05/2023] Open
Abstract
Carcinoma of the stomach is still the second most common cause of cancer death worldwide, although the incidence and mortality have fallen dramatically over the last 50 years in many regions. The incidence of gastric cancer varies in different parts of the world and among various ethnic groups. Despite advances in diagnosis and treatment, the 5-year survival rate of stomach cancer is only 20 per cent. Stomach cancer can be classified into intestinal and diffuse types based on epidemiological and clinicopathological features. The etiology of gastric cancer is multifactorial and includes both dietary and nondietary factors. The major diet-related risk factors implicated in stomach cancer development include high content of nitrates and high salt intake. Accumulating evidence has implicated the role of Helicobacter pylori (H. pylori) infection in the pathogenesis of gastric cancer. The development of gastric cancer is a complex, multistep process involving multiple genetic and epigenetic alterations of oncogenes, tumor suppressor genes, DNA repair genes, cell cycle regulators, and signaling molecules. A plausible program for gastric cancer prevention involves intake of a balanced diet containing fruits and vegetables, improved sanitation and hygiene, screening and treatment of H. pylori infection, and follow-up of precancerous lesions. The fact that diet plays an important role in the etiology of gastric cancer offers scope for nutritional chemoprevention. Animal models have been extensively used to analyze the stepwise evolution of gastric carcinogenesis and to test dietary chemopreventive agents. Development of multitargeted preventive and therapeutic strategies for gastric cancer is a major challenge for the future.
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Affiliation(s)
- Siddavaram Nagini
- Siddavaram Nagini, Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608 002, Tamil Nadu, India
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Jun KH, Kim SY, Yoon JH, Song JH, Park WS. Amplification of the UQCRFS1 Gene in Gastric Cancers. J Gastric Cancer 2012; 12:73-80. [PMID: 22792519 PMCID: PMC3392327 DOI: 10.5230/jgc.2012.12.2.73] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Revised: 05/07/2012] [Accepted: 05/09/2012] [Indexed: 11/28/2022] Open
Abstract
PURPOSE The specific aim of this study is to unravel a DNA copy number alterations, and to search for novel genes that are associated with the development of Korean gastric cancer. MATERIALS AND METHODS We investigated a DNA copy number changes in 23 gastric adenocarcinomas by array-comparative genomic hybridization and quantitative real-time polymerase chain reaction analyses. Besides, the expression of UQCRFS1, which shows amplification in array-CGH, was examined in 186 gastric cancer tissues by an immunohistochemistry, and in 9 gastric cancer cell lines, as well as 24 gastric cancer tissues by immunoblotting. RESULTS We found common gains at 48 different loci, and a common loss at 19 different loci. Amplification of UQCRFS1 gene at 19q12 was found in 5 (21.7%) of the 23 gastric cancers in an array-comparative genomic hybridization and DNA copy number were increased in 5 (20.0%) out of the 25 gastric cancer in quantitative real-time polymerase chain reaction. In immunohistochemistry, the overexpression of the protein was detected in 105 (56.5%) out of the 186 gastric cancer tissues. Statistically, there was no significant relationship between the overexpression of UQCRFS1 and clinicopathologic parameters (P>0.05). In parallel, the overexpression of UQCRFS1 protein was confirmed in 6 (66.7%) of the 9 gastric cancer cell lines, and 12 (50.0%) of the 24 gastric cancer tissues by immunoblotting. CONCLUSIONS These results suggest that the overexpression of UQCRFS1 gene may contribute to the development and/or progression of gastric cancer, and further supported that mitochondrial change may serve as a potential cancer biomarker.
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Affiliation(s)
- Kyong Hwa Jun
- Department of General Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Su Young Kim
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jung Hwan Yoon
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jae Hwi Song
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Won Sang Park
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Carvalho J, van Grieken NC, Pereira PM, Sousa S, Tijssen M, Buffart TE, Diosdado B, Grabsch H, Santos MAS, Meijer G, Seruca R, Carvalho B, Oliveira C. Lack of microRNA-101 causes E-cadherin functional deregulation through EZH2 up-regulation in intestinal gastric cancer. J Pathol 2012; 228:31-44. [PMID: 22450781 DOI: 10.1002/path.4032] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2012] [Revised: 03/10/2012] [Accepted: 03/20/2012] [Indexed: 12/21/2022]
Abstract
E-cadherin expression disruption is commonly observed in metastatic epithelial cancers and is a crucial step in gastric cancer (GC) initiation and progression. As aberrant expression of microRNAs often perturb the normal expression/function of pivotal cancer-related genes, we characterized and dissected a pathway that causes E-cadherin dysfunction via loss of microRNA-101 and up-regulation of EZH2 expression in GC. MicroRNA microarray expression profiling and array-CGH were used to reinforce miR-101 involvement in GC. By using quantitative real-time PCR and quantitative SNaPshot genomic PCR, we confirmed that miR-101 was significantly down-regulated in GC (p < 0.0089) in comparison with normal gastric mucosas and, at least in 65% of the GC cases analysed, this down-regulation was caused by deletions and/or microdeletions at miR-101 genomic loci. Moreover, around 40% of cases showing miR-101 down-regulation displayed concomitant EZH2 over-expression (at the RNA and protein levels), which, in turn, was associated with loss/aberrant expression of E-cadherin. Interestingly, this occurred preferentially in intestinal-type GCs, retaining allele(s) untargeted by classical CDH1-inactivating mechanisms. We also demonstrated that miR-101 gain of function or direct inhibition of EZH2 in Kato III GC cells led to a strong depletion of endogenous EZH2 and consequent rescue of E-cadherin membranous localization, mimicking results obtained in clinical GC samples. In conclusion, we show that deletions and/or microdeletions at both miR-101 genomic loci cause mature miR-101 down-regulation, subsequent EZH2 over-expression and E-cadherin dysfunction, specifically in intestinal-type GC.
