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Kawakami T, Matsubayashi H, Kiyozumi Y, Harada R, Ishihara E, Yoshida M, Ono H, Bando E, Serizawa M, Sugino T. A Japanese family of hereditary diffuse gastric cancer with a germline pathogenic variant of CTNN1A detected via comprehensive genome profiling. Gastric Cancer 2025; 28:544-549. [PMID: 39838246 DOI: 10.1007/s10120-025-01583-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 01/10/2025] [Indexed: 01/23/2025]
Abstract
CTNNA1 codes α-1 catenin, a molecule that functions in intercellular adhesion in combination with E-cadherin (coded by CDH1). A germline pathogenic variant (GPV) of CTNNA1 increases the risk of hereditary diffuse gastric cancer (HDGC); however, this GPV has not been reported in Japan. A 35-year-old Japanese man with an advanced gastric cancer underwent comprehensive genome profiling (CGP), which led to the detection of a CTNNA1 GPV (p.Q662*). His gastric cancer tissues demonstrated a loss of α-1 catenin expression. His mother with a history of gastric signet-ring cell carcinoma had undergone genetic counseling 2 years ago, because of her broad family history of young-onset gastric cancer. Then, she had undergone germline multigene panel testing (MGPT) that included CDH1 but not CTNNA1, and no GPV had been detected. Here, Japanese precision cancer medicine revealed a GPV of a gene rarely associated with HDGC, that could not be detected by common MGPTs.
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Affiliation(s)
- Takeshi Kawakami
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Hiroyuki Matsubayashi
- Division of Genetic Medicine Promotion, Shizuoka Cancer Center, Shizuoka, Japan.
- Division of Endoscopy, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi, Suntogun, Shizuoka, 411-8777, Japan.
| | - Yoshimi Kiyozumi
- Division of Genetic Medicine Promotion, Shizuoka Cancer Center, Shizuoka, Japan
| | - Rina Harada
- Division of Genetic Medicine Promotion, Shizuoka Cancer Center, Shizuoka, Japan
| | - Eiko Ishihara
- Division of Genetic Medicine Promotion, Shizuoka Cancer Center, Shizuoka, Japan
| | - Masao Yoshida
- Division of Endoscopy, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi, Suntogun, Shizuoka, 411-8777, Japan
| | - Hiroyuki Ono
- Division of Endoscopy, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi, Suntogun, Shizuoka, 411-8777, Japan
| | - Etsuro Bando
- Division of Gastric Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | | | - Takashi Sugino
- Division of Pathology, Shizuoka Cancer Center, Shizuoka, Japan
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Rätze MAK, Enserink LNFL, Ishiyama N, van Kempen S, Veltman CHJ, Nijman IJ, Haakma WE, Caldas C, Bernards R, van Diest PJ, Christgen M, Koorman T, Derksen PWB. Afadin loss induces breast cancer metastasis through destabilisation of E-cadherin to F-actin linkage. J Pathol 2025; 266:26-39. [PMID: 40026293 PMCID: PMC11985701 DOI: 10.1002/path.6394] [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: 07/17/2024] [Revised: 11/18/2024] [Accepted: 12/16/2024] [Indexed: 03/05/2025]
Abstract
Afadin is a multimodal scaffolding protein with essential functions in cell-cell adhesion. Although its loss of expression has been linked to breast cancer invasion and metastasis, the underlying mechanisms driving tumour progression upon mutational Afadin (AFDN) loss in breast cancers remains unclear. In the current study we identified a somatic frameshift AFDN mutation (p.Lys630fs) in an invasive breast cancer sample that coincides with loss of Afadin protein expression. Functional studies in E-cadherin-expressing breast cancer cells show that Afadin loss leads to immature and aberrant adherens junction (AJ) formation. The lack of AJ maturation results in a noncohesive cellular phenotype accompanied by Actomyosin-dependent anoikis resistance, which are classical progression hallmarks of single-cell breast cancer invasion. Reconstitution experiments using Afadin truncates show that proper F-actin organisation and epithelial cell-cell adhesion critically depend on the Coiled-Coil domain of Afadin but not on the designated C-terminal F-actin binding domain. Mouse xenograft experiments based on cell lines and primary patient-derived breast cancer organoids demonstrate that Afadin loss induces single-cell lobular-type invasion phenotypes and overt dissemination to the lungs and the peritoneum. In short, Afadin is a metastasis suppressor for breast cancer through stabilisation and maturation of a mechanical E-cadherin to F-actin outside-in link. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Max AK Rätze
