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de Back TR, van Hooff SR, Sommeijer DW, Vermeulen L. Transcriptomic subtyping of gastrointestinal malignancies. Trends Cancer 2024; 10:842-856. [PMID: 39019673 DOI: 10.1016/j.trecan.2024.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 06/17/2024] [Accepted: 06/20/2024] [Indexed: 07/19/2024]
Abstract
Gastrointestinal (GI) cancers are highly heterogeneous at multiple levels. Tumor heterogeneity can be captured by molecular profiling, such as genetic, epigenetic, proteomic, and transcriptomic classification. Transcriptomic subtyping has the advantage of combining genetic and epigenetic information, cancer cell-intrinsic properties, and the tumor microenvironment (TME). Unsupervised transcriptomic subtyping systems of different GI malignancies have gained interest because they reveal shared biological features across cancers and bear prognostic and predictive value. Importantly, transcriptomic subtypes accurately reflect complex phenotypic states varying not only per tumor region, but also throughout disease progression, with consequences for clinical management. Here, we discuss methodologies of transcriptomic subtyping, proposed taxonomies for GI malignancies, and the challenges posed to clinical implementation, highlighting opportunities for future transcriptomic profiling efforts to optimize clinical impact.
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Affiliation(s)
- Tim R de Back
- Cancer Center Amsterdam, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; Oncode Institute, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Sander R van Hooff
- Cancer Center Amsterdam, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; Oncode Institute, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Dirkje W Sommeijer
- Flevohospital, Department of Internal Medicine, Hospitaalweg 1, 1315 RA, Almere, The Netherlands
| | - Louis Vermeulen
- Cancer Center Amsterdam, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; Oncode Institute, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
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Ishikawa A, Fukui T, Kido A, Katsuya N, Kuraoka K, Uraoka N, Suzuki T, Oka S, Kotachi T, Ashktorab H, Smoot D, Yasui W. Discovering cancer stem-like molecule, nuclear factor I X, using spatial transcriptome in gastric cancer. Cancer Sci 2024; 115:3180-3193. [PMID: 39021298 PMCID: PMC11462935 DOI: 10.1111/cas.16288] [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: 04/09/2024] [Revised: 07/03/2024] [Accepted: 07/04/2024] [Indexed: 07/20/2024] Open
Abstract
Gastric cancer (GC) is characterized by significant intratumoral heterogeneity, and stem cells are promising therapeutic targets. Despite advancements in spatial transcriptome analyses, unexplored targets for addressing cancer stemness remain unknown. This study aimed to identify Nuclear Factor IX (NFIX) as a critical regulator of cancer stemness in GC and evaluate its clinicopathological significance and function. Spatial transcriptome analysis of GC was conducted. The correlation between NFIX expression, clinicopathological factors, and prognosis was assessed using immunostaining in 127 GC cases. Functional analyses of cancer cell lines validated these findings. Spatial transcriptome analysis stratified GC tissues based on genetic profiles, identified CSC-like cells, and further refined the classification to identify and highlight the significance of NFIX, as validated by Monocle 3 and CytoTRACE analyses. Knockdown experiments in cancer cell lines have demonstrated the involvement of NFIX in cancer cell proliferation and kinase activity. This study underscores the role of spatial transcriptome analysis in refining GC tissue classification and identifying therapeutic targets, highlighting NFIX as a pivotal factor. NFIX expression is correlated with poor prognosis and drives GC progression, suggesting its potential as a novel therapeutic target for personalized GC therapies.
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Affiliation(s)
- Akira Ishikawa
- Department of Molecular PathologyGraduate School of Biomedical and Health Sciences, Hiroshima UniversityHiroshimaJapan
| | - Takafumi Fukui
- Department of Molecular PathologyGraduate School of Biomedical and Health Sciences, Hiroshima UniversityHiroshimaJapan
| | - Aya Kido
- Department of Molecular PathologyGraduate School of Biomedical and Health Sciences, Hiroshima UniversityHiroshimaJapan
| | - Narutaka Katsuya
- Department of Molecular PathologyGraduate School of Biomedical and Health Sciences, Hiroshima UniversityHiroshimaJapan
| | - Kazuya Kuraoka
- Department of Diagnostic PathologyNational Hospital Organization (NHO), Kure Medical Center and Chugoku Cancer CenterKureHiroshimaJapan
| | - Naohiro Uraoka
- Department of PathologyKure Kyosai Hospital, Federation of National Public Services and Affiliated Personnel Mutual Aid AssociationsKureJapan
| | - Takahisa Suzuki
- Department of SurgeryNational Hospital Organization (NHO), Kure Medical Center and Chugoku Cancer CenterKureHiroshimaJapan
| | - Shiro Oka
- Department of GastroenterologyGraduate School of Biomedical and Health Sciences, Hiroshima UniversityHiroshimaJapan
| | - Takahiro Kotachi
- Department of GastroenterologyGraduate School of Biomedical and Health Sciences, Hiroshima UniversityHiroshimaJapan
| | - Hassan Ashktorab
- Department of Medicine and Cancer CenterHoward University College of MedicineWashingtonDCUSA
| | - Duane Smoot
- Department of MedicineMeharry Medical CollegeNashvilleTennesseeUSA
| | - Wataru Yasui
- Department of Molecular PathologyGraduate School of Biomedical and Health Sciences, Hiroshima UniversityHiroshimaJapan
- Division of PathologyHiroshima City Medical Association Clinical LaboratoryHiroshimaJapan
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Eskuri M, Birkman EM, Kauppila JH. Gastric cancer molecular classification based on immunohistochemistry and in-situ hybridisation and mortality. Histopathology 2024; 85:327-337. [PMID: 38715404 DOI: 10.1111/his.15207] [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: 02/12/2024] [Revised: 03/21/2024] [Accepted: 04/21/2024] [Indexed: 07/16/2024]
Abstract
BACKGROUND AND AIMS Gastric cancers (GC) are divided into subtypes based on molecular profile: Epstein-Barr virus (EBV)-positive, microsatellite instability (MSI), chromosomal instability (CIN) and genomically stable (GS) tumours. The prognostic impact of this classification is unclear. The aim was to evaluate whether the molecular subtypes determined using in-situ hybridisation (ISH) and immunohistochemistry (IHC) are associated with clinicopathological parameters and prognosis. METHODS AND RESULTS The study included 503 GC patients. Based on ISH (EBV) and IHC (MSI and TP53), tumours were divided into EBV-positive, MSI, CIN (EBVneg/MSS/TP53aberrant) and GS (EBVneg/MSS/TP53wild-type) subgroups. Survival analyses with intestinal- and diffuse-type tumours were examined separately. EBV-positive tumours associated with male sex. Both EBV-positive and MSI tumours associated with intestinal type. CIN tumours associated with intestinal-type and positive lymph node status. GS tumours associated with diffuse-type and negative lymph node status. In the total cohort, no significant differences in the 5-year survival were observed. In intestinal tumours, the 5-year survival was better in EBV-positive tumours compared with GS tumours [hazard ratio (HR) = 0.57, 95% confidence interval (CI) = 0.33-0.99]. In diffuse tumours, the 5-year survival was worse in CIN tumours compared with GS tumours (HR = 1.57, 95% CI = 1.14-2.18). In radically resected diffuse tumours, the 5-year survival was worse in MSI tumours compared with GS tumours (HR = 3.26, 95% CI = 1.20-8.82). CONCLUSIONS The molecular classification is associated with histological type but not prognosis in GC. As the prognostic effects of molecular subtypes in intestinal- and diffuse-type cancers may differ, combining histological and molecular information is recommended for future studies.
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Affiliation(s)
- Maarit Eskuri
- Cancer and Translational Medicine Research Unit, Medical Research Center, University of Oulu, Oulu University Hospital, Oulu, Finland
| | - Eva-Maria Birkman
- Department of Pathology, University of Turku, Turku University Hospital, Turku, Finland
| | - Joonas H Kauppila
- Cancer and Translational Medicine Research Unit, Medical Research Center, University of Oulu, Oulu University Hospital, Oulu, Finland
- Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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Omar M, Xu Z, Rand SB, Alexanderani MK, Salles DC, Valencia I, Schaeffer EM, Robinson BD, Lotan TL, Loda M, Marchionni L. Semi-Supervised, Attention-Based Deep Learning for Predicting TMPRSS2:ERG Fusion Status in Prostate Cancer Using Whole Slide Images. Mol Cancer Res 2024; 22:347-359. [PMID: 38284821 PMCID: PMC10985477 DOI: 10.1158/1541-7786.mcr-23-0639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 12/26/2023] [Accepted: 01/22/2024] [Indexed: 01/30/2024]
Abstract
IMPLICATIONS Our study illuminates the potential of deep learning in effectively inferring key prostate cancer genetic alterations from the tissue morphology depicted in routinely available histology slides, offering a cost-effective method that could revolutionize diagnostic strategies in oncology.
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Affiliation(s)
- Mohamed Omar
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
- Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Zhuoran Xu
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
- Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Sophie B. Rand
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
- Dana-Farber Cancer Institute, Boston, Massachusetts
| | | | - Daniela C. Salles
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland
| | - Itzel Valencia
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
| | | | - Brian D. Robinson
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
| | - Tamara L. Lotan
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland
| | - Massimo Loda
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
| | - Luigi Marchionni
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
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Díaz del Arco C, Fernández Aceñero MJ, Ortega Medina L. Molecular Classifications in Gastric Cancer: A Call for Interdisciplinary Collaboration. Int J Mol Sci 2024; 25:2649. [PMID: 38473896 PMCID: PMC10931799 DOI: 10.3390/ijms25052649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/21/2024] [Accepted: 02/22/2024] [Indexed: 03/14/2024] Open
Abstract
Gastric cancer (GC) is a heterogeneous disease, often diagnosed at advanced stages, with a 5-year survival rate of approximately 20%. Despite notable technological advancements in cancer research over the past decades, their impact on GC management and outcomes has been limited. Numerous molecular alterations have been identified in GC, leading to various molecular classifications, such as those developed by The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG). Other authors have proposed alternative perspectives, including immune, proteomic, or epigenetic-based classifications. However, molecular stratification has not yet transitioned into clinical practice for GC, and little attention has been paid to alternative molecular classifications. In this review, we explore diverse molecular classifications in GC from a practical point of view, emphasizing their relationships with clinicopathological factors, prognosis, and therapeutic approaches. We have focused on classifications beyond those of TCGA and the ACRG, which have been less extensively reviewed previously. Additionally, we discuss the challenges that must be overcome to ensure their impact on patient treatment and prognosis. This review aims to serve as a practical framework to understand the molecular landscape of GC, facilitate the development of consensus molecular categories, and guide the design of innovative molecular studies in the field.
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Affiliation(s)
- Cristina Díaz del Arco
- Department of Legal Medicine, Psychiatry and Pathology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (M.J.F.A.); (L.O.M.)
- Department of Pathology, Hospital Clínico San Carlos, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - María Jesús Fernández Aceñero
- Department of Legal Medicine, Psychiatry and Pathology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (M.J.F.A.); (L.O.M.)
- Department of Pathology, Hospital Clínico San Carlos, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Luis Ortega Medina
- Department of Legal Medicine, Psychiatry and Pathology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (M.J.F.A.); (L.O.M.)
- Department of Pathology, Hospital Clínico San Carlos, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
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Wang Y, Wei X, Ke B, Liu J, Guo Y, Liu Y, Chen Y, Ding T, Wang Y, Meng B, Sun B, Zang F. Exploring the molecular characteristics of the malignant potential of gastric adenocarcinoma with enteroblastic differentiation. Histopathology 2023; 83:631-646. [PMID: 37356975 DOI: 10.1111/his.14998] [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: 02/19/2023] [Revised: 05/24/2023] [Accepted: 06/06/2023] [Indexed: 06/27/2023]
Abstract
AIMS Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare subset of alpha-fetoprotein (AFP)-producing carcinomas with poor prognosis. However, the molecular features associated with the malignant potential of GEAD remain partially elucidated. METHODS AND RESULTS In this study, the relationship between clinicopathological parameters and aggressive biological behaviour was analysed in 37 patients with GAED. The results showed that GAED tended to infiltrate the deep layer of the gastric wall and possessed more frequent vascular invasion than conventional gastric adenocarcinoma (CGA) (P < 0.001). All distant metastases were observed in the GAED group, not the CGA group (P < 0.001). High HER2 expression was found in nearly 24.32% of the informative cases, and none showed EBV-encoded RNA positivity or deficient mismatch repair. The most frequently mutated gene in GAED was p53. Programmed cell death-ligand 1 (PD-L1) immunostaining revealed 13 patients with a combined positive score (CPS) ≥ 5 (65%, 13 of 20). Thus, based on these molecular markers (immunostaining, in situ hybridisation and mutation analysis), GAED may be classified as a unique subgroup of the chromosomal instability subtype with HER2+ /EBV- /MSS/TP53+ /PD-L1+ . Next-generation sequencing analyses showed that mutations in the TOPI, ELOA and NOTCH3 genes were found only in GAED, and abnormally expressed genes in GAED were significantly enriched in hepatocellular carcinoma-, gland development-, and gastric cancer-related pathways. CONCLUSION The HER2+ /EBV- /MSS/TP53+ /PD-L1+ profile and hepatocellular carcinoma-related pathways may be significant in the malignant potential of GAED. In addition to anti-HER2 therapy, immune check-point inhibitors may be an effective treatment option for patients with GAED.