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Affiliation(s)
- Joana Carvalho
- Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Portugal; Faculty of Medicine, University of Porto, Portugal
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Buffart TE, Carvalho B, van Grieken NCT, van Wieringen WN, Tijssen M, Kranenbarg EMK, Verheul HMW, Grabsch HI, Ylstra B, van de Velde CJH, Meijer GA. Losses of chromosome 5q and 14q are associated with favorable clinical outcome of patients with gastric cancer. Oncologist 2012; 17:653-62. [PMID: 22531355 DOI: 10.1634/theoncologist.2010-0379] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
PURPOSE To improve the clinical outcome of patients with gastric cancer, intensified combination strategies are currently in clinical development, including combinations of more extensive surgery, (neo)adjuvant chemotherapy, and radiotherapy. The present study used DNA copy number profiling to identify subgroups of patients with different clinical outcomes. We hypothesize that, by identification of subgroups, individual treatment strategies can be selected to improve clinical outcome and to reduce unnecessary treatment toxicity for patients with gastric cancer. EXPERIMENTAL DESIGN DNA from 206 gastric cancer patients was isolated and analyzed by genomewide array comparative genomic hybridization. DNA copy number profiles were correlated with lymph node status and patient survival. In addition, heat shock protein 90 (HSP90) expression was analyzed and correlated with survival in 230 gastric cancer patients. RESULTS Frequent (>20%) DNA copy number gains and losses were observed on several chromosomal regions. Losses on 5q11.2-q31.3 and 14q32.11-q32.33 (14% of patients) were correlated with good clinical outcome in univariate and multivariate analyses, with a median disease-free survival interval of 9.2 years. In addition, loss of expression of HSP90, located on chromosome 14q32.2, was correlated with better patient survival. CONCLUSION Genomewide DNA copy number profiling allowed the identification of a subgroup of gastric cancer patients, marked by losses on chromosomes 5q11.2-q31.3 and 14q32.11-q32.33 or low HSP90 protein expression, with an excellent clinical outcome after surgery alone. We hypothesize that this subgroup of patients most likely will not benefit from (neo)adjuvant systemic treatment and/or radiotherapy, whereas anti-HSP90 therapy may have clinical potential in patients with HSP90-expressing gastric cancer, pending validation in an independent dataset.
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Affiliation(s)
- Tineke E Buffart
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
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24
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Hudler P. Genetic aspects of gastric cancer instability. ScientificWorldJournal 2012; 2012:761909. [PMID: 22606061 PMCID: PMC3353315 DOI: 10.1100/2012/761909] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2011] [Accepted: 11/30/2011] [Indexed: 12/13/2022] Open
Abstract
Unravelling the molecular mechanisms underlying gastric carcinogenesis is one of the major challenges in cancer genomics. Gastric cancer is a very complex and heterogeneous disease, and although much has been learned about the different genetic changes that eventually lead to its development, the detailed mechanisms still remain unclear. Malignant transformation of gastric cells is the consequence of a multistep process involving different genetic and epigenetic changes in numerous genes in combination with host genetic background and environmental factors. The majority of gastric adenocarcinomas are characterized by genetic instability, either microsatellite instability (MSI) or chromosomal instability (CIN). It is believed that chromosome destabilizations occur early in tumour progression. This review summarizes the most common genetic alterations leading to instability in sporadic gastric cancers and its consequences.
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Affiliation(s)
- Petra Hudler
- Medical Centre for Molecular Biology, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, Ljubljana, Slovenia.
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25
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Kong X, Wang JL, Chen HM, Fang JY. Comparison of the clinicopathological characteristics of young and elderly patients with gastric carcinoma: a meta analysis. J Surg Oncol 2012; 106:346-52. [PMID: 22331676 DOI: 10.1002/jso.23004] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2011] [Accepted: 11/21/2011] [Indexed: 12/17/2022]
Abstract
To evaluate the relationship between age and clinicopathological characteristics in gastric carcinoma patients, we performed the meta-analysis based on nine retrospective clinical trials. Comparing elderly patients with young patients it showed lower male/female ratio, more diffuse GC, more Borrmann type IV, more poorly differentiated carcinoma, more peritoneal metastasis, less vascular invasion, fewer partial resections, and better 5-year survival rate. These particular age-related characteristics need to be further investigated.
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Affiliation(s)
- Xuan Kong
- GI Division, Shanghai Jiao-Tong University School of Medicine, Renji Hospital, Shanghai Institute of Digestive Disease, Shanghai, China
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26
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Haan JC, Buffart TE, Eijk PP, van de Wiel MA, van Wieringen WN, Howdle PD, Mulder CJJ, van de Velde CJ, Quirke P, Nagtegaal ID, van Grieken NCT, Grabsch H, Meijer GA, Ylstra B. Small bowel adenocarcinoma copy number profiles are more closely related to colorectal than to gastric cancers. Ann Oncol 2011; 23:367-74. [PMID: 21586687 DOI: 10.1093/annonc/mdr122] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Small bowel adenocarcinoma (SBA) is a rare cancer and consequently, the options for clinical trials are limited. As they are treated according to either a colorectal or a gastric cancer regimen and the molecular biology of a tumor is a pivotal determinant for therapy response, chromosomal copy number aberrations were compared with the colorectal and gastric adenocarcinomas. MATERIALS AND METHODS A total of 85 microsatellite stable (MSS) adenocarcinomas from the stomach, colorectum and small bowel were selected from existing array comparative genomic hybridization (aCGH) datasets. We compared the aCGH profiles of the three tumor sites by supervised analysis and hierarchical clustering. RESULTS Hierarchical clustering revealed substantial overlap of 27 SBA copy number profiles with matched colorectal adenocarcinomas but less overlap with profiles of gastric adenocarcinomas. DNA copy number aberrations located at chromosomes 1p36.3-p34.3, 4p15.3-q35.2, 9p24.3-p11.1, 13q13.2-q31.3 and 17p13.3-p13.2 were the strongest features discriminating SBAs and colorectal adenocarcinomas from gastric adenocarcinomas. CONCLUSIONS We show that MSS SBAs are more similar to colorectal than to gastric cancer, based on the 27 genome-wide DNA copy number profiles that are currently available. These molecular similarities provide added support for treatment of MSS small bowel cancers according to colorectal cancer regimens.