- Department of PathologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Lotte NFL Enserink
- Department of PathologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | | | - Sven van Kempen
- Department of PathologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | | | - Isaac J Nijman
- Center for Molecular Medicine, Cancer Genomics Netherlands, Department of GeneticsUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Wisse E Haakma
- Department of PathologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Carlos Caldas
- Cancer Research UK Cambridge InstituteUniversity of CambridgeCambridgeUK
- Department of OncologyUniversity of CambridgeCambridgeUK
| | - René Bernards
- Division of Molecular Carcinogenesis, Center for Biomedical Genetics and Cancer Genomics CentreThe Netherlands Cancer InstituteAmsterdamThe Netherlands
| | - Paul J van Diest
- Department of PathologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | | | - Thijs Koorman
- Department of PathologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Patrick WB Derksen
- Department of PathologyUniversity Medical Center UtrechtUtrechtThe Netherlands
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Zhan T, Betge J, Schulte N, Dreikhausen L, Hirth M, Li M, Weidner P, Leipertz A, Teufel A, Ebert MP. Digestive cancers: mechanisms, therapeutics and management. Signal Transduct Target Ther 2025; 10:24. [PMID: 39809756 PMCID: PMC11733248 DOI: 10.1038/s41392-024-02097-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 10/20/2024] [Accepted: 11/29/2024] [Indexed: 01/16/2025] Open
Abstract
Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.
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Affiliation(s)
- Tianzuo Zhan
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Johannes Betge
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nadine Schulte
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Lena Dreikhausen
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Michael Hirth
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Moying Li
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Philip Weidner
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Antonia Leipertz
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Andreas Teufel
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Matthias P Ebert
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany.
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
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Khiabany A, Dermanis AA, Liew MS, Ong KR, Kamarajah SK, Griffiths EA. A Systematic Review of Surgical and Pathological Outcomes in Patients With a CDH1 Mutation Undergoing Total Gastrectomy. J Surg Oncol 2024; 130:1539-1550. [PMID: 39257226 DOI: 10.1002/jso.27855] [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: 08/04/2024] [Accepted: 08/10/2024] [Indexed: 09/12/2024]
Abstract
BACKGROUND CDH1 (E-cadherin) genetic mutations are associated with a 30%-70% increased lifetime risk of hereditary diffuse gastric cancer (HDGC). Although prophylactic total gastrectomy (PTG) reduces long-term risk of gastric cancer, the associated morbidity and mortality remain unclear. This systematic review aims to characterise postoperative surgical outcomes in patients undergoing total gastrectomy. METHODS A systematic literature search was performed for studies reporting endoscopic surveillance, surgical and pathological outcomes for patients with CDH1 mutation undergoing a total gastrectomy. RESULTS Thirty-nine studies included 1849 patients, of which 96% had a CDH1 (n = 1777) or CTNNA1 (n = 3) mutation. Endoscopy outcomes were reported for 1640 patients. Cancer foci were identified in 32% (n = 523/1640) and 71% of these patients went on to have a total gastrectomy (n = 369/523). The remaining 78% of patients did not have cancer foci detected on endoscopy (n = 1117/1640). Of these patients, 62% underwent a total gastrectomy (n = 688/1117) and 81% were found to have cancer on surgical histology (n = 556/688). Pathological staging was reported for 790 patients undergoing surgery, of which 68% had pT1 disease (n = 537). Postoperative complications were reported for 430 patients across 23 studies, with the most common complications being anastomotic strictures (25%), anastomotic leaks (13%), wound infections (12%) and pulmonary complications (11%). Only one postoperative death was reported within 30 days. CONCLUSION Rates of early cancers are high in CDH1 patients undergoing PTG, highlighting the need for improvement in reliable endoscopic surveillance. Although postoperative mortality in this surgical cohort remains low, high rates of postoperative complications warrant careful patient counselling.