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Affiliation(s)
- Yong Wang
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Xiyin Wei
- Public Laboratory, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Bin Ke
- Department of Gastric Oncology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Jia Liu
- Department of Colorectal Oncology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yuhong Guo
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yanxue Liu
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yongzi Chen
- Department of Tumor Cell Biology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Tingting Ding
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yalei Wang
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Bin Meng
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Baocun Sun
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Fenglin Zang
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
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Arai T, Komatsu A, Kanazawa N, Nonaka K, Ishiwata T. Clinicopathological and molecular characteristics of gastric papillary adenocarcinoma. Pathol Int 2023; 73:358-366. [PMID: 37341602 DOI: 10.1111/pin.13345] [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: 11/23/2022] [Accepted: 05/25/2023] [Indexed: 06/22/2023]
Abstract
Papillary adenocarcinoma is defined as carcinoma with a well-defined papillary or villous structure. Despite sharing clinicopathological and morphological features with tubular adenocarcinomas, papillary adenocarcinomas frequently show microsatellite instability. The present study aimed to clarify the clinicopathological features, molecular classification, and programmed death-ligand 1 (PD-L1) expression characteristics of papillary adenocarcinoma, especially tumors with microsatellite instability. We examined the microsatellite status and expression of mucin core proteins and PD-L1 as well as the clinicopathological features in 40 gastric papillary adenocarcinomas. Surrogate immunohistochemical analysis of p53 and mismatch repair proteins along with Epstein-Barr virus-encoded RNA in situ hybridization were performed for molecular classification. Female predominance and frequent microsatellite instability were observed in papillary adenocarcinoma in comparison with tubular adenocarcinoma. The presence of microsatellite instability in papillary adenocarcinoma was significantly correlated with older age, tumor-infiltrating lymphocytes, and Crohn's-like lymphoid reactions. Surrogate examination demonstrated that the genomically stable type (17 cases, 42.5%) was the most common, followed by the microsatellite-unstable type (14 cases, 35%). Among the seven cases showing PD-L1-positive expression in tumor cells, four involved carcinomas with microsatellite instability. These results reveal the clinicopathological and molecular characteristics of gastric papillary adenocarcinoma.
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Affiliation(s)
- Tomio Arai
- Department of Pathology, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan
| | - Akiko Komatsu
- Department of Pathology, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan
| | - Nobuo Kanazawa
- Department of Surgery, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan
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Boldrin E, Piano MA, Bernaudo F, Alfieri R, Biasin MR, Montagner IM, Volpato A, Mattara G, Lamacchia F, Magni G, Rosato A, Scapinello A, Pilati P, Curtarello M. p53/ TP53 Status Assessment in Gastroesophageal Adenocarcinoma. Cancers (Basel) 2023; 15:2783. [PMID: 37345120 DOI: 10.3390/cancers15102783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/05/2023] [Accepted: 05/11/2023] [Indexed: 06/23/2023] Open
Abstract
Chromosomal instability (CIN) is very frequent in gastroesophageal adenocarcinoma (GEA) and it is characterized by TP53 deletions/mutations resulting in p53 nuclear accumulation, as revealed by immunohistochemistry (IHC), which considers the cases with "high" staining levels to be positive. Aiming to improve aberrant TP53 detection, droplet digital PCR (ddPCR) was used to evaluate TP53 deletion in formalin-fixed, paraffin-embedded DNA (FFPE-DNA) and cell-free DNA (cfDNA). To further investigate the mutational TP53 profile, next-generation sequencing (NGS) was performed in a subset of FFPE samples. After combining "low" and "high" IHC staining level groups, the proportion of deletion events was significantly higher compared to the "intermediate" group (72.9% vs. 47.5%, p-value = 0.002). The ddPCR TP53 deletion assay was feasible for cfDNA but only had good agreement (72.7%, Cohen's kappa = 0.48) with the assay performed with FFPE-DNA of the "low-level" group. NGS analysis confirmed that, in the "low-level" group, a high percentage (66.7%) of cases were aberrant, with disruptive mutations that probably led to p53 loss. Data suggested that p53 IHC alone underestimates the CIN phenotype in GEA and that molecular analysis in both solid and liquid biopsies could be integrated with it; in particular, in cases of completely negative staining.
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Affiliation(s)
- Elisa Boldrin
- Immunology and Molecular Oncology Diagnostics Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Maria Assunta Piano
- Immunology and Molecular Oncology Diagnostics Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Francesco Bernaudo
- Immunology and Molecular Oncology Diagnostics Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Rita Alfieri
- Surgical Oncology of Digestive Tract Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Maria Raffaella Biasin
- Anatomy and Pathological Histology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Isabella Monia Montagner
- Anatomy and Pathological Histology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Alice Volpato
- Anatomy and Pathological Histology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Genny Mattara
- Surgical Oncology of Digestive Tract Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Francesco Lamacchia
- Surgical Oncology of Digestive Tract Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
- Department of Surgery Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy
| | - Giovanna Magni
- Clinical Research Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Antonio Rosato
- Immunology and Molecular Oncology Diagnostics Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
- Department of Surgery Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy
| | - Antonio Scapinello
- Anatomy and Pathological Histology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Pierluigi Pilati
- Surgical Oncology of Digestive Tract Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Matteo Curtarello
- Immunology and Molecular Oncology Diagnostics Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
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9
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Hirabayashi M, Georges D, Clifford GM, de Martel C. Estimating the Global Burden of Epstein-Barr Virus-Associated Gastric Cancer: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol 2023; 21:922-930.e21. [PMID: 35963539 DOI: 10.1016/j.cgh.2022.07.042] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Evidence suggests that a fraction of new gastric cancer cases may be etiologically associated with Epstein-Barr virus (EBV), a known carcinogenic agent. We aimed to systematically explore the proportion of EBV-positive gastric cancer. METHODS We did a systematic review (PROSPERO CRD42020164473) from January 1990 to August 2021. For each country and geographical region with available data, pooled prevalence and corresponding 95% confidence intervals (CIs) of EBV in gastric tumors were calculated for 3 subtypes of gastric adenocarcinoma (conventional adenocarcinoma, lymphoepithelioma-like gastric carcinoma, and remnant/stump carcinoma). For conventional adenocarcinoma, prevalence ratios (PRs) were presented for sex, Lauren's classification, gastric cancer stage, and anatomical location of the stomach. RESULTS In 220 eligible studies including over 68,000 cases of conventional gastric adenocarcinoma, EBV prevalence in tumor cells was 7.5% (95% CI, 6.9%-8.1%) and was higher in men compared with women (PR, 2.1; 95% CI, 1.9-2.4), in diffuse type compared with intestinal type (PR, 1.3; 95% CI, 1.1-1.5), and in the proximal region compared with the distal region (PR, 2.5; 95% CI, 2.0-3.1). There was no difference in EBV prevalence by gastric cancer stage. EBV prevalence was 75.9% (95% CI, 62.8%-85.5%) among lymphoepithelioma-like gastric carcinoma and 26.3% (95% CI, 22.2%-32.0%) among remnant or stump carcinoma. CONCLUSIONS Assuming a causal association between EBV and gastric cancer, our findings, when applied to the GLOBOCAN 2020 gastric cancer incidence, suggest that primary prevention such as the development of an effective EBV vaccine might prevent 81,000 EBV-associated gastric cancer cases worldwide annually.
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Affiliation(s)
- Mayo Hirabayashi
- Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer, Lyon, France
| | - Damien Georges
- Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer, Lyon, France
| | - Gary M Clifford
- Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer, Lyon, France
| | - Catherine de Martel
- Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer, Lyon, France.
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10
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Li G, Zhou Z, Wang Z, Wang Z. Assessing Epstein-Barr virus in gastric cancer: clinicopathological features and prognostic implications. Infect Agent Cancer 2023; 18:11. [PMID: 36803802 PMCID: PMC9938970 DOI: 10.1186/s13027-023-00489-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 02/14/2023] [Indexed: 02/21/2023] Open
Abstract
BACKGROUND Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) was a unique molecular subtype of gastric cancer (GC). However, the clinicopathological characteristics and prognostic role of EBV infection remains unclear. We aimed to evaluate the clinicopathological features of EBVaGC and its role on prognosis. METHODS EBV-encoded RNA (EBER) in situ hybridization method was used to evaluate the EBV status in GC. The serum tumor markers AFP, CEA, CA19-9 and CA125 of patients were detected before treatment. HER2 expression and microsatellite instability (MSI) status was evaluated according to established criteria. The relationship between EBV infection and clinicopathological factors as well as its role on prognosis were investigated. RESULTS 420 patients were enrolled in the study and of 53 patients (12.62%) were identified as EBVaGC. EBVaGC was more common in males (p = 0.001) and related to early T stage (p = 0.045), early TNM stage (p = 0.001) and lower level of serum CEA (p = 0.039). No association could be found between EBV infection and HER2 expression, MSI status and other factors (p all > 0.05). Kaplan-Meier analysis revealed that both the overall survival and disease-free survival of EBVaGC patients were similar to that of EBV-negative GC (EBVnGC) patients (p = 0.309 and p = 0.264, respectively). CONCLUSION EBVaGC was more common in males and in patients with the early T stage and TNM stage as well as patients with lower serum CEA level. Difference in overall survival and disease-free survival between EBVaGC and EBVnGC patients cannot be detected.
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Affiliation(s)
- Guanghua Li
- grid.412615.50000 0004 1803 6239Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Zhongshan 2nd Street, No. 58, Guangzhou, 510080 Guangdong China
| | - Zhihao Zhou
- grid.412615.50000 0004 1803 6239Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Zhongshan 2nd Street, No. 58, Guangzhou, 510080 Guangdong China
| | - Zhixiong Wang
- grid.412615.50000 0004 1803 6239Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Zhongshan 2nd Street, No. 58, Guangzhou, 510080 Guangdong China
| | - Zhao Wang
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Zhongshan 2nd Street, No. 58, Guangzhou, 510080, Guangdong, China.
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11
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Röcken C. Predictive biomarkers in gastric cancer. J Cancer Res Clin Oncol 2023; 149:467-481. [PMID: 36260159 PMCID: PMC9889517 DOI: 10.1007/s00432-022-04408-0] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Accepted: 10/06/2022] [Indexed: 02/04/2023]
Abstract
Predictive biomarkers are the mainstay of precision medicine. This review summarizes the advancements in tissue-based diagnostic biomarkers for gastric cancer, which is considered the leading cause of cancer-related deaths worldwide. A disease seen in the elderly, it is often diagnosed at an advanced stage, thereby limiting therapeutic options. In Western countries, neoadjuvant/perioperative (radio-)chemotherapy is administered, and adjuvant chemotherapy is administered in the East. The morpho-molecular classification of gastric cancer has opened novel avenues identifying Epstein-Barr-Virus (EBV)-positive, microsatellite instable, genomically stable and chromosomal instable gastric cancers. In chromosomal instable tumors, receptor tyrosine kinases (RKTs) (e.g., EGFR, FGFR2, HER2, and MET) are frequently overexpressed. Gastric cancers such as microsatellite instable and EBV-positive types often express immune checkpoint molecules, such as PD-L1 and VISTA. Genomically stable tumors show alterations in claudin 18.2. Next-generation sequencing is increasingly being used to search for druggable targets in advanced palliative settings. However, most tissue-based biomarkers of gastric cancer carry the risk of a sampling error due to intratumoral heterogeneity, and adequate tissue sampling is of paramount importance.
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Affiliation(s)
- C. Röcken
- Department of Pathology, Christian-Albrechts-University, Arnold-Heller-Str. 3, Haus 14, Haus U33, 24105 Kiel, Germany
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12
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Zeng Y, Jin RU. Molecular pathogenesis, targeted therapies, and future perspectives for gastric cancer. Semin Cancer Biol 2022; 86:566-582. [PMID: 34933124 DOI: 10.1016/j.semcancer.2021.12.004] [Citation(s) in RCA: 90] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 11/29/2021] [Accepted: 12/11/2021] [Indexed: 01/27/2023]
Abstract
Gastric cancer is a major source of global cancer mortality with limited treatment options and poor patient survival. As our molecular understanding of gastric cancer improves, we are now beginning to recognize that these cancers are a heterogeneous group of diseases with incredibly unique pathogeneses and active oncogenic pathways. It is this molecular diversity and oftentimes lack of common oncogenic driver mutations that bestow the poor treatment responses that oncologists often face when treating gastric cancer. In this review, we will examine the treatments for gastric cancer including up-to-date molecularly targeted therapies and immunotherapies. We will then review the molecular subtypes of gastric cancer to highlight the diversity seen in this disease. We will then shift our discussion to basic science and gastric cancer mouse models as tools to study gastric cancer molecular heterogeneity. Furthermore, we will elaborate on a molecular process termed paligenosis and the cyclical hit model as key events during gastric cancer initiation that impart nondividing mature differentiated cells the ability to re-enter the cell cycle and accumulate disparate genomic mutations during years of chronic inflammation and injury. As our basic science understanding of gastric cancer advances, so too must our translational and clinical efforts. We will end with a discussion regarding single-cell molecular analyses and cancer organoid technologies as future translational avenues to advance our understanding of gastric cancer heterogeneity and to design precision-based gastric cancer treatments. Elucidation of interpatient and intratumor heterogeneity is the only way to advance future cancer prevention, diagnoses and treatment.
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Affiliation(s)
- Yongji Zeng
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, USA
| | - Ramon U Jin
- Section of Hematology/Oncology, Department of Medicine, Baylor College of Medicine, Houston, USA.