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Affiliation(s)
- J C Haan
- Department of Pathology, VU University Medical Center, Amsterdam
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27
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Buffart TE, Louw M, van Grieken NCT, Tijssen M, Carvalho B, Ylstra B, Grabsch H, Mulder CJJ, van de Velde CJH, van der Merwe SW, Meijer GA. Gastric cancers of Western European and African patients show different patterns of genomic instability. BMC Med Genomics 2011; 4:7. [PMID: 21226972 PMCID: PMC3033789 DOI: 10.1186/1755-8794-4-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2010] [Accepted: 01/13/2011] [Indexed: 12/14/2022] Open
Abstract
Background Infection with H. pylori is important in the etiology of gastric cancer. Gastric cancer is infrequent in Africa, despite high frequencies of H. pylori infection, referred to as the African enigma. Variation in environmental and host factors influencing gastric cancer risk between different populations have been reported but little is known about the biological differences between gastric cancers from different geographic locations. We aim to study genomic instability patterns of gastric cancers obtained from patients from United Kingdom (UK) and South Africa (SA), in an attempt to support the African enigma hypothesis at the biological level. Methods DNA was isolated from 67 gastric adenocarcinomas, 33 UK patients, 9 Caucasian SA patients and 25 native SA patients. Microsatellite instability and chromosomal instability were analyzed by PCR and microarray comparative genomic hybridization, respectively. Data was analyzed by supervised univariate and multivariate analyses as well as unsupervised hierarchical cluster analysis. Results Tumors from Caucasian and native SA patients showed significantly more microsatellite instable tumors (p < 0.05). For the microsatellite stable tumors, geographical origin of the patients correlated with cluster membership, derived from unsupervised hierarchical cluster analysis (p = 0.001). Several chromosomal alterations showed significantly different frequencies in tumors from UK patients and native SA patients, but not between UK and Caucasian SA patients and between native and Caucasian SA patients. Conclusions Gastric cancers from SA and UK patients show differences in genetic instability patterns, indicating possible different biological mechanisms in patients from different geographical origin. This is of future clinical relevance for stratification of gastric cancer therapy.
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Affiliation(s)
- Tineke E Buffart
- Dept. of Pathology, VU University Medical Center, Amsterdam, The Netherlands
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Zhang D, Wang Z, Luo Y, Xu Y, Liu Y, Yang W, Zhang X. Analysis of DNA copy number aberrations by multiple ligation-dependent probe amplification on 50 intestinal type gastric cancers. J Surg Oncol 2010; 103:124-32. [PMID: 21259245 DOI: 10.1002/jso.21792] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2010] [Accepted: 09/26/2010] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND OBJECTIVES The molecular genetic alterations leading to gastric malignancy are largely unknown. This study aimed to unravel the genomic DNA copy number aberrations (CNAs) profile during gastric tumorigenesis. METHODS In this study, we performed genomic profiling in a set of 50 intestinal type gastric carcinomas by a PCR-based relative quantification method, multiple ligation-dependent probe amplification (MLPA) with 112 cancer-related gene loci selected throughout each human chromosome as probes of MLPA assay. RESULTS Numerous chromosomal DNA CNAs, including gains of 3p22, 4q25, 8q24, 11p13, and 20q13, and losses of 1p36 and 9p21, were identified by MLPA assay as recurrent DNA CNAs in gastric cancer. Moreover, we found the median numbers of gains, losses, and total CNAs were significantly higher in lymph node metastasis positive patients than in cases without metastasis. And gain of 11p13 and losses of 9p21.3, 11q13.3, 17q25.3, and 22q11.23 were associated with lymph node metastasis (P < 0.05). Finally, two major groups, including G1 + 2 with a large number of CNAs and G3 + 4 with a small number of CNAs, can be successfully distinguished by hierarchical cluster analysis. CONCLUSIONS Our results proved MLPA is a reliable and efficient method to evaluate DNA copy number changes in gastric cancers.
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Affiliation(s)
- Dai Zhang
- McKusick-Zhang Center for Genetic Medicine and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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Rajkumar T, Vijayalakshmi N, Gopal G, Sabitha K, Shirley S, Raja UM, Ramakrishnan SA. Identification and validation of genes involved in gastric tumorigenesis. Cancer Cell Int 2010; 10:45. [PMID: 21092330 PMCID: PMC3004887 DOI: 10.1186/1475-2867-10-45] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Accepted: 11/24/2010] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Gastric cancer is one of the common cancers seen in south India. Unfortunately more than 90% are advanced by the time they report to a tertiary centre in the country. There is an urgent need to characterize these cancers and try to identify potential biomarkers and novel therapeutic targets. MATERIALS AND METHODS We used 24 gastric cancers, 20 Paired normal (PN) and 5 apparently normal gastric tissues obtained from patients with non-gastric cancers (Apparently normal - AN) for the microarray study followed by validation of the significant genes (n = 63) by relative quantitation using Taqman Low Density Array Real Time PCR. We then used a custom made Quantibody protein array to validate the expression of 15 proteins in gastric tissues (4 AN, 9 PN and 9 gastric cancers). The same array format was used to study the plasma levels of these proteins in 58 patients with gastric cancers and 18 from patients with normal/non-malignant gastric conditions. RESULTS Seventeen genes (ASPN, CCL15/MIP-1δ, MMP3, SPON2, PRSS2, CCL3, TMEPAI/PMEPAI, SIX3, MFNG, SOSTDC1, SGNE1, SST, IGHA1, AKR1B10, FCGBP, ATP4B, NCAPH2) were shown to be differentially expressed between the tumours and the paired normal, for the first time. EpCAM (p = 0.0001), IL8 (p = 0.0003), CCL4/MIP-1β (p = 0.0026), CCL20/MIP-3α (p = 0.039) and TIMP1 (p = 0.0017) tissue protein levels were significantly different (Mann Whitney U test) between tumours versus AN & PN. In addition, median plasma levels of IL8, CXCL9/MIG, CCL3/MIP-1α, CCL20/MIP-3α, PDGFR-B and TIMP1 proteins were significantly different between the non-malignant group and the gastric cancer group. The post-surgical levels of EpCAM, IGFBP3, IL8, CXCL10/IP10, CXCL9/MIG, CCL3/MIP-1α, CCL20/MIP-3α, SPP1/OPN and PDGFR-B showed a uniform drop in all the samples studied. CONCLUSIONS Our study has identified several genes differentially expressed in gastric cancers, some for the first time. Some of these have been confirmed at the protein level, as well. Some of these proteins will need to be evaluated further for their potential as diagnostic biomarkers in gastric cancers and some could be useful as follow-up markers in gastric cancer.