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Affiliation(s)
- Atousa Khiabany
- Department of Upper Gastrointestinal Surgery, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Trust, Birmingham, UK
| | - Alexander A Dermanis
- Department of Upper Gastrointestinal Surgery, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Trust, Birmingham, UK
| | - Mei Sien Liew
- Department of Upper Gastrointestinal Surgery, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Trust, Birmingham, UK
| | - Kai Ren Ong
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Sivesh K Kamarajah
- Department of Upper Gastrointestinal Surgery, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Trust, Birmingham, UK
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Ewen A Griffiths
- Department of Upper Gastrointestinal Surgery, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Trust, Birmingham, UK
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
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Sreeram A, Stroobant EE, Laszkowska M, Guilford P, Shimada S, Nishimura M, Shah S, Vardhana S, Tang LH, Strong VE. Disappearing Signet Ring Cell Adenocarcinoma in Gastric Cancer Patients. Ann Surg Oncol 2024; 31:9030-9038. [PMID: 39343820 DOI: 10.1245/s10434-024-16117-8] [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: 05/07/2024] [Accepted: 08/16/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND The incidence of diffuse-type gastric cancer is increasing steadily in the United States, Europe, and Asia. This subtype is known for aggressive clinical characteristics and transmural invasion. However, T1a diffuse-type cancers have been observed to have a better 5-year, disease-specific mortality than stage-matched intestinal tumors, supporting a clinical difference in these early-stage cancers. METHODS Data on all living patients with T1a gastric adenocarcinoma with a finding of signet ring cell morphology on pathology and ≥1 year of follow-up from 2013 to 2023 at Memorial Sloan Kettering Cancer Center (MSK) was collected from a prospectively maintained database. Patients with known CDH1 or CTNNA1 mutations were excluded. RESULTS In 7 of 30 patients, sporadic pathologically confirmed T1a signet ring cell (diffuse) cancer identified on initial biopsy was no longer detectable upon subsequent biopsy or resection with mean follow-up of 50 months. CONCLUSIONS These cases allude to the distinct pathways of carcinogenesis in T1a signet ring cell cancers. Potential factors that may underlie the spontaneous regression of these T1a cancers include complete removal at initial biopsy, immune clearance, and lack of survival advantage conferred by signet ring cell genetic alterations in these cases. Given their more indolent behavior at an earlier stage, we suggest that these lesions can be closely followed by endoscopy in select circumstances with thorough disease assessment and an experienced care team.
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Affiliation(s)
- Aravind Sreeram
- Department of Surgery, Gastric and Mixed Tumor Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Emily E Stroobant
- Department of Surgery, Gastric and Mixed Tumor Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Monika Laszkowska
- Department of Medicine, Gastroenterology, Hepatology, and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Parry Guilford
- Department of Biochemistry, Cancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatu), University of Otago, Dunedin, New Zealand
| | - Shoji Shimada
- Department of Surgery, Gastric and Mixed Tumor Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Makoto Nishimura
- Department of Medicine, Gastroenterology, Hepatology, and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sohrab Shah
- Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Santosha Vardhana
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Laura H Tang
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Vivian E Strong
- Department of Surgery, Gastric and Mixed Tumor Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Boudouaia-Ouali A, Dali-Sahi M. Alpha T-catenin: a crucial tumor suppressor in cancer pathogenesis. J Mol Histol 2024; 55:655-660. [PMID: 39083160 DOI: 10.1007/s10735-024-10232-2] [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: 04/14/2024] [Accepted: 07/21/2024] [Indexed: 10/10/2024]
Abstract
Alpha T-catenin has recently been identified as a crucial tumor suppressor in various cancer types, with roles that go beyond just providing structural support in adherens junctions. This review brings together recent findings on alpha T-catenin's important involvement in key signaling pathways related to cancer progression. We present strong evidence of its regulatory role in Wnt signaling, a pathway often disrupted in colorectal cancer, and explain how it inhibits cell proliferation and tumor growth. We also discuss the significant downregulation of alpha T-catenin in colorectal cancers and its potential as a prognostic marker. Moreover, this review looks at how increasing alpha T-catenin levels can reduce tumor growth and spread, suggesting new therapeutic strategies. Additionally, we reveal alpha T-catenin's unexpected impact on NF-κB signaling in basal E-cadherin-negative breast cancer, expanding its importance across different cancer types. By bringing these findings together, we provide a thorough understanding of alpha T-catenin's tumor-suppressing actions, setting the stage for new targeted therapies and diagnostic tools in cancer treatment.