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13
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Abstract
Gastric cancer (GC) is one of the most common lethal malignant neoplasms worldwide, with limited treatment options for both locally advanced and/or metastatic conditions, resulting in a dismal prognosis. Although the widely used morphological classifications may be helpful for endoscopic or surgical treatment choices, they are still insufficient to guide precise and/or personalized therapy for individual patients. Recent advances in genomic technology and high-throughput analysis may improve the understanding of molecular pathways associated with GC pathogenesis and aid in the classification of GC at the molecular level. Advances in next-generation sequencing have enabled the identification of several genetic alterations through single experiments. Thus, understanding the driver alterations involved in gastric carcinogenesis has become increasingly important because it can aid in the discovery of potential biomarkers and therapeutic targets. In this article, we review the molecular classifications of GC, focusing on The Cancer Genome Atlas (TCGA) classification. We further describe the currently available biomarker-targeted therapies and potential biomarker-guided therapies. This review will help clinicians by providing an inclusive understanding of the molecular pathology of GC and may assist in selecting the best treatment approaches for patients with GC.
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Affiliation(s)
- Moonsik Kim
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea.
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14
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Rigter LS, Snaebjornsson P, Rosenberg EH, Altena E, van Grieken NCT, Aleman BMP, Kerst JM, Morton L, Schaapveld M, Meijer GA, van Leeuwen FE, van Leerdam ME. Molecular characterization of gastric adenocarcinoma diagnosed in patients previously treated for Hodgkin lymphoma or testicular cancer. PLoS One 2022; 17:e0270591. [PMID: 35877698 PMCID: PMC9312836 DOI: 10.1371/journal.pone.0270591] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 06/14/2022] [Indexed: 11/19/2022] Open
Abstract
Introduction The risk of developing gastric cancer is increased in patients treated with radiotherapy for Hodgkin lymphoma (HL) or testicular cancer (TC). This study aims to assess if gastric adenocarcinoma after treatment for HL/TC (t-GC) is molecularly different from gastric adenocarcinoma in the general population. Methods Patients were diagnosed with t-GC ≥5 years after treatment for HL/TC. Four molecular subtypes were identified using immunohistochemical and molecular analyses: Epstein-Barr virus (EBV), mismatch repair (MMR) deficiency or microsatellite instability (MSI), aberrant p53 staining as surrogate for chromosomal instability (sCIN), and a surrogate for genomic stability (sGS) without these aberrations. Results were compared with gastric cancer in the general population (p-GC) described in literature. Results Molecular subtyping of 90 t-GCs resulted in 3% EBV, 8% MSI, 36% sCIN and 53% sGS. 3/6 of MSI t-GCs had MLH1 promoter methylation and 2/6 were explained by double somatic mutations in MMR genes. T-GCs were more frequently sGS than p-GCs (53% vs. 38%, p = 0.04). T-GC was more frequently sGS in HL/TC patients diagnosed before 1990, than after 1990 (63% vs. 38%, p = 0.03). T-GCs located in the antrum, an area that receives high irradiation doses, were more frequently sGS (61% vs. 28% in p-GCs, p = 0.02). Conclusion Our results demonstrate that t-GCs are more frequently of the sGS subtype than p-GCs. An association of t-GC of the sGS subtype with prior anticancer treatment is suggested by the high frequency in HL/TC patients who were treated before 1990, a time period in which HL/TC treatments were more extensive.
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Affiliation(s)
- Lisanne S. Rigter
- Department of Gastroenterology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Petur Snaebjornsson
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Efraim H. Rosenberg
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Estelle Altena
- Department of Gastroenterology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | | | - Berthe M. P. Aleman
- Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jan M. Kerst
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Lindsay Morton
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Michael Schaapveld
- Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Gerrit A. Meijer
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Flora E. van Leeuwen
- Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Monique E. van Leerdam
- Department of Gastroenterology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- * E-mail:
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15
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Putative Clinical Potential of ERBB2 Amplification Assessment by ddPCR in FFPE-DNA and cfDNA of Gastroesophageal Adenocarcinoma Patients. Cancers (Basel) 2022; 14:cancers14092180. [PMID: 35565309 PMCID: PMC9102116 DOI: 10.3390/cancers14092180] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/15/2022] [Accepted: 04/21/2022] [Indexed: 01/27/2023] Open
Abstract
Simple Summary Gastroesophageal adenocarcinoma (GEA) has a poor prognosis. However, since the HER2 positive subgroup could benefit from trastuzumab targeted therapy, considerable effort has been spent in determining the HER2 status in these patients. To date, immunohistochemistry and in situ hybridization are the gold standard methods for assessing HER2/ERBB2 overexpression/amplification in tumor specimens. However, they have several limitations due to their cost, the large number of undetermined cases, and the impossibility of longitudinal patient monitoring. Here, we report the potential of a molecular method (droplet digital PCR) to investigate ERBB2 status in both solid and liquid biopsies of GEA. Results suggest that this methodology could be used to implement current histological analysis in solid biopsy and that it may be feasible in liquid biopsy. An alternative, more sensitive method of assessing HER2 status may aid physicians in their therapeutic decision-making, benefiting the patient. Liquid biopsy could also overcome the limitations of tissue-based analyses. Abstract Anti-HER2 monoclonal antibody trastuzumab improves the survival of those patients with advanced gastroesophageal adenocarcinoma (GEA) exhibiting HER2/ERBB2 overexpression/amplification. The current gold standard methods used to diagnose the HER2 status in GEA are immunohistochemistry (IHC) and silver or fluorescence in situ hybridization (SISH or FISH). However, they do not permit spatial and temporal tumor monitoring, nor do they overcome intra-cancer heterogeneity. Droplet digital PCR (ddPCR) was used to implement the assessment of HER2 status in formalin-fixed paraffin-embedded (FFPE) tumor DNA from a retrospective cohort (86 patients) and in cell-free DNA (cfDNA) samples from a prospective cohort (28 patients). In comparison to IHC/SISH, ddPCR assay revealed ERBB2 amplification in a larger patient fraction, including HER2 2+ and 0–1+ of the retrospective cohort (45.3% vs. 15.1%). In addition, a considerable number of HER2 2+ and 0–1+ prospective patients who were negative in FFPE by both IHC/SISH and ddPCR, showed ERBB2 amplification in the cfDNA collected just before surgery. cfDNA analysis in a few longitudinal cases revealed an increasing ERBB2 trend at progression. In conclusion, ddPCR in liquid biopsy may improve the detection rate of HER2 positive patients, preventing those patients who could benefit from targeted therapy from being incorrectly excluded.
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16
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Yasuda T, Lee HS, Nam SY, Katoh H, Ishibashi Y, Yamagata Murayama S, Matsui H, Masuda H, Rimbara E, Sakurazawa N, Suzuki H, Yoshida H, Seto Y, Ishikawa S, Jeon SW, Nakamura M, Nomura S. Non-Helicobacter pylori Helicobacter (NHPH) positive gastric cancer. Sci Rep 2022; 12:4811. [PMID: 35314746 PMCID: PMC8938428 DOI: 10.1038/s41598-022-08962-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 03/14/2022] [Indexed: 12/28/2022] Open
Abstract
Genetic analysis and culturing techniques for gastric non-Helicobacter pylori Helicobacter (NHPH) are progressing. NHPH is reported to accompany nodular gastritis, gastric MALT lymphoma, and mild gastritis. However, only a few gastric cancer cases infected by NHPH have been reported. PCR analysis specific for NHPH and H. pylori was performed for DNA from gastric mucosa of 282 Korean gastric cancer patients, who were treated with endoscopic submucosal dissection. For more precise strain detection of NHPH, NHPH-positive mucosa was stained by immunohistochemistry specific for Helicobacter suis. The Cancer Genome Atlas (TCGA) classification was analyzed for these 3 gastric cancer sub-groups by in situ hybridization and immunohistochemistry. Among 281 patients, 3 patients (1.1%) were positive for NHPH. One patient (Patient 1) was also positive for H. pylori by PCR, another patient (Patient 3) was positive for serum IgG for H. pylori, and the other patient (Patient 2) had no evidence for H. pylori infection. Gastric mucosa of Patients 2 and 3 were positive for H. suis staining. All three NHPH-positive gastric cancers were located in the antrum, and belonged to the Chromosomal Instability Type of TCGA classification. Gastric NHPH can be a cause of gastric cancer, although likely with lower pathogenesis than H. pylori.
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Affiliation(s)
- Tomohiko Yasuda
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.,Department of Gastrointestinal Surgery, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
| | - Hyun Seok Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Korea
| | - Su Youn Nam
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Korea
| | - Hiroto Katoh
- Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yuko Ishibashi
- Department of Breast and Endocrine Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Somay Yamagata Murayama
- Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hidenori Matsui
- Omura Satoshi Memorial Institute, Kitasato University, Tokyo, Japan
| | - Hiroki Masuda
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.,Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Emiko Rimbara
- Department of Bacteriology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Nobuyuki Sakurazawa
- Department of Gastrointestinal Surgery, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
| | - Hideyuki Suzuki
- Department of Gastrointestinal Surgery, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
| | - Hiroshi Yoshida
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Yasuyuki Seto
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Shumpei Ishikawa
- Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Seong Woo Jeon
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Korea
| | | | - Sachiyo Nomura
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
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Minciuna CE, Tanase M, Manuc TE, Tudor S, Herlea V, Dragomir MP, Calin GA, Vasilescu C. The seen and the unseen: Molecular classification and image based-analysis of gastrointestinal cancers. Comput Struct Biotechnol J 2022; 20:5065-5075. [PMID: 36187924 PMCID: PMC9489806 DOI: 10.1016/j.csbj.2022.09.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 09/07/2022] [Accepted: 09/07/2022] [Indexed: 11/13/2022] Open
Abstract
Gastrointestinal cancers account for 22.5% of cancer related deaths worldwide and represent circa 20% of all cancers. In the last decades, we have witnessed a shift from histology-based to molecular-based classifications using genomic, epigenomic, and transcriptomic data. The molecular based classification revealed new prognostic markers and may aid the therapy selection. Because of the high-costs to perform a molecular classification, in recent years immunohistochemistry-based surrogate classification were developed which permit the stratification of patients, and in parallel multiple groups developed hematoxylin and eosin whole slide image analysis for sub-classifying these entities. Hence, we are witnessing a return to an image-based classification with the purpose to infer hidden information from routine histology images that would permit to detect the patients that respond to specific therapies and would be able to predict their outcome. In this review paper, we will discuss the current histological, molecular, and immunohistochemical classifications of the most common gastrointestinal cancers, gastric adenocarcinoma, and colorectal adenocarcinoma, and will present key aspects for developing a new artificial intelligence aided image-based classification of these malignancies.
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18
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Pereira MA, Ramos MFKP, Dias AR, Cardili L, Ribeiro RRE, de Castria TB, Zilberstein B, Nahas SC, Ribeiro U, de Mello ES. RhoA, Claudin 18, and c-MET in Gastric Cancer: Clinicopathological Characteristics and Prognostic Significance in Curative Resected Patients. Med Sci (Basel) 2021; 10:4. [PMID: 35076580 PMCID: PMC8788521 DOI: 10.3390/medsci10010004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/23/2021] [Accepted: 12/27/2021] [Indexed: 12/26/2022] Open
Abstract
Background: Recently, markers related to molecular classification were suggested as promising therapeutic targets for treatment and prediction of prognosis in gastric cancer (GC), including c-MET, RhoA, and Claudin-18 (CLDN18). This study aimed to investigate their expression in GC and its correlation with clinicopathological characteristics and survival. Methods: We retrospectively evaluated GC patients who underwent curative gastrectomy. c-MET, RhoA, and CLDN18 were analyzed through immunohistochemistry (IHC), and groups for analysis were determined according to the median values obtained for each marker. Results: Among the 349 GC evaluated, 180 (51.6%), 59 (16.9%), and 61 (17.5%) patients were completely negative for c-MET, RhoA, and CLDN18, respectively. Total gastrectomy, D1 lymphadenectomy, poorly differentiated histology, and greater inflammatory infiltrate were more frequent in the c-MET-negative group. Diffuse type, greater inflammatory infiltrate, and advanced pT and pTNM stage were associated with low-RhoA GC. The venous invasion was more frequent in the low-CLDN18 group. Furthermore, c-MET was positively correlated with RhoA and negatively with CLDN18. HER2 expression was associated with c-MET-positive and high-CLDN18 GC; and loss of E-cadherin expression in c-MET-negative and low-RhoA GC. c-MET-negative and Low-RhoA were significantly associated with worse disease-free survival. Conclusions: c-MET, RhoA, and CLD18 expression occurred frequently in GC. RhoA GC had distinct clinicopathological characteristics related to prognosis. c-MET and RhoA were associated with survival but were not independent predictors of prognosis.
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Affiliation(s)
- Marina Alessandra Pereira
- Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 01246-000, Brazil; (M.F.K.P.R.); (A.R.D.); (L.C.); (R.R.e.R.); (T.B.d.C.); (B.Z.); (S.C.N.); (U.R.J.); (E.S.d.M.)