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Affiliation(s)
- Thangarajan Rajkumar
- Dept. of Molecular Oncology, Cancer Institute (WIA), 38, Sardar Patel Road, Chennai - 600036, India
| | | | - Gopisetty Gopal
- Dept. of Molecular Oncology, Cancer Institute (WIA), 38, Sardar Patel Road, Chennai - 600036, India
| | - Kesavan Sabitha
- Dept. of Molecular Oncology, Cancer Institute (WIA), 38, Sardar Patel Road, Chennai - 600036, India
| | - Sundersingh Shirley
- Dept. of Pathology, Cancer Institute (WIA), 38, Sardar Patel Road, Chennai - 600036, India
| | - Uthandaraman M Raja
- Dept. of Molecular Oncology, Cancer Institute (WIA), 38, Sardar Patel Road, Chennai - 600036, India
| | - Seshadri A Ramakrishnan
- Dept. of Surgical Oncology, Cancer Institute (WIA), 38, Sardar Patel Road, Chennai - 600036, India
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Xie HL, Li ZY, Gan RL, Li XJ, Zhang QL, Hui M, Zhou XT. Differential gene and protein expression in primary gastric carcinomas and their lymph node metastases as revealed by combined cDNA microarray and tissue microarray analysis. J Dig Dis 2010; 11:167-75. [PMID: 20579220 DOI: 10.1111/j.1751-2980.2010.00432.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To gain insight into the molecular events of lymph node metastasis of human gastric carcinoma. METHODS The gene expression profile of five matched primary gastric carcinomas and their lymph node metastases was analyzed by complementary DNA (cDNA) microarray. Differential genes were identified in the metastatic and corresponding primary tumor pairs. Among the differentially expressed genes, carbonic anhydrase II (CAII) and insulin-like growth factor binding protein 4 (IGFBP 4) genes were detected by RT-PCR. CTTN protein expression was examined by tissue microarray. RESULTS There was a high expression (over twofold) of 44 genes and a low expression (under twofold) of 32 genes in lymph node metastasis compared with primary gastric carcinoma, respectively. CAII mRNA was downregulated and IGFBP 4 mRNA was upregulated in paired lymph node metastases of gastric carcinomas. The overexpression of CTTN protein was related to the lymph node metastasis and the clinical stage of gastric carcinomas. CONCLUSION This study showed that there is a low expression of genes relative to growth signal and immune response in lymph node metastases, and a high expression of genes relative to growth factor, cell cycle, cell motility and adhesion in lymph node metastases compared with primary gastric carcinomas. The expression of CTTN was related to the invasion and metastasis of gastric cancer.
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Affiliation(s)
- Hai Long Xie
- Cancer Research Institute, Medical College of University of South China, Hengyang, Hunan Province, China
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Uchida M, Tsukamoto Y, Uchida T, Ishikawa Y, Nagai T, Hijiya N, Nguyen LT, Nakada C, Kuroda A, Okimoto T, Kodama M, Murakami K, Noguchi T, Matsuura K, Tanigawa M, Seto M, Ito H, Fujioka T, Takeuchi I, Moriyama M. Genomic profiling of gastric carcinoma in situ and adenomas by array-based comparative genomic hybridization. J Pathol 2010; 221:96-105. [PMID: 20217874 DOI: 10.1002/path.2686] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Although genomic copy number aberrations (CNAs) of gastric carcinoma at the advanced stage have already been extensively characterized by array comparative genomic hybridization (array CGH) analysis, those of gastric carcinoma in situ (CIS) are still poorly understood. Furthermore, no reports have demonstrated correlations between CNAs and histopathological features of gastric adenoma. In this study, we investigated CNAs of 20 gastric CISs (Vienna category 4.2) and 20 adenomas including seven low-grade adenomas (LGA; Vienna category 3) and 13 high-grade adenomas (HGA; Vienna category 4.1), using oligonucleotide-based array CGH. The most frequent aberrations in CIS were gains at 8q (85%) and 20q (50%), and losses at 5q (50%) and 17p (50%), suggesting that these CNAs are involved in the development of CIS. We found that the pattern of CNAs in HGA was quite different from that in LGA. The most frequent CNAs in HGA were gains at 8q (62%) and 7pq (54%), whereas those in LGA were gain at 7q21.3-q22.1 (57%) and loss at 5q (43%). Interestingly, gains at 8q and 7pq, both of which occurred most frequently in HGA, were not detected in any cases of LGA. Of note, 8q gain was detected most frequently in both HGA and CIS but was undetected in LGA. Since HGA is believed to have a higher risk of progression to invasive carcinoma than LGA, these data suggest that 8q gain is important for the malignant transformation of gastric adenoma.
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Affiliation(s)
- Masahiro Uchida
- Department of Molecular Pathology, Oita University, Oita, Japan
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Diosdado B, Buffart TE, Watkins R, Carvalho B, Ylstra B, Tijssen M, Bolijn AS, Lewis F, Maude K, Verbeke C, Nagtegaal ID, Grabsch H, Mulder CJJ, Quirke P, Howdle P, Meijer GA. High-resolution array comparative genomic hybridization in sporadic and celiac disease-related small bowel adenocarcinomas. Clin Cancer Res 2010; 16:1391-401. [PMID: 20179237 DOI: 10.1158/1078-0432.ccr-09-1773] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE The molecular pathogenesis of small intestinal adenocarcinomas is not well understood. Understanding the molecular characteristics of small bowel adenocarcinoma may lead to more effective patient treatment. EXPERIMENTAL DESIGN Forty-eight small bowel adenocarcinomas (33 non-celiac disease related and 15 celiac disease related) were characterized for chromosomal aberrations by high-resolution array comparative hybridization, microsatellite instability, and APC promoter methylation and mutation status. Findings were compared with clinicopathologic and survival data. Furthermore, molecular alterations were compared between celiac disease-related and non-celiac disease-related small bowel adenocarcinomas. RESULTS DNA copy number changes were observed in 77% small bowel adenocarcinomas. The most frequent DNA copy number changes found were gains on 5p15.33-5p12, 7p22.3-7q11.21, 7q21.2-7q21.3, 7q22.1-7q34, 7q36.1, 7q36.3, 8q11.21-8q24.3, 9q34.11-9q34.3, 13q11-13q34, 16p13.3, 16p11.2, 19q13.2, and 20p13-20q13.33, and losses on 4p13-4q35.2, 5q15-5q21.1, and 21p11.2-21q22.11. Seven highly amplified regions were identified on 6p21.1, 7q21.1, 8p23.1, 11p13, 16p11.2, 17q12-q21.1, and 19q13.2. Celiac disease-related and non-celiac disease-related small bowel adenocarcinomas displayed similar chromosomal aberrations. Promoter hypermethylation of the APC gene was found in 48% non-celiac disease-related and 73% celiac disease-related small bowel adenocarcinomas. No nonsense mutations were found. Thirty-three percent of non-celiac disease-related small bowel adenocarcinomas showed microsatellite instability, whereas 67% of celiac disease-related small bowel adenocarcinomas were microsatellite unstable. CONCLUSIONS Our study characterized chromosomal aberrations and amplifications involved in small bowel adenocarcinoma. At the chromosomal level, celiac disease-related and non-celiac disease-related small bowel adenocarcinomas did not differ. A defect in the mismatch repair pathways seems to be more common in celiac disease-related than in non-celiac disease-related small bowel adenocarcinomas. In contrast to colon and gastric cancers, no APC nonsense mutations were found in small bowel adenocarcinoma. However, APC promoter methylation seems to be a common event in celiac disease-related small bowel adenocarcinoma. Clin Cancer Res; 16(5); 1391-401.