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Affiliation(s)
| | - Majda Dali-Sahi
- Department of Biology, University of Tlemcen, 13000, Tlemcen, Algeria
- Analytical Chemistry and Electrochemistry Laboratory, University of Tlemcen, 13000, Tlemcen, Algeria
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Kővári B, Carneiro F, Lauwers GY. Epithelial tumours of the stomach. MORSON AND DAWSON'S GASTROINTESTINAL PATHOLOGY 2024:227-286. [DOI: 10.1002/9781119423195.ch13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Maoz A, Rodriguez NJ, Yurgelun MB, Syngal S. Gastrointestinal Cancer Precursor Conditions and Their Detection. Hematol Oncol Clin North Am 2024; 38:783-811. [PMID: 38760197 PMCID: PMC11537157 DOI: 10.1016/j.hoc.2024.04.002] [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] [Indexed: 05/19/2024]
Abstract
Gastrointestinal cancers are a leading cause of cancer morbidity and mortality. Many gastrointestinal cancers develop from cancer precursor lesions, which are commonly found in individuals with hereditary cancer syndromes. Hereditary cancer syndromes have advanced our understanding of cancer development and progression and have facilitated the evaluation of cancer prevention and interception efforts. Common gastrointestinal hereditary cancer syndromes, including their organ-specific cancer risk and surveillance recommendations, are reviewed in this article. The management of common gastroesophageal, pancreatic, and colonic precursor lesions is also discussed, regardless of their genetic background. Further research is needed to advance chemoprevention and immunoprevention strategies.
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Affiliation(s)
- Asaf Maoz
- Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Harvard Medical School, Boston, MA, USA. https://twitter.com/asaf_maoz
| | - Nicolette J Rodriguez
- Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, 75 Francis Street, Boston MA 02115, USA; Division of Cancer Genetics and Prevention, 450 Brookline Avenue, Boston MA 02215, USA. https://twitter.com/Dr_NJRodriguez
| | - Matthew B Yurgelun
- Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Harvard Medical School, Boston, MA, USA. https://twitter.com/MattYurgelun
| | - Sapna Syngal
- Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
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Herrera-Pariente C, Bonjoch L, Muñoz J, Fernàndez G, Soares de Lima Y, Mahmood R, Cuatrecasas M, Ocaña T, Lopez-Prades S, Llargués-Sistac G, Domínguez-Rovira X, Llach J, Luzko I, Díaz-Gay M, Lazaro C, Brunet J, Castillo-Manzano C, García-González MA, Lanas A, Carrillo M, Hernández San Gil R, Quintero E, Sala N, Llort G, Aguilera L, Carot L, Diez-Redondo P, Jover R, Ramon Y Cajal T, Cubiella J, Castells A, Balaguer F, Bujanda L, Castellví-Bel S, Moreira L. CTNND1 is involved in germline predisposition to early-onset gastric cancer by affecting cell-to-cell interactions. Gastric Cancer 2024; 27:747-759. [PMID: 38796558 PMCID: PMC11193828 DOI: 10.1007/s10120-024-01504-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 04/20/2024] [Indexed: 05/28/2024]
Abstract
BACKGROUND CDH1 and CTNNA1 remain as the main genes for hereditary gastric cancer. However, they only explain a small fraction of gastric cancer cases with suspected inherited basis. In this study, we aimed to identify new hereditary genes for early-onset gastric cancer patients (EOGC; < 50 years old). METHODS After germline exome sequencing in 20 EOGC patients and replication of relevant findings by gene-panel sequencing in an independent cohort of 152 patients, CTNND1 stood out as an interesting candidate gene, since its protein product (p120ctn) directly interacts with E-cadherin. We proceeded with functional characterization by generating two knockout CTNND1 cellular models by gene editing and introducing the detected genetic variants using a lentiviral delivery system. We assessed β-catenin and E-cadherin levels, cell detachment, as well as E-cadherin localization and cell-to-cell interaction by spheroid modeling. RESULTS Three CTNND1 germline variants [c.28_29delinsCT, p.(Ala10Leu); c.1105C > T, p.(Pro369Ser); c.1537A > G, p.(Asn513Asp)] were identified in our EOGC cohorts. Cells encoding CTNND1 variants displayed altered E-cadherin levels and intercellular interactions. In addition, the p.(Pro369Ser) variant, located in a key region in the E-cadherin/p120ctn binding domain, showed E-cadherin mislocalization. CONCLUSIONS Defects in CTNND1 could be involved in germline predisposition to gastric cancer by altering E-cadherin and, consequently, cell-to-cell interactions. In the present study, CTNND1 germline variants explained 2% (3/172) of the cases, although further studies in larger external cohorts are needed.