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Garcia‐Pelaez J, Barbosa‐Matos R, Gullo I, Carneiro F, Oliveira C. Histological and mutational profile of diffuse gastric cancer: current knowledge and future challenges. Mol Oncol 2021; 15:2841-2867. [PMID: 33724653 PMCID: PMC8564639 DOI: 10.1002/1878-0261.12948] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 02/23/2021] [Accepted: 03/12/2021] [Indexed: 12/18/2022] Open
Abstract
Gastric cancer (GC) pathogenesis is complex and heterogeneous, reflecting morphological, molecular and genetic diversity. Diffuse gastric cancer (DGC) and intestinal gastric cancer (IGC) are the major histological types. GC may be sporadic or hereditary; sporadic GC is related to environmental and genetic low-risk factors and hereditary GC is caused by inherited high-risk mutations, so far identified only for the diffuse histotype. DGC phenotypic heterogeneity challenges the current understanding of molecular mechanisms underlying carcinogenesis. The definition of a DGC-specific mutational profile remains controversial, possibly reflecting the heterogeneity of DGC-related histological subtypes [signet-ring cell carcinoma (SRCC) and poorly cohesive carcinoma not otherwise specified (PCC-NOS)]. Indeed, DGC and DGC-related subtypes may present specific mutational profiles underlying the particularly aggressive behaviour and dismal prognosis of DGC vs IGC and PCC-NOS vs SRCC. In this systematic review, we revised the histological presentations, molecular classifications and approved therapies for gastric cancer, with a focus on DGC. We then analysed results from the most relevant studies, reporting mutational analysis data specifying mutational frequencies, and their relationship with DGC and IGC histological types, and with specific DGC subtypes (SRCC and PCC-NOS). We aimed at identifying histology-associated mutational profiles with an emphasis in DGC and its subtypes (DGC vs IGC; sporadic vs hereditary DGC; and SRCC vs PCC-NOS). We further used these mutational profiles to identify the most commonly affected molecular pathways and biological functions, and explored the clinical trials directed specifically to patients with DGC. This systematic analysis is expected to expose a DGC-specific molecular profile and shed light into potential targets for therapeutic intervention, which are currently missing.
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Affiliation(s)
- José Garcia‐Pelaez
- i3S – Instituto de Investigação e Inovação em Saúde da Universidade do PortoPortugal
- IPATIMUP – Institute of Molecular Pathology and ImmunologyUniversity of PortoPortugal
- Doctoral Programme on BiomedicineFaculty of MedicineUniversity of PortoPortugal
| | - Rita Barbosa‐Matos
- i3S – Instituto de Investigação e Inovação em Saúde da Universidade do PortoPortugal
- IPATIMUP – Institute of Molecular Pathology and ImmunologyUniversity of PortoPortugal
- Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences (BiotechHealth)ICBAS – Institute of Biomedical Sciences Abel SalazarUniversity of PortoPortugal
| | - Irene Gullo
- i3S – Instituto de Investigação e Inovação em Saúde da Universidade do PortoPortugal
- IPATIMUP – Institute of Molecular Pathology and ImmunologyUniversity of PortoPortugal
- Department of PathologyFMUP ‐ Faculty of Medicine of the University of PortoPortugal
- Department of PathologyCHUSJ – Centro Hospitalar Universitário São JoãoPortoPortugal
| | - Fátima Carneiro
- i3S – Instituto de Investigação e Inovação em Saúde da Universidade do PortoPortugal
- IPATIMUP – Institute of Molecular Pathology and ImmunologyUniversity of PortoPortugal
- Department of PathologyFMUP ‐ Faculty of Medicine of the University of PortoPortugal
- Department of PathologyCHUSJ – Centro Hospitalar Universitário São JoãoPortoPortugal
| | - Carla Oliveira
- i3S – Instituto de Investigação e Inovação em Saúde da Universidade do PortoPortugal
- IPATIMUP – Institute of Molecular Pathology and ImmunologyUniversity of PortoPortugal
- Department of PathologyFMUP ‐ Faculty of Medicine of the University of PortoPortugal
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Ramos MFKP, Pereira MA, de Mello ES, Cirqueira CDS, Zilberstein B, Alves VAF, Ribeiro-Junior U, Cecconello I. Gastric cancer molecular classification based on immunohistochemistry and in situ hybridization: Analysis in western patients after curative-intent surgery. World J Clin Oncol 2021; 12:688-701. [PMID: 34513602 PMCID: PMC8394162 DOI: 10.5306/wjco.v12.i8.688] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/09/2021] [Accepted: 07/23/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is a highly heterogeneous disease, and the identification of molecular subtyping of gastric adenocarcinoma emerged as a promising option to define therapeutic strategies and prognostic subgroups. However, the costs and technical complexity of molecular methodologies remains an obstacle to its adoption, and their clinical significance by other approaches needs further evidence.
AIM To evaluate the clinicopathological characteristics and long-term survival of GC based on the subgroups of molecular classification by immunohistochemistry (IHC) and in situ hybridization (ISH).
METHODS We retrospectively evaluated all patients who underwent D2-gastrectomy between 2009 and 2016 in a Western cohort of GC patients treated with curative intent. Microsatellite instability (MSI) status, E-cadherin, and p53 expression were analyzed by IHC, and Epstein-Barr virus (EBV) by ISH. Tissue microarrays were constructed for analysis. Clinicopathological characteristics and survival of GC were evaluated according to subtypes defined by The Cancer Genome Atlas (TCGA) Research Network Group and Asian Cancer Research Group (ACRG) classification systems.
RESULTS A total of 287 GC patients were included. Based on IHC and ISH analysis, five profiles were defined as follows: E-cadherin aberrant (9.1%), MSI (20.9%), p53 aberrant (36.6%), EBV positivity (10.5%), and p53 normal (31%), which corresponded to tumors that showed no alteration in another profile. A flowchart according to the TCGA and ACRG classifications were used to define the subtypes, where clinical and pathological characteristics associated with GC subtypes were evidenced. Proximal location (P < 0.001), total gastrectomy (P = 0.001), and intense inflammatory infiltrate (P < 0.001) were characteristics related to EBV subtype. MSI subtype was predominantly associated with advanced age (P = 0.017) and the presence of comorbidities (P = 0.011). While Laurén diffuse type (P < 0.001) and advanced stage (P = 0.029) were related to genomically stable (GS) subtype. GS tumors and microsatellite stable/epithelial to mesenchymal transition phenotype subtype had worse disease-free survival (DFS) and overall survival (OS) than other subtypes. Conversely, MSI subtype of GC had better survival in both classifications. Type of gastrectomy, pT and the TCGA subtypes were independent factors associated to DFS and OS.
CONCLUSION The IHC/ISH analysis was able to distinguish immunophenotypic groups of GC with distinct characteristics and prognosis, resembling the subtypes of the molecular classifications. Accordingly, this method of classification may represent a viable option for use in a clinical setting.
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Affiliation(s)
- Marcus Fernando Kodama Pertille Ramos
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas, HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01249000, Brazil
| | - Marina Alessandra Pereira
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas, HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01249000, Brazil
| | - Evandro Sobroza de Mello
- Department of Pathology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo 01249000, Brazil
| | | | - Bruno Zilberstein
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas, HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01249000, Brazil
| | - Venancio Avancini Ferreira Alves
- Department of Pathology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo 01249000, Brazil
| | - Ulysses Ribeiro-Junior
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas, HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01249000, Brazil
| | - Ivan Cecconello
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas, HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01249000, Brazil
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21
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Daun T, Nienhold R, Paasinen-Sohns A, Frank A, Sachs M, Zlobec I, Cathomas G. Combined Simplified Molecular Classification of Gastric Adenocarcinoma, Enhanced by Lymph Node Status: An Integrative Approach. Cancers (Basel) 2021; 13:cancers13153722. [PMID: 34359622 PMCID: PMC8345215 DOI: 10.3390/cancers13153722] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/12/2021] [Accepted: 07/19/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary In this study, we present a simple but comprehensive molecular analysis of gastric carcinoma. The two major existing classification schemes show some discrepancies and are highly technically demanding, which makes them hardly feasible in daily diagnostic routines. Our workflow is based on simple and commercially available technology and provides a potential consensus approach by integrating the two major classification schemes. Furthermore, our approach allows the molecular subtypes to be assigned to different prognostic groups. We are convinced that our approach may help to better understand the molecular mechanisms of this worldwide health burden and that it could pave the way for new therapeutic targets. Abstract Gastric adenocarcinoma (GAC) is a heterogeneous disease and at least two major studies have recently provided a molecular classification for this tumor: The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ARCG). Both classifications quote four molecular subtypes, but these subtypes only partially overlap. In addition, the classifications are based on complex and cost-intensive technologies, which are hardly feasible for everyday practice. Therefore, simplified approaches using immunohistochemistry (IHC), in situ hybridization (ISH) as well as commercially available next generation sequencing (NGS) have been considered for routine use. In the present study, we screened 115 GAC by IHC for p53, MutL Homolog 1 (MLH1) and E-cadherin and performed ISH for Epstein–Barr virus (EBV). In addition, sequencing by NGS for TP53 and tumor associated genes was performed. With this approach, we were able to define five subtypes of GAC: (1) Microsatellite Instable (MSI), (2) EBV-associated, (3) Epithelial Mesenchymal Transition (EMT)-like, (4) p53 aberrant tumors surrogating for chromosomal instability and (5) p53 proficient tumors surrogating for genomics stable cancers. Furthermore, by considering lymph node metastasis in the p53 aberrant GAC, a better prognostic stratification was achieved which finally allowed us to separate the GAC highly significant in a group with poor and good-to-intermediate prognosis, respectively. Our data show that molecular classification of GAC can be achieved by using commercially available assays including IHC, ISH and NGS. Furthermore, we present an integrative workflow, which has the potential to overcome the uncertainty resulting from discrepancies from existing classification schemes.
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Affiliation(s)
- Till Daun
- Institute of Pathology, Cantonal Hospital Basel-Land, 4410 Liestal, Switzerland; (T.D.); (R.N.); (A.P.-S.); (A.F.); (M.S.)
| | - Ronny Nienhold
- Institute of Pathology, Cantonal Hospital Basel-Land, 4410 Liestal, Switzerland; (T.D.); (R.N.); (A.P.-S.); (A.F.); (M.S.)
| | - Aino Paasinen-Sohns
- Institute of Pathology, Cantonal Hospital Basel-Land, 4410 Liestal, Switzerland; (T.D.); (R.N.); (A.P.-S.); (A.F.); (M.S.)
| | - Angela Frank
- Institute of Pathology, Cantonal Hospital Basel-Land, 4410 Liestal, Switzerland; (T.D.); (R.N.); (A.P.-S.); (A.F.); (M.S.)
| | - Melanie Sachs
- Institute of Pathology, Cantonal Hospital Basel-Land, 4410 Liestal, Switzerland; (T.D.); (R.N.); (A.P.-S.); (A.F.); (M.S.)
| | - Inti Zlobec
- Institute of Pathology, University of Bern, 3008 Bern, Switzerland;
| | - Gieri Cathomas
- Institute of Pathology, Cantonal Hospital Basel-Land, 4410 Liestal, Switzerland; (T.D.); (R.N.); (A.P.-S.); (A.F.); (M.S.)
- Correspondence: ; Tel.: +41-61-925-2622
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22
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MSI Analysis in Solid and Liquid Biopsies of Gastroesophageal Adenocarcinoma Patients: A Molecular Approach. Int J Mol Sci 2021; 22:ijms22147244. [PMID: 34298864 PMCID: PMC8303574 DOI: 10.3390/ijms22147244] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/22/2021] [Accepted: 06/30/2021] [Indexed: 12/24/2022] Open
Abstract
Gastroesophageal adenocarcinoma (GEA) patients with the microsatellite instability (MSI) subtype emerged as optimal candidates for immunotherapy. To date, immunohistochemistry (IHC) is the gold standard for MSI assessment in formalin-fixed paraffin-embedded (FFPE) specimens. However, IHC, although useful for diagnostic typing, cannot be used to analyze cell-free DNA (cfDNA) in liquid biopsy, a tool that could overcome tumor heterogeneity and enable longitudinal monitoring. In order to find an alternative diagnostic method to IHC, we analyzed 86 retrospective GEAs FFPE samples with multiplex PCR. Moreover, to verify the feasibility of MSI detection in liquid biopsy, cfDNA samples of five patients that resulted in having MSI in a prospective cohort of 35 patients were evaluated by multiplex PCR, real-time PCR and droplet digital PCR (ddPCR). Analysis of FFPE showed 100% concordance between multiplex PCR and IHC (Cohen’s Kappa agreement = 1). On the contrary, only ddPCR was able to detect MSI in cfDNAs of T3/T4 GEA patients. In conclusion, data highlight the molecular analysis as an optimal alternative to IHC for the diagnostic typing and suggest that the ddPCR assay can be considered as the most reliable and promising molecular approach to detect MSI in the cfDNA of GEA patients.