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Affiliation(s)
- Begoña Diosdado
- Departments of Pathology and Gastroenterology, VU University Medical Center, Amsterdam, The Netherlands.
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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: 41] [Impact Index Per Article: 2.7] [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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Wang S, Tian L, Zeng Z, Zhang M, Wu K, Chen M, Fan D, Hu P, Sung JJY, Yu J. IkappaBalpha polymorphism at promoter region (rs2233408) influences the susceptibility of gastric cancer in Chinese. BMC Gastroenterol 2010; 10:15. [PMID: 20132559 PMCID: PMC2829487 DOI: 10.1186/1471-230x-10-15] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2009] [Accepted: 02/05/2010] [Indexed: 01/15/2023] Open
Abstract
Background Nuclear factor of kappa B inhibitor alpha (IκBα) protein is implicated in regulating a variety of cellular process from inflammation to tumorigenesis. The objective of this study was to investigate the susceptibility of rs2233408 T/C genotype in the promoter region of IκBα to gastric cancer and the association of this polymorphism with clinicopathologic variables in gastric cancer patients. Methods A population-based case-control study was conducted between 1999 and 2006 in Guangdong Province, China. A total of 564 gastric cancer patients and 566 healthy controls were enrolled in this study. rs2233408 genotypes in IκBα were analyzed by TaqMan SNP genotyping assay. Results Both rs2233408 T homozygote (TT) and T heterozygotes (TC and TT) had significantly reduced gastric cancer risk (TT: OR = 0.250, 95% CI = 0.069-0.909, P = 0.035; TC and TT: OR = 0.721, 95% CI = 0.530-0.981, P = 0.037), compared with rs2233408 C homozygote (CC). rs2233408 T heterozygotes were significantly associated with reduced risk of intestinal-type gastric cancer with ORs of 0.648 (95% CI = 0.459-0.916, P = 0.014), but not with the diffuse or mix type of gastric cancer. The association between rs2233408 T heterozygotes and gastric cancer appeared more apparent in the older patients (age>40) (OR = 0.674, 95% CI = 0.484-0.939, P = 0.02). rs2233408 T heterozygotes was associated with non-cardiac gastric cancer (OR = 0.594, 95% CI = 0.411-0.859, P = 0.006), but not with cardiac gastric cancer. However, rs2233408 polymorphism was not associated with the prognosis of gastric cancer patients. Conclusions IκBα rs2233408 T heterozygotes were associated with reduced risk of gastric cancer, especially for the development of certain subtypes of gastric cancer in Chinese population.
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Affiliation(s)
- Shiyan Wang
- Institute of Digestive Disease and Department of Meddicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
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Abstract
Despite a sharp decline in the incidence of gastric cancer during the second half of the 20th century, this malignancy remains the second leading cause of cancer mortality in the world. The incidence and mortality rate of gastric cancer increase with age; at present, the median ages at diagnosis are 67 years for men and 72 years for women in the US. This article reviews and discusses current medical treatment options for both the general population and elderly gastric cancer patients. Management of localized gastric cancer has changed significantly over recent years. Adjuvant chemoradiation is not generally recommended outside the US. After decades of trials of adjuvant chemotherapy with inconclusive results, a significant survival benefit for perioperative combination chemotherapy - as compared with surgery alone - in patients with resectable or locally advanced gastro-oesophageal cancer was recently demonstrated in the UK MAGIC trial. A further large, randomized trial from Japan demonstrated a significant survival benefit for adjuvant chemotherapy with S-1 after D2 resection for gastric cancer. However, both trials are applicable only to the population in which the trials were conducted. Specific data on elderly patients are missing. For patients with metastatic disease, oral fluoropyrimidines, such as capecitabine, have been developed. In Asian patients, treatment with the oral fluoropyrimidine S-1 is safe and effective. Docetaxel, oxaliplatin and irinotecan have demonstrated activity against gastric cancer in appropriately designed, randomized, phase III trials and have increased the available treatment options significantly. In addition, according to preliminary data, trastuzumab in combination with chemotherapy has significantly improved activity when compared to chemotherapy alone in patients with human epidermal receptor (HER)-2-positive gastric and gastro-oesophageal cancers. Thus, therapeutic decisions in patients with advanced gastric cancer may be adapted to the molecular subtype and co-morbidities of the individual patient. Data from retrospective analyses suggest that oxaliplatin seems to be better tolerated than cisplatin in elderly patients.