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Affiliation(s)
- Cristina Herrera-Pariente
- Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain
| | - Laia Bonjoch
- Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain
| | - Jenifer Muñoz
- Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain
| | | | - Yasmin Soares de Lima
- Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain
| | - Romesa Mahmood
- Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain
| | - Miriam Cuatrecasas
- Pathology, Hospital Clínic, FRCB-IDIBAPS, CIBEREHD, 08036, Barcelona, Spain
| | - Teresa Ocaña
- Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain
| | | | - Gemma Llargués-Sistac
- Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain
| | - Xavier Domínguez-Rovira
- Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain
| | - Joan Llach
- Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain
| | - Irina Luzko
- Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain
| | - Marcos Díaz-Gay
- Department of Cellular and Molecular Medicine and Department of Bioengineering and Moores Cancer Center, UC San Diego, La Jolla, San Diego, CA, 92093, USA
| | - Conxi Lazaro
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, CIBERONC, 08908, Barcelona, Spain
| | - Joan Brunet
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, CIBERONC, 08908, Barcelona, Spain
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBGI, 17190, Girona, Spain
| | | | - María Asunción García-González
- Instituto de Investigación Sanitaria Aragón, Instituto Aragonés de Ciencias de La Salud, CIBEREHD, 50009, Zaragoza, Spain
| | - Angel Lanas
- Instituto de Investigación Sanitaria Aragón, Instituto Aragonés de Ciencias de La Salud, CIBEREHD, 50009, Zaragoza, Spain
- Gastroenterology, Hospital Clínico Universitario de Zaragoza, Instituto de Investigación Sanitaria Aragón, Universidad de Zaragoza, CIBEREHD, 50009, Zaragoza, Spain
| | - Marta Carrillo
- Gastroenterology, Centro de Investigación Biomédica de Canarias (CIBICAN), Hospital Universitario de Canarias, Instituto Universitario de Tecnologías Biomédicas (ITB), Universidad de La Laguna, 38320, Santa Cruz de Tenerife, Spain
| | | | - Enrique Quintero
- Gastroenterology, Centro de Investigación Biomédica de Canarias (CIBICAN), Hospital Universitario de Canarias, Instituto Universitario de Tecnologías Biomédicas (ITB), Universidad de La Laguna, 38320, Santa Cruz de Tenerife, Spain
| | - Nuria Sala
- Unit of Nutrition and Cancer, Translational Research Laboratory, Catalan Institute of Oncology (ICO) and Bellvitge Biomedical Research Institute (IDIBELL), 08908, Barcelona, Spain
| | - Gemma Llort
- Medical Oncology, Parc Taulí University Hospital, 08208, Sabadell, Spain
| | - Lara Aguilera
- Gastroenterology, Vall d'Hebron Research Institute, 08035, Barcelona, Spain
| | - Laura Carot
- Gastroenterology, Hospital del Mar, 08003, Barcelona, Spain
| | | | - Rodrigo Jover
- Gastroenterology, Departamento de Medicina Clínica, Hospital General Universitario Dr. Balmis, Instituto de Investigación Sanitaria ISABIAL, Universidad Miguel Hernández, 03010, Alicante, Spain
| | | | - Joaquín Cubiella
- Gastroenterology, Complexo Hospitalario de Ourense, CIBEREHD, 32005, Ourense, Spain
| | - Antoni Castells
- Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain
| | - Francesc Balaguer
- Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain
| | - Luis Bujanda
- Department of Hepatology and Gastroenterology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Biodonostia Health Research Institute - Donostia University Hospital, Universidad del País Vasco (UPV/EHU), 20014, San Sebastián, Spain
| | - Sergi Castellví-Bel
- Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain
| | - Leticia Moreira
- Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain.
- Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain.
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10
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Fernández Aceñero MJ, Díaz del Arco C. Hereditary Gastrointestinal Tumor Syndromes: When Risk Comes with Your Genes. Curr Issues Mol Biol 2024; 46:6440-6471. [PMID: 39057027 PMCID: PMC11275188 DOI: 10.3390/cimb46070385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 06/19/2024] [Accepted: 06/25/2024] [Indexed: 07/28/2024] Open
Abstract
Despite recent campaigns for screening and the latest advances in cancer therapy and molecular biology, gastrointestinal (GI) neoplasms remain among the most frequent and lethal human tumors. Most GI neoplasms are sporadic, but there are some well-known familial syndromes associated with a significant risk of developing both benign and malignant GI tumors. Although some of these entities were described more than a century ago based on clinical grounds, the increasing molecular information obtained with high-throughput techniques has shed light on the pathogenesis of several of them. The vast amount of information gained from next-generation sequencing has led to the identification of some high-risk genetic variants, although others remain to be discovered. The opportunity for genetic assessment and counseling in these families has dramatically changed the management of these syndromes, though it has also resulted in significant psychological distress for the affected patients, especially those with indeterminate variants. Herein, we aim to summarize the most relevant hereditary cancer syndromes involving the stomach and colon, with an emphasis on new molecular findings, novel entities, and recent changes in the management of these patients.