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23
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Dornellas AFL, Ramos MFKP, Pereira MA, Cardili L, Dias AR, de Castria TB. Locally Advanced Gastric Adenocarcinoma with Impressive Response to Hemostatic Radiation: the Possible Role of p53 Status and Eosinophilic Infiltrate. J Gastrointest Cancer 2021; 52:788-791. [PMID: 32954464 DOI: 10.1007/s12029-020-00520-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2020] [Indexed: 02/08/2023]
Affiliation(s)
- Abraão Ferreira Lopes Dornellas
- Cancer Institute, Hospital das Clinicas, University of Sao Paulo Medical School, Av Dr Arnaldo 251, São Paulo, SP, 01249000, Brazil.
| | | | - Marina Alessandra Pereira
- Cancer Institute, Hospital das Clinicas, University of Sao Paulo Medical School, Av Dr Arnaldo 251, São Paulo, SP, 01249000, Brazil
| | - Leonardo Cardili
- Cancer Institute, Hospital das Clinicas, University of Sao Paulo Medical School, Av Dr Arnaldo 251, São Paulo, SP, 01249000, Brazil
| | - Andre Roncon Dias
- Cancer Institute, Hospital das Clinicas, University of Sao Paulo Medical School, Av Dr Arnaldo 251, São Paulo, SP, 01249000, Brazil
| | - Tiago Biachi de Castria
- Cancer Institute, Hospital das Clinicas, University of Sao Paulo Medical School, Av Dr Arnaldo 251, São Paulo, SP, 01249000, Brazil
- Sirio-Libanes Hospital, Sao Paulo, Brazil
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24
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Ultrastaging Using Ex Vivo Sentinel Lymph Node Mapping and One-Step Nucleic Acid Amplification (OSNA) in Gastric Cancer: Experiences of a European Center. Cancers (Basel) 2021; 13:cancers13112683. [PMID: 34072392 PMCID: PMC8198451 DOI: 10.3390/cancers13112683] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/11/2021] [Accepted: 05/27/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary In this study, the effectiveness of One-step nucleic acid amplification (OSNA) in combination with ex vivo SLN mapping is compared with conventional histology including immunohistochemistry. OSNA lymph node evaluation has been performed in 41 gastric cancer cases. It showed a high effectiveness with sensitivity, specificity, and accuracy rates of 85.4%, 93.5%, and 92.4%, respectively The LN status could be predicted in 40 cases and led to upstaging in three cases (14%). The OSNA method proved its potential to increase the sensitivity of metastases detection. Abstract Background: In this study, the effectiveness of One-step nucleic acid amplification (OSNA) in combination with ex vivo SLN mapping is compared with conventional histology including immunohistochemistry. Methods: LNs were retrieved from gastrectomy specimens in an unfixed state. After ex vivo SLN mapping using methylene-blue, LNs were sliced to provide samples for histology and OSNA. Results: In total, 334 LNs were retrieved in the fresh state from 41 patients. SLN detection was intended in 40 cases but was successful in only 29, with a correct LN status prediction in 23 cases (79%). Excluding one case out of 41 with a failure likely caused by a processing error, OSNA showed a high effectiveness with sensitivity, specificity, and accuracy rates of 85.4%, 93.5%, and 92.4%, respectively. The LN status could be predicted in all but one case, in which the single positive LN was not eligible for OSNA testing. Moreover, OSNA evaluation led to upstaging from N0 to N+ in three cases (14%). Conclusion: The ex vivo SLN protocol used resulted in a relatively poor detection rate. However, the OSNA method was not hampered by this detection rate and proved its potential to increase the sensitivity of metastases detection.
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25
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Díaz Del Arco C, Estrada Muñoz L, Ortega Medina L, Fernández Aceñero MJ. [Update on gastric cancer. New molecular classifications]. REVISTA ESPANOLA DE PATOLOGIA : PUBLICACION OFICIAL DE LA SOCIEDAD ESPANOLA DE ANATOMIA PATOLOGICA Y DE LA SOCIEDAD ESPANOLA DE CITOLOGIA 2021; 54:102-113. [PMID: 33726886 DOI: 10.1016/j.patol.2020.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 05/17/2020] [Accepted: 06/01/2020] [Indexed: 06/12/2023]
Abstract
Gastric cancer (GC) is an aggressive tumor, which is usually diagnosed at an advanced stage and shows high mortality rates. Several GC classifications have been published, based on features such as tumor location, endoscopic features or microscopic architecture. However, TNM stage remains the mainstay of GC management and treatment. In the last years, technical advances have allowed us to investigate the biological heterogeneity of GC and develop new molecular classifications. This knowledge may enhance current classifications, and has the potential to refine GC management and aid in the identification of new molecular targets. In this literature review we have summarized the main findings in epidemiology, screening, classification systems and treatment of GC, focusing on the molecular alterations and new molecular classifications published in the last years.
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Affiliation(s)
- Cristina Díaz Del Arco
- Universidad Complutense de Madrid, España; Anatomía Patológica, Hospital Clínico San Carlos, Madrid, España.
| | | | - Luis Ortega Medina
- Universidad Complutense de Madrid, España; Anatomía Patológica, Hospital Clínico San Carlos, Madrid, España
| | - Ma Jesús Fernández Aceñero
- Universidad Complutense de Madrid, España; Anatomía Patológica, Hospital General Universitario Gregorio Marañón, Madrid, España
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26
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Sentani K, Imai T, Kobayashi G, Hayashi T, Sasaki N, Oue N, Yasui W. Histological diversity and molecular characteristics in gastric cancer: relation of cancer stem cell-related molecules and receptor tyrosine kinase molecules to mixed histological type and more histological patterns. Gastric Cancer 2021; 24:368-381. [PMID: 33118117 DOI: 10.1007/s10120-020-01133-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 09/28/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric cancers (GCs) are still one of the leading causes of cancer-related mortality. The histological and molecular features of GC may differ widely from area to area within the same tumor. Intratumoral heterogeneity has been considered a major obstacle to an efficient diagnosis and successful molecular treatment. METHODS We selected and reevaluated 842 GC cases and analyzed the relationship between numbers or composites of histological patterns within tumors, and clinicopathological parameters in mucosal and invasive areas. In addition, we searched for the GC-associated molecules or molecular subtypes marking histological diversities. RESULTS GC cases with more histological numbers or mixed types in invasive areas showed significantly higher T grade and staging, whereas those in mucosal areas did not show any significant associations. GCs with histological diversities showed poorer prognosis and characteristically expressed cancer stem cell-related molecules (CD44, CD133 or ALDH1) and receptor tyrosine kinase molecules (HER2, EGFR or c-MET) as well as Helicobacter pylori infection. Expressions of CD44, HER2, c-MET, laminin 5·2 or retained E-cadherin in mucosal areas were predictive of more histological numbers and mixed types in invasive areas. In addition, the chromosomal instability subtype of GC showed significant associations with more histological numbers and mixed histological type, whereas the genomic stability subtype of GC showed a significant relationship with pure type. CONCLUSIONS We displayed the relationship between histological diversity and molecular features in GC, and we hope that the present data can contribute to the early diagnosis and prevention, and effective treatment of GC.
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Affiliation(s)
- Kazuhiro Sentani
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Takeharu Imai
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Go Kobayashi
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Tetsutaro Hayashi
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Naomi Sasaki
- Department of Pathology, Kure-Kyosai Hospital, Federation of National Public Service Personnel Mutual Aid Associations, Hiroshima, Japan
| | - Naohide Oue
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Wataru Yasui
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
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27
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Rubio CA. Two intertwined compartments coexisting in sporadic conventional colon adenomas. Intest Res 2021; 19:12-20. [PMID: 32079382 PMCID: PMC7873396 DOI: 10.5217/ir.2019.00133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 12/05/2019] [Accepted: 12/27/2019] [Indexed: 11/14/2022] Open
Abstract
Sporadic conventional colon adenomas are microscopically built of 2 intertwined compartments: one on top, harboring the dysplastic tissue that defines their histo-biomolecular attributes, and the other below, composed of non-dysplastic crypts with corrupted shapes (CCS). The CCS of 306 colon adenomas revealed asymmetric, haphazardly-distributed proliferating cell-domains (PC). In contrast, the PC-domains in normal controls were symmetric, being limited to the lower thirds of the crypts. In 28% out of 501 sporadic conventional adenomas, foci of p53-upregulated dysplastic tissue were found. The CCS in 30% of 108 sporadic adenomas showed p53-upregulated single cells, suggesting mounting somatic mutations. No p53-upregulated cells were found in the crypts of controls. In polypoid adenomas, the mucosa of the stalk without dysplastic tissue on top disclosed CCS with asymmetrical PC-domains and single p53-upregulated cells. The latter observations suggested that CCS had developed prior to and not after the growth of the dysplastic tissue on top. CCS were also found below colon adenomas in carcinogen-treated rats. It is concluded that the 2 intertwined histo-biological compartments of sporadic conventional colon adenomas are probably interdependent components. These findings may open new directions aimed to uncover the link between the normal colonic mucosa and the histogenesis of, conventional adenomas.
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Affiliation(s)
- Carlos A. Rubio
- Gastrointestinal Research Laboratory, Department of Pathology, Karolinska Institute and University Hospital, Stockholm, Sweden
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28
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Schoop I, Maleki SS, Behrens HM, Krüger S, Haag J, Röcken C. p53 immunostaining cannot be used to predict TP53 mutations in gastric cancer: results from a large Central European cohort. Hum Pathol 2020; 105:53-66. [PMID: 32971129 DOI: 10.1016/j.humpath.2020.09.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 09/13/2020] [Accepted: 09/14/2020] [Indexed: 12/26/2022]
Abstract
Four molecular subgroups of gastric cancer (GC) have been proposed, ie, Epstein-Barr virus (EBV)-positive, microsatellite instable, chromosomal instable (CIN), and genomically stable GC. Based on the complex relationship between chromosomal instability and TP53 mutational status, we hypothesized that the typical clinicopathological characteristics caused by chromosomal instability are correlated with the p53 expression that is detected by immunohistochemistry. Four hundred sixty-seven whole-tissue sections of patients with therapy-naive GC were stained with anti-p53 antibody. The histoscore and staining pattern were analyzed for each slide. Different algorithms of immunohistochemistry evaluation were formed and correlated with clinicopathological characteristics. The algorithms were validated by assessing the mutational status of TP53 in 111 cases. Four hundred forty-two GCs were p53 positive, and 25 were negative, including 414 GCs with a homogeneous pattern and 53 GCs with a heterogeneous staining pattern. There was no correlation with overall or tumor-specific survival. In comparison with clinicopathological characteristics, the algorithm high versus low showed correlations with microsatellite instability, hepatocyte growth factor receptor (MET), and TP53 mutational status. The algorithm Q1/Q4 versus Q2/Q3 appeared to be correlated with the phenotype as per the Laurén classification, microsatellite instability, EBV status, and p53 expression pattern. The algorithm <90% = 0 and <50% = 3+ versus ≥90% = 0 or ≥50% = 3+ showed correlations with the EBV status, microsatellite instability, grading, and p53 expression pattern. The algorithm homogeneous versus heterogeneous did not correlate with any clinicopathological characteristic. Our results showed that the immunohistochemistry of p53, TP53 mutational status, and CIN subtype were connected. However, different algorithms for p53 immunohistochemical evaluation cannot be used to predict TP53 mutations in CIN GCs in individual cases.
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Affiliation(s)
- Isabelle Schoop
- Department of Pathology, Christian-Albrechts-University, D-24105 Kiel, Germany
| | - Saffiyeh Saboor Maleki
- Department of Pathology, Christian-Albrechts-University, D-24105 Kiel, Germany; Institute for Cardiovascular Prevention, Ludwig Maximilians University, D-80336 Munich, Germany
| | | | - Sandra Krüger
- Department of Pathology, Christian-Albrechts-University, D-24105 Kiel, Germany
| | - Jochen Haag
- Department of Pathology, Christian-Albrechts-University, D-24105 Kiel, Germany
| | - Christoph Röcken
- Department of Pathology, Christian-Albrechts-University, D-24105 Kiel, Germany.
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29
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Cartwright E, Athauda A, Chau I. Emerging precision therapies for gastric cancer. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2020. [DOI: 10.1080/23808993.2020.1760089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
| | - Avani Athauda
- Department of Medicine, Royal Marsden Hospital, London and Surrey, UK
| | - Ian Chau
- Department of Medicine, Royal Marsden Hospital, London and Surrey, UK
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30
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Kayamba V, Butt J, Waterboer T, Besa E, Choudhry N, Hamasuku A, Julius P, Heimburger DC, Atadzhanov M, Kelly P. Molecular profiling of gastric cancer in a population with high HIV prevalence reveals a shift to MLH1 loss but not the EBV subtype. Cancer Med 2020; 9:3445-3454. [PMID: 32207245 PMCID: PMC7221426 DOI: 10.1002/cam4.3001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 02/19/2020] [Accepted: 03/01/2020] [Indexed: 12/29/2022] Open
Abstract
The human immunodeficiency virus (HIV) pandemic heavily affects sub-Saharan Africa. It is associated with persistently active Epstein-Barr virus (EBV) infection. To determine if this translates into increased frequency of EBV-associated gastric cancer (EBVaGC), we evaluated molecular profiles of gastric cancer (GC) in Zambia. Patients with GC or premalignant gastric lesions were enrolled in Lusaka, Zambia. We used patients without any of these lesions as a control group. Chromogenic in situ hybridization (CISH) on tumor tissue was used to identify EBVaGC. To identify the microsatellite unstable subtype, immunofluorescence staining for MutL homolog 1 (MLH1) was used. Exposure to EBV and HIV was assessed serologically. We enrolled 369 patients (median age 52 years [IQR 41-65]; 198 (54%) female). Of these, 72 (20%) had GC and 35 (9%) had gastric premalignant lesions (PL). CISH identified EBVaGC in 5/44 (11%) of those with adequate tissue, while MLH1 loss was identified in 29/45 (64%). Both GC and PL were associated with the highest titers of antibodies to Early antigen-diffuse (OR 2.5, 95% CI 1.0-6.1, P = .048 and OR 3.9, 95% CI 1.1-12.9, P = .03, respectively) at high concentrations. Human immunodeficiency virus infection was associated with a range of antibodies to EBV, but not with any cancer subtype. Despite the association of HIV with persistent EBV, the proportion of EBVaGC in Zambia is similar to populations with a low prevalence of HIV infection. The proportion of microsatellite unstable tumors may be higher than other populations.