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Affiliation(s)
- Anna Dorothea Wagner
- Multidisciplinary Oncology Center, University of Lausanne Hospitals, Lausanne, Switzerland
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Kim HG, Lee S, Kim DY, Ryu SY, Joo JK, Kim JC, Lee KH, Lee JH. Aberrant methylation of DNA mismatch repair genes in elderly patients with sporadic gastric carcinoma: A comparison with younger patients. J Surg Oncol 2010; 101:28-35. [PMID: 19894224 DOI: 10.1002/jso.21432] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hypermethylation of promoters that regulate the expression of DNA repair genes is associated with gastric carcinoma (GC). Little is known regarding the association between age of disease onset and differences in molecular profiles. METHODS The two study groups consisted of 100 elderly patients and 100 younger patients. The aberrant DNA methylation patterns of four mismatch repair genes, hMLH1, hMSH2, hMSH3, and MGMT, were compared by bisulfite modification and methylation-specific PCR (MSP). RESULTS The methylation frequencies for hMLH1 and hMSH3 were significantly higher for the elderly than for the younger GC patients (P < 0.001 and P = 0.031, respectively). A significant correlation was observed between aberrant hMLH1, hMSH3, and MGMT methylation and the loss of hMLH1, hMSH3, and MGMT protein expression (P < 0.001, P = 0.002, and P = 0.001, respectively). The prevalence of aberrant hMLH1 and hMSH3 methylation increased significantly with age. CONCLUSION These results suggest that the methylation of hMLH1 and hMSH3 is age related and thus may play an important role in gastric carcinogenesis in the elderly. Screening for hMLH1 and hMSH3 methylation may have clinical significance for the evaluation of elderly patients with GC.
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Affiliation(s)
- Ho Gun Kim
- Division of Gastroenterologic Surgery, Department of Surgery, Chonnam National University Medical School, Gwangju 501-757, Korea
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Nakamura Y, Migita T, Hosoda F, Okada N, Gotoh M, Arai Y, Fukushima M, Ohki M, Miyata S, Takeuchi K, Imoto I, Katai H, Yamaguchi T, Inazawa J, Hirohashi S, Ishikawa Y, Shibata T. Krüppel-like factor 12 plays a significant role in poorly differentiated gastric cancer progression. Int J Cancer 2009; 125:1859-67. [PMID: 19588488 DOI: 10.1002/ijc.24538] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Gastric cancer is the second common malignant neoplasia in Japan, and its poorly differentiated form is a deadly disease. To identify novel candidate oncogenes contributing to its genesis, we examined copy-number alterations in 50 primary poorly differentiated gastric cancers using an array-based comparative genomic hybridization (array-CGH). Many genetic changes were identified, including a novel amplification of the 13q22 locus. Several genes are located in this locus, and selective knockdown of one for the Krüppel-like factor 12 (KLF12) induced significant growth-arrest in the HGC27 gastric cancer cell line. Microarray analysis also demonstrated that genes associated with cell proliferation were mostly changed by KLF12 knockdown. To explore the oncogenic function of KLF12, we introduced a full length of human KLF12 cDNA into NIH3T3 and AZ-521 cell lines and found that overexpression significantly enhanced their invasive potential. In clinical samples, KLF12 mRNA in cancer tissue was increased in 11 of 28 cases (39%) when compared with normal gastric epithelium. Clinicopathological analysis further demonstrated a significant correlation between KLF12mRNA levels and tumor size (p = 0.038). These data suggest that the KLF12 gene plays an important role in poorly differentiated gastric cancer progression and is a potential target of therapeutic measures.
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Affiliation(s)
- Yu Nakamura
- Cancer Genomics Project, National Cancer Center Research Institute, Tokyo 104-0045, Japan
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Buffart TE, van Grieken NCT, Tijssen M, Coffa J, Ylstra B, Grabsch HI, van de Velde CJH, Carvalho B, Meijer GA. High resolution analysis of DNA copy-number aberrations of chromosomes 8, 13, and 20 in gastric cancers. Virchows Arch 2009; 455:213-23. [PMID: 19697059 PMCID: PMC2744787 DOI: 10.1007/s00428-009-0814-y] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2009] [Revised: 07/12/2009] [Accepted: 07/16/2009] [Indexed: 02/06/2023]
Abstract
DNA copy-number gains of chromosomes 8q, 13q, and 20q are frequently observed in gastric cancers. Moreover gain of chromosome 20q has been associated with lymph node metastasis. The aim of this study was to correlate DNA copy-number changes of individual genes on chromosomes 8q, 13q, and 20q in gastric adenocarcinomas to clinicopathological data. DNA isolated from 63 formalin-fixed and paraffin-embedded gastric adenocarcinoma tissue samples was analyzed by whole-genome microarray comparative genomic hybridization and by multiplex ligation-dependent probe amplification (MLPA), targeting 58 individual genes on chromosomes 8, 13, and 20. Using array comparative genomic hybridization, gains on 8q, 13q, and 20q were observed in 49 (77.8%), 25 (39.7%), and 49 (77.8%) gastric adenocarcinomas, respectively. Gain of chromosome 20q was significantly correlated with lymph node metastases (p = 0.05) and histological type (p = 0.02). MLPA revealed several genes to be frequently gained in DNA copy number. The oncogene c-myc on 8q was gained in 73% of the cancers, while FOXO1A and ATP7B on 13q were both gained in 28.6% of the cases. Multiple genes on chromosome 20q showed gains in more than 60% of the cancers. DNA copy-number gains of TNFRSF6B (20q13.3) and ZNF217 (20q13.2) were significantly associated with lymph node metastasis (p = 0.02) and histological type (p = 0.02), respectively. In summary, gains of chromosomes 8q, 13q, and 20q in gastric adenocarcinomas harbor DNA copy-number gains of known and putative oncogenes. ZNF217 and TNFRSF6B are associated with important clinicopathological variables, including lymph node status.
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Affiliation(s)
- Tineke E Buffart
- Department of Pathology, VU University Medical Center, PO Box 7057, 1007, Amsterdam, The Netherlands
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Abstract
Gastric cancer is the second most frequent cause of cancer death worldwide, although much geographical variation in incidence exists. Prevention and personalised treatment are regarded as the best options to reduce gastric cancer mortality rates. Prevention strategies should be based on specific risk profiles, including Helicobacter pylori genotype, host gene polymorphisms, presence of precursor lesions, and environmental factors. Although adequate surgery remains the cornerstone of gastric cancer treatment, this single modality treatment seems to have reached its maximum achievable effect for local control and survival. Minimally invasive techniques can be used for treatment of early gastric cancers. Achievement of locoregional control for advanced disease remains very difficult. Extended resections that are standard practice in some Asian countries have not been shown to be as effective in other developed countries. We present an update of the incidence, causes, pathology, and treatment of gastric cancer, consisting of surgery, new strategies with neoadjuvant and adjuvant chemotherapy or radiotherapy, or both, novel treatment strategies using gene signatures, and the effect of caseload on patient outcomes.