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Affiliation(s)
- María Jesús Fernández Aceñero
- Department of Legal Medicine, Psychiatry and Pathology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Department of Pathology, Hospital Clínico San Carlos, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Cristina Díaz del Arco
- Department of Legal Medicine, Psychiatry and Pathology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Department of Pathology, Hospital Clínico San Carlos, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
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11
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Harrold EC, Stadler ZK. Upper Gastrointestinal Cancers and the Role of Genetic Testing. Hematol Oncol Clin North Am 2024; 38:677-691. [PMID: 38458854 DOI: 10.1016/j.hoc.2024.01.006] [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] [Indexed: 03/10/2024]
Abstract
Beyond the few established hereditary cancer syndromes with an upper gastrointestinal cancer component, there is increasing recognition of the contribution of novel pathogenic germline variants (gPVs) to upper gastrointestinal carcinogenesis. The detection of gPVs has potential implications for novel treatment approaches of the index cancer patient as well as long-term implications for surveillance and risk-reducing measures for cancer survivors and far-reaching implications for the patients' family. With widespread availability of multigene panel testing, new associations may be identified with germline-somatic integration being critical to determining true causality of novel gPVs. Comprehensive cancer care should incorporate both somatic and germline testing.
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Affiliation(s)
- Emily C Harrold
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medical Oncology, Mater Misericordiae University Hospital, Dublin, Ireland. https://twitter.com/EmilyHarrold6
| | - Zsofia K Stadler
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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12
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Zhou CM, Zhao SH. Evaluation of the value of combined detection of tumor markers CA724, carcinoembryonic antigen, CA242, and CA19-9 in gastric cancer. World J Gastrointest Oncol 2024; 16:1737-1744. [PMID: 38764828 PMCID: PMC11099441 DOI: 10.4251/wjgo.v16.i5.1737] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/08/2024] [Accepted: 03/20/2024] [Indexed: 05/09/2024] Open
Abstract
BACKGROUND Gastric cancer is a global health concern that poses a significant threat to human well-being. AIM To detecting serum changes in carcinoembryonic antigen (CEA), carbohydrate antigens (CA) 724, CA242, and CA19-9 expression among patients with gastric cancer. METHODS Eighty patients diagnosed with gastric cancer between January 2020 and January 2023 were included in the observation group, while 80 patients with benign gastric diseases were included in the control group. Both groups were tested for tumor markers (CA724, CEA, CA242, and CA19-9]. Tumor marker indicators (CA724, CEA, CA242, and CA19-9) were compared between the two groups, assessing positive rates of tumor markers across various stages in the observation group. Additionally, single and combined detection of various tumor markers were examined. RESULTS The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value observed for the combined detection of CA724, CEA, CA242, and CA19-9 were higher than those of CA724, CEA, CA242, and CA19-9 individually. Therefore, the combined detection of CA724, CEA, CA242, and CA19-9 has a high diagnostic accuracy and could reduce the occurrence of missed or misdiagnosed cases, facilitating the early diagnosis and treatment of patients. CONCLUSION CA724, CEA, CA242, and CA19-9 serum levels in gastric cancer patients significantly surpassed those in non-gastric cancer patients (P < 0.05). Their combined detection can improve the diagnostic accuracy for gastric cancer, warranting clinical promotion.
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Affiliation(s)
- Chong-Mei Zhou
- Department of Clinical Laboratory, Henan Provincial People's Hospital, Zhengzhou 450003, Henan Province, China
| | - Shao-Hua Zhao
- Department of Clinical Laboratory, Henan Provincial People's Hospital, Zhengzhou 450003, Henan Province, China
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13
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Bamaga A, Muthaffar O, Alyazidi A, Bahowarth S, Shawli M, Alotibi F, Alsehemi M, Almohammal M, Alawwadh A, Alghamdi N. MED23 pathogenic variant: genomic-phenotypic analysis. J Med Life 2024; 17:500-507. [PMID: 39144687 PMCID: PMC11320618 DOI: 10.25122/jml-2024-0065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 05/02/2024] [Indexed: 08/16/2024] Open
Abstract
The mediator complex subunit 23 (MED23) gene encodes a protein that acts as a tail module mediator complex, a multi-subunit co-activator involved in several cellular activities. MED23 has been shown to have substantial roles in myogenesis and other molecular mechanisms. The functions of MED23 in the neurological system remain unclear and the clinical phenotype is not thoroughly described. Whole exome sequencing was used to identify a novel mutation in the MED23 gene. DNA capture probes using next-generation sequencing-based copy number variation analysis with Illumina array were performed. The clinical, demographic, neuroimaging, and electrophysiological data of the patients were collected, and similarly, the data of all reported cases in the literature were extracted to compare findings. Screening a total of 9,662 articles, we identified 22 main regulatory processes for the MED23 gene, including suppressive activity for carcinogenic processes. MED23 is also involved in the brain's neurogenesis and functions. The identified cases mainly presented with intellectual disability (87.5%) and developmental delay (50%). Seizures were present in only 18.75% of the patients. Slow backgrounds and spike and sharp-wave complexes were reported on the electroencephalogram (EEG) of a few patients and delayed myelination, thin corpus callosum, and pontine hypoplasia on magnetic resonance imaging (MRI). The MED23 gene regulates several processes in which its understanding promotes considerable therapeutic potential for patients. It is crucial to consider genetic and laboratory testing, particularly when encountering potential carriers. Intellectual disability and developmental delay are the most notable clinical signs with heterogeneous features on EEG and MRI.