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Affiliation(s)
- Violet Kayamba
- Tropical Gastroenterology & Nutrition GroupDepartment of Internal MedicineLusakaZambia
- University of Zambia School of MedicineLusakaZambia
| | - Julia Butt
- Cancer Control and Population Sciences ProgramDuke Cancer InstituteDuke UniversityDurhamNCUSA
- Department of Population Health SciencesDuke UniversityDurhamNCUSA
- Infection and Cancer Epidemiology GroupGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Tim Waterboer
- Infection and Cancer Epidemiology GroupGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Ellen Besa
- Tropical Gastroenterology & Nutrition GroupDepartment of Internal MedicineLusakaZambia
| | - Naheed Choudhry
- Blizard InstituteBarts & The London School of Medicine and DentistryQueen Mary University of LondonLondonUK
| | | | - Peter Julius
- University of Zambia School of MedicineLusakaZambia
| | - Douglas C. Heimburger
- Vanderbilt Institute for Global Health and Department of MedicineVanderbilt University Medical CenterNashvilleTNUSA
| | | | - Paul Kelly
- Tropical Gastroenterology & Nutrition GroupDepartment of Internal MedicineLusakaZambia
- University of Zambia School of MedicineLusakaZambia
- Blizard InstituteBarts & The London School of Medicine and DentistryQueen Mary University of LondonLondonUK
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31
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Di Pinto F, Armentano R, Arborea G, Schena N, Donghia R, Valentini AM. Are Immunohistochemical Markers Useful in Phenotypic Gastric Cancer Classification? Oncology 2020; 98:566-574. [PMID: 32316005 DOI: 10.1159/000506077] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 01/21/2020] [Indexed: 11/19/2022]
Abstract
To identify useful markers for prognostic and therapeutic purposes, The Cancer Genome Atlas (TCGA) provided a molecular classification of gastric cancers (GCs). Previous studies have used immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) to define immunophenotypic surrogate markers of the molecular alterations. Some critical issues concerning the correct definition of immunophenotypic groups have emerged in these studies that employed tissue microarrays (TMAs). We performed an immunophenotypic classification by evaluating MLH1, p53, HER2, E-cadherin, and Epstein-Barr virus (EBV) on the whole section of the surgical GC samples compared to most of the studies conducted on TMAs. We also investigated the immunohistochemical expression of PD-L1, a known therapeutic target. We identified the following immunophenotypic groups: EBV (2.9%); mismatch repair deficient (MMR-D) (7.2%); overexpressed p53 and/or HER2+ (61.4%); aberrant E-cadherin (11.4%); and normal pattern (17.1%). The use of surgical samples emphasized that some immunohistochemical markers were not useful for properly classifying the GC specimens. We can state that EBV (significantly correlated to PD-L1 expression) and MMR-D GCs are well-defined groups, mutually exclusive, and easily assessable with IHC and CISH, and could be candidates for immunotherapy with PD-1/PD-L1 inhibitors. As regards p53, our findings suggest that IHC assessment may be responsible for a misclassification of GC groups. Immunohistochemical evaluation of E-cadherin needs to be standardized, particularly in terms of the heterogeneous cytoplasmic/membranous staining pattern. Whether to consider the normal-pattern group as a separate category remains to be clarified. Because GC specimens with known therapeutic targets account for only 40%, we suggest reviewing the immunophenotypic classification to find new therapeutic targets, such as PD-L1, MLH1, and HER2.
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Affiliation(s)
- Federica Di Pinto
- Department of Pathology, National Institute of Gastroenterology "S. de Bellis," Research Hospital, Castellana Grotte, Bari, Italy
| | - Raffaele Armentano
- Department of Pathology, National Institute of Gastroenterology "S. de Bellis," Research Hospital, Castellana Grotte, Bari, Italy
| | - Graziana Arborea
- Department of Pathology, National Institute of Gastroenterology "S. de Bellis," Research Hospital, Castellana Grotte, Bari, Italy
| | - Nicolò Schena
- Department of Pathology, National Institute of Gastroenterology "S. de Bellis," Research Hospital, Castellana Grotte, Bari, Italy
| | - Rossella Donghia
- Unit of Epidemiological Research on Frailty Phenotype, National Institute of Gastroenterology "S. de Bellis," Research Hospital, Castellana Grotte, Bari, Italy
| | - Anna Maria Valentini
- Department of Pathology, National Institute of Gastroenterology "S. de Bellis," Research Hospital, Castellana Grotte, Bari, Italy,
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Ramos MFKP, Pereira MA, Amorim LC, de Mello ES, Faraj SF, Ribeiro U, Hoff PMG, Cecconello I, de Castria TB. Gastric cancer molecular classification and adjuvant therapy: Is there a different benefit according to the subtype? J Surg Oncol 2020; 121:804-813. [PMID: 31797380 DOI: 10.1002/jso.25792] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 11/24/2019] [Indexed: 02/05/2023]
Abstract
BACKGROUND Gastric cancer (GC) has been defined in distinct molecular subtypes with different therapeutic implications. However, its clinical significance and prognosis regarding standard chemotherapy (CMT) remains unclear. This study aimed to analyze the impact of perioperative or adjuvant treatment among subtypes of GC. METHODS We retrospectively evaluated all stage II/III patients with GC who underwent a curative gastrectomy. Based on immunohistochemistry and in situ hybridization techniques, GC was classified into five subtypes: Epstein-Barr virus (EBV) positive, microsatellite instability (MSI), e-cadherin aberrant, p53-aberrant, and p53-normal. RESULTS Among the 178 CG included, 111 patients received CMT and 67 were treated with surgery alone. Survival analysis showed that p53-aberrant GC treated with CMT had better disease-free survival (DFS) compared with surgery alone (P = .001).There was no significant difference in DFS between patients who received CMT and those with surgery alone for EBV, MSI, E-cadherin, and p53-normal GC. An improvement in overall survival was observed only for E-cadherin (P = .001) and p53-aberrant (P < .001) patients who received CMT. CONCLUSIONS CMT showed different impact on the survival of CG according to the molecular subtype. No survival benefit was observed for EBV and MSI groups who received CMT. GC with p53-aberrant had a significant benefit in survival with standard therapy.
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Affiliation(s)
- Marcus F K P Ramos
- Department of Gastroenterology, Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Marina A Pereira
- Department of Pathology, Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Larissa C Amorim
- Department of Radiology and Oncology, Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Evandro S de Mello
- Department of Pathology, Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Sheila F Faraj
- Department of Pathology, Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Ulysses Ribeiro
- Department of Gastroenterology, Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Paulo M G Hoff
- Department of Radiology and Oncology, Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Ivan Cecconello
- Department of Gastroenterology, Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Tiago B de Castria
- Department of Radiology and Oncology, Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil
- Sirio-Libanes Hospital, Sao Paulo, Brazil
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Agnes A, Biondi A, Laurino A, Persiani R, D'Ugo D. Global updates in the treatment of gastric cancer: a systematic review. Part 1: staging, classification and surgical treatment. Updates Surg 2020; 72:341-353. [PMID: 32157635 DOI: 10.1007/s13304-020-00736-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Accepted: 02/25/2020] [Indexed: 02/07/2023]
Abstract
Gastric cancer (GC) is the fifth malignancy and the third cause of cancer death worldwide, according to the global cancer statistics presented in 2018. Its definition and staging have been revised in the eight edition of the AJCC/TNM classification, which took effect in 2018. Novel molecular classifications for GC have been recently established and the process of translating these classifications into clinical practice is ongoing. The cornerstone of GC treatment is surgical, in a context of multimodal therapy. Surgical treatment is being standardized, and is evolving according to new anatomical concepts and to the recent technological developments. This is leading to a massive improvement in the use of mini-invasive techniques. Mini-invasive techniques aim to be equivalent to open surgery from an oncologic point of view, with better short-term outcomes. The persecution of better short-term outcomes also includes the optimization of the perioperative management, which is being implemented on large scale according to the enhanced recovery after surgery principles. In the era of precision medicine, multimodal treatment is also evolving. The long-time-awaited results of many trials investigating the role for preoperative and postoperative management have been published, changing the clinical practice. Novel investigations focused both on traditional chemotherapeutic regimens and targeted therapies are currently ongoing. Modern platforms increase the possibility for further standardization of the different treatments, promote the use of big data, and open new possibilities for surgical learning. This systematic review in two parts assesses all the current updates in GC treatment.
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Affiliation(s)
- Annamaria Agnes
- Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli, Largo A. Gemelli n. 8, 00168, Rome, Italy
| | - Alberto Biondi
- General Surgery Unit, Abdominal Surgery Area, Dipartimento Di Scienze Gastroenterologiche, Nefrourologiche Ed Endocrinometaboliche, IRCSS Fondazione Policlinico Universitario Agostino Gemelli, Largo A. Gemelli n. 8, 00168, Rome, Italy. .,Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli, Largo A. Gemelli n. 8, 00168, Rome, Italy. .,General Surgery Unit, Abdominal Surgery Area, Dipartimento Di Scienze Gastroenterologiche, Nefro-Urologiche Ed Endocrinometaboliche, IRCSS Fondazione Policlinico Universitario Agostino Gemelli, Largo Francesco Vito n. 1, 00168, Rome, Italy.
| | - Antonio Laurino
- Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli, Largo A. Gemelli n. 8, 00168, Rome, Italy
| | - Roberto Persiani
- General Surgery Unit, Abdominal Surgery Area, Dipartimento Di Scienze Gastroenterologiche, Nefrourologiche Ed Endocrinometaboliche, IRCSS Fondazione Policlinico Universitario Agostino Gemelli, Largo A. Gemelli n. 8, 00168, Rome, Italy.,Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli, Largo A. Gemelli n. 8, 00168, Rome, Italy
| | - Domenico D'Ugo
- General Surgery Unit, Abdominal Surgery Area, Dipartimento Di Scienze Gastroenterologiche, Nefrourologiche Ed Endocrinometaboliche, IRCSS Fondazione Policlinico Universitario Agostino Gemelli, Largo A. Gemelli n. 8, 00168, Rome, Italy.,Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli, Largo A. Gemelli n. 8, 00168, Rome, Italy
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Histo- and immunohistochemistry-based estimation of the TCGA and ACRG molecular subtypes for gastric carcinoma and their prognostic significance: A single-institution study. PLoS One 2019; 14:e0224812. [PMID: 31790410 PMCID: PMC6886787 DOI: 10.1371/journal.pone.0224812] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 10/22/2019] [Indexed: 02/07/2023] Open
Abstract
Gastric cancers comprise molecularly heterogeneous diseases; four molecular subtypes were identified in the cancer genome atlas (TCGA) study, with implications in patient management. In our efforts to devise a clinically feasible means of subtyping, we devised an algorithm based on histology and five stains available in most academic pathology laboratories. This algorithm was used to subtype our cohort of 107 gastric cancer patients from a single institution (St. Michael’s Hospital, Toronto, Canada), which was divided into 3 cases of EBV-positive, 23 of MSI, 27 of GS and 54 of CIN tumours. 87% of the tumours with diffuse histology were classified as GS subtype, which was notable for younger age. Examining for characteristic molecular features, aberrant p53 immunostaining was seen most frequently in the CIN subtype (43% in CIN vs. 6% in others), whereas ARID1A loss was rarely seen (6% vs. 35% in others). HER2 overexpression was seen exclusively in CIN tumours (17% of CIN tumours). PD-L1 positivity was seen predominantly in the EBV and MSI tumours. As with the TCGA study, no survival differences were seen between the subtypes. A similar strategy was employed to approximate the Asian Cancer Research Group (ACRG) molecular subtyping, with the addition of p53 IHC to the algorithm. We observed rates of ARID1A loss and HER2 overexpression that were comparable to the ACRG study. In summary, our algorithm allowed for clinically feasible means of subtyping gastric carcinoma that recapitulated the key molecular features reported in the large scale studies.
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Pereira MA, Ramos MFKP, Dias AR, Faraj SF, Ribeiro RRE, de Castria TB, Zilberstein B, Alves VAF, Ribeiro U, de Mello ES. Expression Profile of Markers for Targeted Therapy in Gastric Cancer Patients: HER-2, Microsatellite Instability and PD-L1. Mol Diagn Ther 2019; 23:761-771. [PMID: 31595457 DOI: 10.1007/s40291-019-00424-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND The assessment of human epidermal growth factor receptor 2 (HER2), microsatellite instability (MSI) and programmed cell death-ligand 1 (PD-L1) expression is relevant for the selection and effectiveness of targeted therapy in gastric cancer (GC). OBJECTIVE We aimed to investigate the clinicopathological characteristics and prognosis of GC patients according to these profiles. METHODS GC patients who underwent gastrectomy with D2 lymphadenectomy were eligible. HER2, MSI status and PD-L1 expression were analyzed by immunohistochemistry (IHC). Patients were grouped as follows: HER2+ group, immunotherapy (IT) group (MSI and/or PD-L1+), and non-targeted therapy (NTT) group (stable microsatellite and HER2/PD-L1-). RESULTS Among 282 patients, 50 (17.7%) were HER2+ and 79 (28%) MSI/PD-L1+. Fifteen had HER2+ and MSI/PD-L1+, while 168 (59.6%) were in the NTT group. HER2+ GCs were related to male gender (p = 0.007), intestinal type (p = 0.001) and less advanced pTNM stage (p = 0.029). Older age (p = 0.003), subtotal gastrectomy (p = 0.025), intestinal type (p = 0.008), pN0 status (p = 0.002) and less advanced pTNM stage (p = 0.001) were associated with the IT group. IT GC had better disease-free survival (DFS) and overall survival than the NTT group (p = 0.015 and p = 0.027, respectively). Concerning patients eligible for the standard adjuvant therapy, the treatment impacted positively on DFS for HER2+ and NTT groups (p = 0.003 and p = 0.042, respectively). No difference in DFS was seen between IT patients who received perioperative/adjuvant therapy and those treated only with surgery (p = 0.160). CONCLUSIONS GC patients who exhibited markers that can serve as an indication for known targeted therapy represent 40.4% of cases. The IT group was associated with a better prognosis. No benefit with standard adjuvant treatment appears to be achieved in MSI/PD-L1+ GCs.
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Affiliation(s)
- Marina Alessandra Pereira
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Avenida Doutor Arnaldo, 251, São Paulo, 01246-000, Brazil.