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Affiliation(s)
- Henk H Hartgrink
- Department of Surgery, Leiden University Medical Centre, Leiden, the Netherlands
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Zeng J, Wang L, Li Q, Li W, Björkholm M, Jia J, Xu D. FoxM1is up-regulated in gastric cancer and its inhibition leads to cellular senescence, partially dependent onp27kip1. J Pathol 2009; 218:419-27. [DOI: 10.1002/path.2530] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Hartgrink HH, Jansen EPM, van Grieken NCT, van de Velde CJH. Gastric cancer. LANCET (LONDON, ENGLAND) 2009. [PMID: 19625077 DOI: 10.1016/s0140-6736(09)] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Gastric cancer is the second most frequent cause of cancer death worldwide, although much geographical variation in incidence exists. Prevention and personalised treatment are regarded as the best options to reduce gastric cancer mortality rates. Prevention strategies should be based on specific risk profiles, including Helicobacter pylori genotype, host gene polymorphisms, presence of precursor lesions, and environmental factors. Although adequate surgery remains the cornerstone of gastric cancer treatment, this single modality treatment seems to have reached its maximum achievable effect for local control and survival. Minimally invasive techniques can be used for treatment of early gastric cancers. Achievement of locoregional control for advanced disease remains very difficult. Extended resections that are standard practice in some Asian countries have not been shown to be as effective in other developed countries. We present an update of the incidence, causes, pathology, and treatment of gastric cancer, consisting of surgery, new strategies with neoadjuvant and adjuvant chemotherapy or radiotherapy, or both, novel treatment strategies using gene signatures, and the effect of caseload on patient outcomes.
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Affiliation(s)
- Henk H Hartgrink
- Department of Surgery, Leiden University Medical Centre, Leiden, the Netherlands
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Vékony H, Röser K, Löning T, Ylstra B, Meijer GA, van Wieringen WN, van de Wiel MA, Carvalho B, Kok K, Leemans CR, van der Waal I, Bloemena E. Copy number gain at 8q12.1-q22.1 is associated with a malignant tumor phenotype in salivary gland myoepitheliomas. Genes Chromosomes Cancer 2009; 48:202-12. [PMID: 19009612 DOI: 10.1002/gcc.20631] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Salivary gland myoepithelial tumors are relatively uncommon tumors with an unpredictable clinical course. More knowledge about their genetic profiles is necessary to identify novel predictors of disease. In this study, we subjected 27 primary tumors (15 myoepitheliomas and 12 myoepithelial carcinomas) to genome-wide microarray-based comparative genomic hybridization (array CGH). We set out to delineate known chromosomal aberrations in more detail and to unravel chromosomal differences between benign myoepitheliomas and myoepithelial carcinomas. Patterns of DNA copy number aberrations were analyzed by unsupervised hierarchical cluster analysis. Both benign and malignant tumors revealed a limited amount of chromosomal alterations (median of 5 and 7.5, respectively). In both tumor groups, high frequency gains (> or =20%) were found mainly at loci of growth factors and growth factor receptors (e.g., PDGF, FGF(R)s, and EGFR). In myoepitheliomas, high frequency losses (> or =20%) were detected at regions of proto-cadherins. Cluster analysis of the array CGH data identified three clusters. Differential copy numbers on chromosome arm 8q and chromosome 17 set the clusters apart. Cluster 1 contained a mixture of the two phenotypes (n = 10), cluster 2 included mostly benign tumors (n = 10), and cluster 3 only contained carcinomas (n = 7). Supervised analysis between malignant and benign tumors revealed a 36 Mbp-region at 8q being more frequently gained in malignant tumors (P = 0.007, FDR = 0.05). This is the first study investigating genomic differences between benign and malignant myoepithelial tumors of the salivary glands at a genomic level. Both unsupervised and supervised analysis of the genomic profiles revealed chromosome arm 8q to be involved in the malignant phenotype of salivary gland myoepitheliomas.
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Affiliation(s)
- Hedy Vékony
- Department of Oral and Maxillofacial Surgery/Oral Pathology, Academic Centre for Dentistry (ACTA), VU University Medical Center, Amsterdam, The Netherlands
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Buffart TE, Tijssen M, El-Bchiri J, Duval A, van de Wiel MA, Ylstra B, Meijer GA, Carvalho B. NMD inhibition fails to identify tumour suppressor genes in microsatellite stable gastric cancer cell lines. BMC Med Genomics 2009; 2:39. [PMID: 19563644 PMCID: PMC2709900 DOI: 10.1186/1755-8794-2-39] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2008] [Accepted: 06/29/2009] [Indexed: 12/05/2022] Open
Abstract
Background Gastric cancers frequently show chromosomal alterations which can cause activation of oncogenes, and/or inactivation of tumour suppressor genes. In gastric cancer several chromosomal regions are described to be frequently lost, but for most of the regions, no tumour suppressor genes have been identified yet. The present study aimed to identify tumour suppressor genes inactivated by nonsense mutation and deletion in gastric cancer by means of GINI (gene identification by nonsense mediated decay inhibition) and whole genome copy number analysis. Methods Two non-commercial gastric cancer cell lines, GP202 and IPA220, were transfected with siRNA directed against UPF1, to specifically inhibit the nonsense mediated decay (NMD) pathway, and with siRNA directed against non-specific siRNA duplexes (CVII) as a control. Microarray expression experiments were performed in triplicate on 4 × 44 K Agilent arrays by hybridizing RNA from UPF1-transfected cells against non-specific CVII-transfected cells. In addition, array CGH of the two cell lines was performed on 4 × 44K agilent arrays to obtain the DNA copy number profiles. Mutation analysis of GINI candidates was performed by sequencing. Results UPF1 expression was reduced for >70% and >80% in the GP202 and IPA220 gastric cancer cell lines, respectively. Integration of array CGH and microarray expression data provided a list of 134 and 50 candidate genes inactivated by nonsense mutation and deletion for GP202 and IPA220, respectively. We selected 12 candidate genes for mutation analysis. Of these, sequence analysis was performed on 11 genes. One gene, PLA2G4A, showed a silent mutation, and in two genes, CTSA and PTPRJ, missense mutations were detected. No nonsense mutations were detected in any of the 11 genes tested. Conclusion Although UPF1 was substantially repressed, thus resulting in the inhibition of the NMD system, we did not find genes inactivated by nonsense mutations. Our results show that the GINI strategy leads to a high number of false positives.