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Affiliation(s)
- Ahmed Bamaga
- Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Neuromuscular Medicine Unit, Department of Pediatrics, Faculty of Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
| | - Osama Muthaffar
- Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Anas Alyazidi
- Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sarah Bahowarth
- Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammed Shawli
- Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Fahad Alotibi
- Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Matar Alsehemi
- Pediatric Neurology Unit, Department of Pediatrics, King Fahad Hospital, Albaha, Saudi Arabia
| | | | - Adel Alawwadh
- Department of Pediatrics, Khamis Mushait Maternity and Children Hospital, Abha, Saudi Arabia
| | - Njood Alghamdi
- Faculty of Medicine, Albaha University, Albaha, Saudi Arabia
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14
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Maalouf H, Saber T, Ghattas S, Meguerian-Bedoyan Z, El Rassi Z. CDH1 gene mutation, a challenging surgical topic: Case report and literature review. Int J Surg Case Rep 2024; 116:109422. [PMID: 38394940 PMCID: PMC10943988 DOI: 10.1016/j.ijscr.2024.109422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/15/2024] [Accepted: 02/17/2024] [Indexed: 02/25/2024] Open
Abstract
INTRODUCTION Gastric cancer is one of the top 5 cancers worldwide. Most gastric cancers are classified as sporadic with the exception of around 3 % that are associated with specific syndromes or genes. Hereditary diffuse gastric cancer is a very rare type of gastric cancer, associated with loss of function of a tumor suppressor gene CDH1 which has a high penetrance that can reach 90 % over a lifetime. CASE PRESENTATION Here we present the case of a 31 years old male patient carrying the CDH1 gene who presented for prophylactic total gastrectomy and D1 lymphadenectomy followed by a roux en y esophago-jejunostomy for digestive tract reconstruction. The patient had a preoperative negative gastroscopy for gastric cancer. On final pathology, few 2 mm foci of signet ring cells involving the lamina propria (T1a) were identified. CLINICAL DISCUSSION Randomized clinical trial data concerning HDGC is lacking. Individuals who meet the genetic testing criteria developed by the IGCLC, testing should be obtainable from the legal age of consent that range from 16 to 18 years of age. CDH1 is the main gene that is tested. The mainstay treatment of choice for HDGC is total gastrectomy and Roux-en-Y esophago-jejunostomy in asymptomatic patients but should only be undertaken after baseline endoscopy. CONCLUSION Genetic testing for CDH1 should be carried in high-risk populations. Due to its high penetrance, any person carrying the CDH1 gene should be managed by a prophylactic gastrectomy and D1 lymphadenectomy with close follow up for any future breast neoplasm.
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Affiliation(s)
- Hani Maalouf
- Department of General Surgery, University of Balamand, Beirut, Lebanon
| | - Toufic Saber
- Department of General Surgery, University of Balamand, Beirut, Lebanon
| | - Souad Ghattas
- Department of General Surgery, University of Balamand, Beirut, Lebanon.