- Centro de Investigação Translacional em Oncologia (LIM24), Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil.
| | - Marcus Fernando Kodama Pertille Ramos
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Avenida Doutor Arnaldo, 251, São Paulo, 01246-000, Brazil
- Centro de Investigação Translacional em Oncologia (LIM24), Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - André Roncon Dias
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Avenida Doutor Arnaldo, 251, São Paulo, 01246-000, Brazil
- Centro de Investigação Translacional em Oncologia (LIM24), Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Sheila Friedrich Faraj
- Centro de Investigação Translacional em Oncologia (LIM24), Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
- Department of Pathology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Renan Ribeiro E Ribeiro
- Centro de Investigação Translacional em Oncologia (LIM24), Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
- Department of Pathology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Tiago Biachi de Castria
- Department of Radiology and Oncology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Bruno Zilberstein
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Avenida Doutor Arnaldo, 251, São Paulo, 01246-000, Brazil
| | - Venancio Avancini Ferreira Alves
- Department of Pathology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Ulysses Ribeiro
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Avenida Doutor Arnaldo, 251, São Paulo, 01246-000, Brazil
- Centro de Investigação Translacional em Oncologia (LIM24), Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Evandro Sobroza de Mello
- Centro de Investigação Translacional em Oncologia (LIM24), Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
- Department of Pathology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
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Bösch F, Todorova R, Link H, Westphalen CB, Boeck S, Heinemann V, Werner J, Kirchner T, Angele MK, Neumann J. Molecular subtyping of gastric cancer with respect to the growth pattern of lymph-node metastases. J Cancer Res Clin Oncol 2019; 145:2689-2697. [PMID: 31541339 DOI: 10.1007/s00432-019-03029-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 09/16/2019] [Indexed: 12/15/2022]
Abstract
PURPOSE Gastric cancer is the third leading cause of cancer-related death. Recently, innovative diagnostic and prognostic molecular subtypes have been proposed. We revealed that extranodal extension (ENE) of lymph-node metastases independently influences survival. Therefore, the aim of the present study was to evaluate novel molecular subtyping with regard to the growth pattern of lymph-node metastases. METHODS A total of 189 gastric carcinomas with lymph-node metastases were analyzed. The expression of p53, SOX2, SOX9, and the mismatch-repair gene products MLH1, PMS2, MSH2, and MSH6 were analyzed by immunohistochemistry. To determine the correlation with EBV infection, in situ hybridization for EBV-encoded small RNA (EBER) was applied. RESULTS ENE was present in 36% of patients. EBV-positive carcinoma was evident in 5.8%, and p53 aberrant (chromosomal instable) tumors in 22.2%, a gastric cancer with deficient mismatch-repair status in 9%, and MSS/p53neg/EBVneg tumors were seen in 63% of patients. There was no significant correlation between the presence or absence of ENE and the molecular subtypes. However, a significant association between molecular subgroups and the Lauren classification, the oncogene SOX2, and tumor grading was detected. CONCLUSION The present findings suggest that alterations in gastric cancer leading to ENE are not associated with alterations underpinning the molecular subgroups. Nonetheless, molecular subtyping on the basis of IHC and ISH is feasible and might become clinical routine. Thus, further studies are needed to clarify the mechanisms of extranodal extension in gastric cancer.
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Affiliation(s)
- Florian Bösch
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Rumyana Todorova
- Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-University Munich, Thalkirchnerstr. 36, 80337, Munich, Germany
| | - Helena Link
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
- Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-University Munich, Thalkirchnerstr. 36, 80337, Munich, Germany
| | - C Benedikt Westphalen
- Department of Medicine 3 and Comprehensive Cancer Center, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Stefan Boeck
- Department of Medicine 3 and Comprehensive Cancer Center, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Volker Heinemann
- Department of Medicine 3 and Comprehensive Cancer Center, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Thomas Kirchner
- Department of Medicine 3 and Comprehensive Cancer Center, Ludwig-Maximilians-University Munich, Munich, Germany
- German Cancer Consortium (DKTK), 69120, Heidelberg, Germany
- German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Martin K Angele
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jens Neumann
- Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-University Munich, Thalkirchnerstr. 36, 80337, Munich, Germany.
- Department of Medicine 3 and Comprehensive Cancer Center, Ludwig-Maximilians-University Munich, Munich, Germany.
- German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
- German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
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Jeon J, Cheong JH. Clinical Implementation of Precision Medicine in Gastric Cancer. J Gastric Cancer 2019; 19:235-253. [PMID: 31598369 PMCID: PMC6769368 DOI: 10.5230/jgc.2019.19.e25] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 07/28/2019] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is one of the deadliest malignancies in the world. Currently, clinical treatment decisions are mostly made based on the extent of the tumor and its anatomy, such as tumor-node-metastasis staging. Recent advances in genome-wide molecular technology have enabled delineation of the molecular characteristics of GC. Based on this, efforts have been made to classify GC into molecular subtypes with distinct prognosis and therapeutic response. Simplified algorithms based on protein and RNA expressions have been proposed to reproduce the GC classification in the clinical field. Furthermore, a recent study established a single patient classifier (SPC) predicting the prognosis and chemotherapy response of resectable GC patients based on a 4-gene real-time polymerase chain reaction assay. GC patient stratification according to SPC will enable personalized therapeutic strategies in adjuvant settings. At the same time, patient-derived xenografts and patient-derived organoids are now emerging as novel preclinical models for the treatment of GC. These models recapitulate the complex features of the primary tumor, which is expected to facilitate both drug development and clinical therapeutic decision making. An integrated approach applying molecular patient stratification and patient-derived models in the clinical realm is considered a turning point in precision medicine in GC.
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Affiliation(s)
- Jaewook Jeon
- Yonsei University College of Medicine, Seoul, Korea
| | - Jae-Ho Cheong
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul, Korea.,Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.,Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seoul, Korea.,Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Korea
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Valentini AM, Di Pinto F, Coletta S, Guerra V, Armentano R, Caruso ML. Tumor microenvironment immune types in gastric cancer are associated with mismatch repair however, not HER2 status. Oncol Lett 2019; 18:1775-1785. [PMID: 31423245 PMCID: PMC6614673 DOI: 10.3892/ol.2019.10513] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 02/18/2019] [Indexed: 12/14/2022] Open
Abstract
The treatment of patients with human epidermal growth factor receptor 2 (HER2)-negative gastric cancer is a major challenge. Immunotherapy using immune checkpoint inhibitors is a rapidly growing field. In a number of malignancy types it has been demonstrated that patients with mismatch repair deficiency efficiently respond to programmed death-ligand 1 (PD-L1) blockade therapy. Recent studies have evaluated tumor microenvironment immune types to predict which patients may clinically benefit from immunotherapy. The present study aimed to evaluate the immunohistochemical expression of PD-L1 in 70 gastric cancer tissue samples. Potential associations between PD-L1 expression and mismatch repair deficiency, HER2 and Epstein Barr virus (EBV) status were then investigated in the context of the tumor microenvironment. A positive association was identified for PD-L1 expression with mismatch repair deficiency and EBV status; however, no association was revealed with HER2 status. Immunohistochemistry was then used to classify the microenvironment immune types. This demonstrated that the majority of the gastric cancer samples (73%) belonged to the tumor microenvironment immune type II [PD-L1-/cluster of differentiation 8 (CD8)+ low], which involves an immune ignorant state and has a low sensitivity to immunotherapy. However, 7% of the gastric cancer cases were identified to belong to the tumor microenvironment immune type I (PD-L1+/CD8+ high), which exhibits adaptive immune escape responses and a high chance of reversion with immune checkpoint blockade therapy. In conclusion, the present study emphasized the importance of evaluating tumor microenvironment immune types, mismatch repair deficiency status and EBV status, rather than PD-L1 expression alone, when evaluating the eligibility of a patient for immunotherapy with anti-programmed cell death protein-1/PD-L1 antibodies.
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Affiliation(s)
- Anna Maria Valentini
- Department of Pathology, National Institute of Gastroenterology ‘S. de Bellis’, Research Hospital, Castellana Grotte, I-70013 Bari, Italy
| | - Federica Di Pinto
- Department of Pathology, National Institute of Gastroenterology ‘S. de Bellis’, Research Hospital, Castellana Grotte, I-70013 Bari, Italy
| | - Sergio Coletta
- Department of Pathology, National Institute of Gastroenterology ‘S. de Bellis’, Research Hospital, Castellana Grotte, I-70013 Bari, Italy
| | - Vito Guerra
- Department of Epidemiology, National Institute of Gastroenterology ‘S. de Bellis’, Research Hospital, Castellana Grotte, I-70013 Bari, Italy
| | - Raffaele Armentano
- Department of Pathology, National Institute of Gastroenterology ‘S. de Bellis’, Research Hospital, Castellana Grotte, I-70013 Bari, Italy
| | - Maria Lucia Caruso
- Department of Pathology, National Institute of Gastroenterology ‘S. de Bellis’, Research Hospital, Castellana Grotte, I-70013 Bari, Italy
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Lai YC, Yeh TS, Wu RC, Tsai CK, Yang LY, Lin G, Kuo MD. Acute Tumor Transition Angle on Computed Tomography Predicts Chromosomal Instability Status of Primary Gastric Cancer: Radiogenomics Analysis from TCGA and Independent Validation. Cancers (Basel) 2019; 11:641. [PMID: 31075839 PMCID: PMC6562475 DOI: 10.3390/cancers11050641] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 04/16/2019] [Accepted: 05/07/2019] [Indexed: 01/14/2023] Open
Abstract
Chromosomal instability (CIN) of gastric cancer is correlated with distinct outcomes. This study aimed to investigate the role of computed tomography (CT) imaging traits in predicting the CIN status of gastric cancer. We screened 443 patients in the Cancer Genome Atlas gastric cancer cohort to filter 40 patients with complete CT imaging and genomic data as the training cohort. CT imaging traits were subjected to logistic regression to select independent predictors for the CIN status. For the validation cohort, we prospectively enrolled 18 gastric cancer patients for CT and tumor genomic analysis. The imaging predictors were tested in the validation cohort using receiver operating characteristic curve (ROC) analysis. Thirty patients (75%) in the training cohort and 9 patients (50%) in the validation cohort had CIN subtype gastric cancers. Smaller tumor diameter (p = 0.017) and acute tumor transition angle (p = 0.045) independently predict CIN status in the training cohort. In the validation cohort, acute tumor transition angle demonstrated the highest accuracy, sensitivity, and specificity of 88.9%, 88.9%, and 88.9%, respectively, and areas under ROC curve of 0.89. In conclusion, this pilot study showed acute tumor transition angle on CT images may predict the CIN status of gastric cancer.
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Affiliation(s)
- Ying-Chieh Lai
- Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.
- Imaging Core Lab, Institute for Radiological Research, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.
| | - Ta-Sen Yeh
- Department of General Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.
| | - Ren-Chin Wu
- Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.
| | - Cheng-Kun Tsai
- Imaging Core Lab, Institute for Radiological Research, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.
- Clinical Metabolomics Core Lab, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
| | - Lan-Yan Yang
- Clinical Trial Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
| | - Gigin Lin
- Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.
- Imaging Core Lab, Institute for Radiological Research, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.
- Clinical Metabolomics Core Lab, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
| | - Michael D Kuo
- Department of Diagnostic Radiology, University of Hong Kong, Hong Kong 999077, China.
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Tsuruta S, Ohishi Y, Fujiwara M, Ihara E, Ogawa Y, Oki E, Nakamura M, Oda Y. Gastric hepatoid adenocarcinomas are a genetically heterogenous group; most tumors show chromosomal instability, but MSI tumors do exist. Hum Pathol 2019; 88:27-38. [PMID: 30946937 DOI: 10.1016/j.humpath.2019.03.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 03/15/2019] [Accepted: 03/15/2019] [Indexed: 02/07/2023]
Abstract
The Cancer Genome Atlas Research Network classified gastric adenocarcinoma into four molecular subtypes: (1) Epstein-Barr virus-positive (EBV), (2) microsatellite-instable (MSI), (3) chromosomal instable (CIN), and (4) genomically stable (GS). The molecular subtypes of gastric hepatoid adenocarcinomas are still largely unknown. We analyzed 52 hepatoid adenocarcinomas for the expression of surrogate markers of molecular subtypes (MLH1, p53, and EBER in situ hybridization) and some biomarkers (p21, p16, Rb, cyclin D1, cyclin E, β-catenin, Bcl-2, IMP3, ARID1A and HER2), and mutations of TP53, CTNNB1, KRAS, and BRAF. We analyzed 36 solid-type poorly differentiated adenocarcinomas as a control group. Hepatoid adenocarcinomas were categorized as follows: EBV group (EBER-positive), no cases (0%); MSI group (MLH1 loss), three cases (6%); "CIN or GS" (CIN/GS) group (EBER-negative, MLH1 retained), 49 cases (94%). In the CIN/GS group, most of the tumors (59%) had either p53 overexpression or TP53 mutation and a coexisting tubular intestinal-type adenocarcinoma component (90%), suggesting that most hepatoid adenocarcinomas should be categorized as a true CIN group. Hepatoid adenocarcinomas showed relatively frequent expressions of HER2 (score 3+/2+: 21%/19%). Hepatoid adenocarcinomas showed shorter survival, more frequent overexpressions of p16 (67%) and IMP3 (98%) than the control group. None of hepatoid adenocarcinomas had KRAS or CTNNB1 mutations except for one case each, and no hepatoid adenocarcinomas had BRAF mutation. In conclusion, gastric hepatoid adenocarcinomas are a genetically heterogenous group. Most hepatoid adenocarcinomas are "CIN," but a small number of hepatoid adenocarcinomas with MSI do exist. Hepatoid adenocarcinomas are characterized by overexpressions of p16 and IMP3.