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Affiliation(s)
- Tineke E Buffart
- Dept Pathology, VU University Medical Center, Amsterdam, The Netherlands.
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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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Battling cancer on many fronts. Meeting on New Battlefields in Human Cancer--Attacking in Many Fronts. EMBO Rep 2009; 9:853-8. [PMID: 18688257 DOI: 10.1038/embor.2008.140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2008] [Accepted: 06/23/2008] [Indexed: 11/08/2022] Open
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Tsukamoto Y, Uchida T, Karnan S, Noguchi T, Nguyen LT, Tanigawa M, Takeuchi I, Matsuura K, Hijiya N, Nakada C, Kishida T, Kawahara K, Ito H, Murakami K, Fujioka T, Seto M, Moriyama M. Genome-wide analysis of DNA copy number alterations and gene expression in gastric cancer. J Pathol 2008; 216:471-82. [PMID: 18798223 DOI: 10.1002/path.2424] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Genomic copy number aberrations (CNAs) are believed to play a major role in the development and progression of human cancers. Although many CNAs have been reported in gastric cancer, their genome-wide transcriptional consequences are poorly understood. In this study, to reveal the impact of CNAs on genome-wide expression in gastric cancer, we analysed 30 cases of gastric cancers for their CNAs by array comparative genomic hybridization (array CGH) and 24 of these 30 cases for their expression profiles by oligonucleotide-expression microarray. We found that with the application of laser microdissection, most CNAs were detected at higher frequency than in previous studies. Notably, gain at 20q13 was detected in almost all cases (97%), suggesting that this may play an important role in the pathogenesis of gastric cancer. By comparing the array CGH data with expression profiles of the same samples, we showed that both genomic amplification and deletion strongly influence the expression of genes in altered genomic regions. Furthermore, we identified 125 candidate genes, consisting of 114 up-regulated genes located in recurrent regions (>10%) of amplification and 11 down-regulated genes located in recurrent regions of deletion. Up-regulation of several candidate genes, such as CDC6, SEC61G, ANP32E, BYSL and FDFT1, was confirmed by immunohistochemistry. Interestingly, some candidate genes were localized at genomic loci adjacent to well-known genes such as EGFR, ERBB2 and SMAD4, and concordantly deregulated by genomic alterations. Based on these results, we propose that our list of candidate genes may contain novel genes involved in the pathogenesis of advanced gastric cancer.
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Affiliation(s)
- Y Tsukamoto
- Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan
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Abstract
T-lymphocyte maturation associated protein, MAL, has been described as a tumour-suppressor gene with diagnostic value in colorectal and oesophageal cancers, and can be inactivated by promoter hypermethylation. The aim of this study was to analyse the prevalence of MAL promoter hypermethylation and the association with mRNA expression in gastric cancers and to correlate methylation status to clinicopathological data. Bisulphite-treated DNA isolated from formalin-fixed and paraffin-embedded samples of 202 gastric adenocarcinomas and 22 normal gastric mucosae was subjected to real-time methylation-specific PCR (Q-MSP). Two regions within the MAL promoter (M1 and M2) were analysed. In addition, 17 frozen gastric carcinomas and two gastric cancer cell lines were analysed both by Q-MSP and real-time RT–PCR. Methylation of M1 and M2 occurred in 71 and 80% of the gastric cancers, respectively, but not in normal gastric mucosa tissue. Hypermethylation of M2, but not M1, correlated with significantly better disease-free survival in a univariate (P=0.03) and multivariate analysis (P=0.03) and with downregulation of expression (P=0.01). These results indicate that MAL has a putative tumour-suppressor gene function in gastric cancer, and detection of promoter hypermethylation may be useful as a prognostic marker.
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Buffart TE, Israeli D, Tijssen M, Vosse SJ, Mršić A, Meijer GA, Ylstra B. Across array comparative genomic hybridization: A strategy to reduce reference channel hybridizations. Genes Chromosomes Cancer 2008; 47:994-1004. [DOI: 10.1002/gcc.20605] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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Nasri S, More H, Graziano F, Ruzzo A, Wilson E, Dunbier A, McKinney C, Merriman T, Guilford P, Magnani M, Humar B. A novel diffuse gastric cancer susceptibility variant in E-cadherin (CDH1) intron 2: a case control study in an Italian population. BMC Cancer 2008; 8:138. [PMID: 18482459 PMCID: PMC2412889 DOI: 10.1186/1471-2407-8-138] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2007] [Accepted: 05/15/2008] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Inherited genetic factors such as E-cadherin (CDH1) promoter variants are believed to influence the risk towards sporadic diffuse gastric cancer (DGC). Recently, a new regulatory region essential for CDH1 transcription has been identified in CDH1 intron 2. METHODS We genotyped all known polymorphisms located within conserved sequences of CDH1 intron 2 (rs10673765, rs9932686, rs1125557, rs9282650, rs9931853) in an Italian population consisting of 134 DGC cases and 100 healthy controls (55 patient relatives and 45 unrelated, matched individuals). The influence of individual variants on DGC risk was assessed using chi2-tests and logistic regression. The relative contribution of alleles was estimated by haplotype analysis. RESULTS We observed a significant (p < 0.0004) association of the CDH1 163+37235G>A variant (rs1125557) with DGC risk. Odds ratios were 4.55 (95%CI = 2.09-9.93) and 1.38 (95%CI = 0.75-2.55) for AA and GA carriers, respectively. When adjusted for age, sex, smoking status, alcohol intake and H. pylori infection, the risk estimates remained largely significant for AA carriers. Haplotype analysis suggested the 163+37235A-allele contributes to disease risk independently of the other variants studied. CONCLUSION The CDH1 163+37235G>A polymorphism may represent a novel susceptibility variant for sporadic DGC if confirmed in other populations. Considering the broad expression of E-cadherin in epithelia, this exploratory study encourages further evaluation of the 163+37235A-allele as a susceptibility variant in other carcinomas.
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Affiliation(s)
- Soroush Nasri
- Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin 9054, Aotearoa New Zealand.
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