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Affiliation(s)
- Shinichi Tsuruta
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yoshihiro Ohishi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Minako Fujiwara
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Eikichi Ihara
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
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Díaz Del Arco C, Estrada Muñoz L, Molina Roldán E, Cerón Nieto MÁ, Ortega Medina L, García Gómez de Las Heras S, Fernández Aceñero MJ. Immunohistochemical classification of gastric cancer based on new molecular biomarkers: a potential predictor of survival. Virchows Arch 2018; 473:687-695. [PMID: 30140949 DOI: 10.1007/s00428-018-2443-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 08/11/2018] [Accepted: 08/15/2018] [Indexed: 12/17/2022]
Abstract
Several classification systems have been described for stratifying patients with gastric carcinoma (GC). However, their prognostic value is low, and there is an urgent need for identification of molecular markers and development of new classifications. Retrospective study of 206 cases of GC diagnosed and surgically resected in our hospital between 2000 and 2017. Clinicopathological features of all cases were assessed and tissue microarrays were constructed for immunohistochemical (IHC) study. Patients were stratified based on IHC results. Mean patient age was 71 years and most patients were male (54.6%). Most tumors were located in the gastric antrum and body, and they were mostly fungoid or ulcerative lesions. GC were mainly intestinal-type tumors and 60.3% were diagnosed at pT3. 56.2% of patients showed recurrences and 29.4% died due to GC. According to our IHC classification, 23.5% of tumors showed microsatellite instability, 6% were E-cadherin negative, 53.5% were stable-p53 not overexpressed, and 17% were stable with p53 overexpression. IHC classification was significantly correlated with patient gender, gross morphology, Laurén classification, tumor necrosis, perineural infiltration, type of leading edge, and patient outcome. Multivariate analysis showed that IHC subtype was significantly and independently associated with overall survival, together with clinical symptoms, signet cell phenotype, tumor grade and vessel invasion. The application of IHC classifications based on molecular biomarkers in clinical practice can aid in the stratification of GC patients. More studies are needed to evaluate the reproducibility and clinical significance of these classifications.
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Affiliation(s)
- Cristina Díaz Del Arco
- Department of Surgical Pathology, Hospital Clínico San Carlos, 28040, Madrid, Spain.
- Complutense University of Madrid, Madrid, Spain.
| | - Lourdes Estrada Muñoz
- Department of Surgical Pathology, Hospital Rey Juan Carlos, Madrid, Spain
- Rey Juan Carlos University, Alcorcón, Madrid, Spain
| | - Elena Molina Roldán
- Department of Surgical Pathology, Hospital Clínico San Carlos, 28040, Madrid, Spain
| | | | - Luis Ortega Medina
- Department of Surgical Pathology, Hospital Clínico San Carlos, 28040, Madrid, Spain
- Complutense University of Madrid, Madrid, Spain
| | | | - Mª Jesús Fernández Aceñero
- Department of Surgical Pathology, Hospital Clínico San Carlos, 28040, Madrid, Spain
- Complutense University of Madrid, Madrid, Spain
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42
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Hewitt LC, Inam IZ, Saito Y, Yoshikawa T, Quaas A, Hoelscher A, Bollschweiler E, Fazzi GE, Melotte V, Langley RE, Nankivell M, Cunningham D, Allum W, Hutchins GG, Grabsch HI. Epstein-Barr virus and mismatch repair deficiency status differ between oesophageal and gastric cancer: A large multi-centre study. Eur J Cancer 2018; 94:104-114. [PMID: 29550565 PMCID: PMC5914544 DOI: 10.1016/j.ejca.2018.02.014] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 02/06/2018] [Accepted: 02/08/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND Oesophageal (OeC) and gastric (GC) cancer patients are treated with similar multimodal therapy and have poor survival. There remains an urgent clinical need to identify biomarkers to individualise patient management and improve outcomes. Therapy with immune checkpoint inhibitors has shown promising results in other cancers. Proposed biomarkers to predict potential response to immune checkpoint inhibitors include DNA mismatch repair (MMR) and/or Epstein-Barr virus (EBV) status. The aim of this study was to establish and compare EBV status and MMR status in large multi-centre series of OeC and GC. METHODS EBV was assessed by EBV-encoded RNA (EBER) in situ hybridisation and MMR protein expression by immunohistochemistry (IHC) in 988 OeC and 1213 GC from multiple centres. In a subset of OeC, microsatellite instability (MSI) was tested in parallel with MMR IHC. RESULTS Frequency of MMR deficiency (MMRdef) and MSI was low in OeC (0.8% and 0.6%, respectively) compared with GC (10.3%). None of the OeCs were EBER positive in contrast to 4.8% EBER positive GC. EBV positive GC patients were younger (p = 0.01), more often male (p = 0.001) and had a better overall survival (p = 0.012). MMRdef GC patients were older (p = 0.001) and showed more often intestinal-type histology (p = 0.022). CONCLUSIONS This is the largest study to date indicating that EBV and MMRdef do not play a role in OeC carcinogenesis in contrast to GC. The potential clinical usefulness of determining MMRdef/EBV status to screen patients for eligibility for immune-targeting therapy differs between OeC and GC patients.
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Affiliation(s)
- L C Hewitt
- Department of Pathology and GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands; Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
| | - I Z Inam
- Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
| | - Y Saito
- Department of Pathology and GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - T Yoshikawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan
| | - A Quaas
- Institute for Pathology, University Hospital Cologne, Cologne, Germany
| | - A Hoelscher
- German Center for Esophageal and Gastric Surgery, Agaplesion Markus Hospital, Frankfurt, Germany
| | - E Bollschweiler
- Department of Visceral Surgery, University Hospital Cologne, Cologne, Germany
| | - G E Fazzi
- Department of Pathology and GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - V Melotte
- Department of Pathology and GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands; Department of Clinical Genetics, University of Rotterdam, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - R E Langley
- Medical Research Council Clinical Trials Unit at University College London, London, UK
| | - M Nankivell
- Medical Research Council Clinical Trials Unit at University College London, London, UK
| | - D Cunningham
- The Royal Marsden Hospital NHS Foundation Trust, London and Surrey, UK
| | - W Allum
- Department of Surgery, Royal Marsden National Health Services Foundation Trust, London, UK
| | - G G Hutchins
- Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
| | - H I Grabsch
- Department of Pathology and GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands; Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
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43
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Zou L, Wu Y, Ma K, Fan Y, Dong D, Geng N, Li E. Molecular classification of esophagogastric junction carcinoma correlated with prognosis. Onco Targets Ther 2017; 10:4765-4772. [PMID: 29026322 PMCID: PMC5626374 DOI: 10.2147/ott.s145912] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
A novel molecular classification of gastric cancer by the Asian Cancer Research Group (ACRG) is a potential advance in diagnosis and treatment, and it helps to determine prognosis. The use of immunohistochemistry (IHC) rather than gene expression analysis to determine tumor subtypes was evaluated with the aim of determining the feasibility of using the ACRG molecular classification. A total of 69 esophagogastric junction (EGJ) carcinomas were classified as microsatellite instable (MSI, 17.40%, 12 of 69), microsatellite stable with markers of epithelial-to-mesenchymal transition (MSS/EMT, 18.84%, 13 of 69), microsatellite stable with active tumor protein 53 (MSS/TP53+, 27.53%, 19 of 69), and microsatellite stable with inactive TP53 (MSS/TP53-, 36.23%, 25 of 69). The molecular classification did not significantly correlate with anyone of the clinicopathological characteristics of the EGJ carcinoma patients, including age, gender, depth of tumor invasion, the presence of lymph node metastasis, histologic grade, and p-TNM stage of the American Joint Committee on Cancer (P>0.05). Kaplan-Meier survival analysis and log rank tests showed that molecular classification, histologic grade, p-TNM stage, and postoperative adjuvant chemotherapy were significantly associated with overall survival (OS; P<0.05). MSI tumors had the best overall prognosis followed by MSS/TP53- and MSS/TP53+. MSS/EMT tumors had the worst overall prognosis. Multivariate analysis revealed that histologic grade (hazard ratio [HR] =2.216, 95% CI =1.202-4.086), p-TNM stage (HR =2.216, 95% CI =1.202-4.086), and molecular subtype (HR =2.216, 95% CI =1.202-4.086) were independently associated with OS. The preliminary results suggested that the ACRG molecular classification may be a valuable independent prognostic marker for EGJ carcinoma patients and could be performed by IHC analysis.
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Affiliation(s)
- Long Zou
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an.,Department of Gastroenterology, Shangluo Central Hospital, Shangluo, Shaanxi, People's Republic of China
| | - Yinying Wu
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an
| | - Ke Ma
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an
| | - Yangwei Fan
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an
| | - Danfeng Dong
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an
| | - Ningyan Geng
- Department of Gastroenterology, Shangluo Central Hospital, Shangluo, Shaanxi, People's Republic of China
| | - Enxiao Li
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an
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Baek DW, Kang BW, Hwang S, Kim JG, Seo AN, Bae HI, Kwon OK, Lee SS, Chung HY, Yu W. Clinical Significance of p53 Protein Expression, Beta-catenin Expression and HER2 Expression for Epstein-Barr Virus-associated Gastric Cancer. Chonnam Med J 2017; 53:140-146. [PMID: 28584793 PMCID: PMC5457949 DOI: 10.4068/cmj.2017.53.2.140] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 03/10/2017] [Accepted: 03/16/2017] [Indexed: 12/13/2022] Open
Abstract
This study assessed the expression of the p53 protein, beta-catenin, and HER2 and their prognostic implications in patients with EBV-associated gastric cancer (EBVaGC). After reviewing 1318 consecutive cases of surgically resected or endoscopic submucosal dissected gastric cancers, 117 patients were identified as EBV-positive using EBV-encoded RNA in-situ hybridization. The immunohistochemistry results were interpreted as follows: strong p53 nuclear expression in at least 50% of tumor nuclei was interpreted as a positive result, strong beta-catenin expression in at least 10% of cytoplasmic nuclei was interpreted as a positive result, and moderate or strong complete or basolateral membrane staining in 10% of tumor cells was interpreted as a positive result for HER2. Immunohistochemical staining for p53 was performed on tumor tissue from 105 patients, among whom 25 (23.8%) tested positive. Meanwhile, beta-catenin expression was positive in 10 patients (17.5%) and HER2 expression was positive in 8 patients (6.8%). The positive expression of p53 was significantly associated with a high T stage (p=0.006). More patients with lymph node metastasis were p53-positive (p=0.013). In the univariate analysis, the p53-positive patients showed significantly decreased disease-free survival (DFS) when compared with the p53-negative patients (p=0.022), although the p53 status was only marginally associated with overall survival (OS) (p=0.080). However, p53 expression showed no prognostic significance on DFS in the multivariate analysis. Moreover, beta-catenin and HER2 showed no association with DFS and OS in the survival analysis. The current study found a significant correlation between p53 expression and tumor progression and lymph node metastases in patients with EBVaGC.
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Affiliation(s)
- Dong Won Baek
- Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University Cancer Research Institute, Kyungpook National University School of Medicine, Daegu, Korea
| | - Byung Woog Kang
- Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University Cancer Research Institute, Kyungpook National University School of Medicine, Daegu, Korea
| | - Soyoon Hwang
- Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University Cancer Research Institute, Kyungpook National University School of Medicine, Daegu, Korea
| | - Jong Gwang Kim
- Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University Cancer Research Institute, Kyungpook National University School of Medicine, Daegu, Korea
| | - An Na Seo
- Department of Pathology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Han Ik Bae
- Department of Pathology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Oh Kyoung Kwon
- Department of Surgery, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Seung Soo Lee
- Department of Surgery, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Ho Young Chung
- Department of Surgery, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Wansik Yu
- Department of Surgery, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
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45
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Maleki SS, Röcken C. Chromosomal Instability in Gastric Cancer Biology. Neoplasia 2017; 19:412-420. [PMID: 28431273 PMCID: PMC5397576 DOI: 10.1016/j.neo.2017.02.012] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 02/21/2017] [Indexed: 02/08/2023] Open
Abstract
Gastric cancer (GC) is the fifth most common cancer in the world and accounts for 7% of the total cancer incidence. The prognosis of GC is dismal in Western countries due to late diagnosis: approximately 70% of the patients die within 5 years following initial diagnosis. Recently, integrative genomic analyses led to the proposal of a molecular classification of GC into four subtypes, i.e.,microsatellite-instable, Epstein-Barr virus–positive, chromosomal-instable (CIN), and genomically stable GCs. Molecular classification of GC advances our knowledge of the biology of GC and may have implications for diagnostics and patient treatment. Diagnosis of microsatellite-instable GC and Epstein-Barr virus–positive GC is more or less straightforward. Microsatellite instability can be tested by immunohistochemistry (MLH1, PMS2, MSH2, and MSH6) and/or molecular-biological analysis. Epstein-Barr virus–positive GC can be tested by in situ hybridization (Epstein-Barr virus encoded small RNA). However, with regard to CIN, testing may be more complicated and may require a more in-depth knowledge of the underlying mechanism leading to CIN. In addition, CIN GC may not constitute a distinct subgroup but may rather be a compilation of a more heterogeneous group of tumors. In this review, we aim to clarify the definition of CIN and to point out the molecular mechanisms leading to this molecular phenotype and the challenges faced in characterizing this type of cancer.
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Affiliation(s)
| | - Christoph Röcken
- Department of Pathology, Christian-Albrechts-University, Kiel, Germany.
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