| | | | - Ziad El Rassi
- Head of General Surgery Department, Saint Georges Hospital University Medical Center, Beirut, Lebanon
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15
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Han X, Jia X, Sheng C, Li M, Han J, Duan F, Wang K. A comparison analysis of the somatic mutations in early-onset gastric cancer and traditional gastric cancer. Clin Res Hepatol Gastroenterol 2024; 48:102287. [PMID: 38253255 DOI: 10.1016/j.clinre.2024.102287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 01/19/2024] [Accepted: 01/20/2024] [Indexed: 01/24/2024]
Abstract
BACKGROUND Early onset gastric cancer (EOGC) has been on the rise in recent years and differs slightly in pathology from traditional gastric cancer (TGC). Somatic mutations have an essential role in the development of gastric cancer. We aimed to investigate these two types of gastric cancers at the level of somatic mutations and to further understanding of gastric cancer development. METHODS Somatic mutation, copy number variation (CNV), and clinical information were obtained from TCGA and UCSC Xena. Samples were divided into EOGC (< 50 years old, N = 28) and TGC (≥ 50 years old, N = 395) groups based on age. R packages "maftools" and "sigminer" were used to identify mutation signatures, while CNV information was processed using GISTIC2.0. RESULTS CDH1(21 %, P = 0.030) and ARID1A (28 %, P = 0.014) were more common in EOGC and TGC, respectively. The mutation frequency of ARID1A increased with age, while the opposite was true for CDH1. Sex, Lauren classifications, tumor mutation burden levels, mutation status of TP53, MUC6, NIPBL, KRAS, and copy number variation of the WOOX can affect the activity of the mutant signature. CONCLUSIONS Early-onset gastric cancer and traditional gastric cancer have distinct somatic mutation signatures, each with its own relatively specific high-frequency mutated genes, and the gene's mutation frequency correlates with age. Several clinical factors and genetic status affect the activity of some mutational features in gastric cancer in both groups.
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Affiliation(s)
- Xiaoxuan Han
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China; Key Laboratory of Tumor Epidemiology of Henan Province, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, China
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China; Key Laboratory of Tumor Epidemiology of Henan Province, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, China.
| | - Xiaoxiao Jia
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China; Key Laboratory of Tumor Epidemiology of Henan Province, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, China
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China; Key Laboratory of Tumor Epidemiology of Henan Province, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, China.
| | - Chong Sheng
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China; Key Laboratory of Tumor Epidemiology of Henan Province, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, China
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China; Key Laboratory of Tumor Epidemiology of Henan Province, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, China.
| | - Mengyuan Li
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China; Key Laboratory of Tumor Epidemiology of Henan Province, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, China
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China; Key Laboratory of Tumor Epidemiology of Henan Province, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, China.
| | - Jinxi Han
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China; Key Laboratory of Tumor Epidemiology of Henan Province, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, China
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China; Key Laboratory of Tumor Epidemiology of Henan Province, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, China.
| | - Fujiao Duan
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China; Key Laboratory of Tumor Epidemiology of Henan Province, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, China
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China; Key Laboratory of Tumor Epidemiology of Henan Province, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, China.
| | - Kaijuan Wang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China; Key Laboratory of Tumor Epidemiology of Henan Province, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, China
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China; Key Laboratory of Tumor Epidemiology of Henan Province, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, China.
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16
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Mostaghimi T, Bahadoran E, Bakht M, Taheri S, Sadeghi H, Babaei A. Role of lncRNAs in Helicobacter pylori and Epstein-Barr virus associated gastric cancers. Life Sci 2024; 336:122316. [PMID: 38035995 DOI: 10.1016/j.lfs.2023.122316] [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: 09/30/2023] [Revised: 11/17/2023] [Accepted: 11/27/2023] [Indexed: 12/02/2023]
Abstract
Helicobacter pylori infection is a risk factor for the development of gastric cancer (GC), and the role of co-infection with viruses, such as Epstein-Barr virus, in carcinogenesis cannot be ignored. Furthermore, it is now known that genetic factors such as long non-coding RNAs (lncRNAs) are involved in many diseases, including GC. On the other side, they can also be used as therapeutic goals. Modified lncRNAs can cause aberrant expression of genes encoding proximal proteins, which are essential for the development of carcinoma. In this review, we present the most recent studies on lncRNAs in GC, concentrating on their roles in H. pylori and EBV infections, and discuss some of the molecular mechanisms of these GC-related pathogens. There was also a discussion of the research gaps and future perspectives.
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Affiliation(s)
- Talieh Mostaghimi
- Department of Medical Microbiology and Biotechnology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Ensiyeh Bahadoran
- School of Medicine, Qazvin University of Medical Science, Qazvin, Iran
| | - Mehdi Bakht
- Medical Microbiology Research Center, Qazvin University of Medical Science, Qazvin, Iran
| | - Shiva Taheri
- Medical Microbiology Research Center, Qazvin University of Medical Science, Qazvin, Iran
| | - Hamid Sadeghi
- Medical Microbiology Research Center, Qazvin University of Medical Science, Qazvin, Iran
| | - Abouzar Babaei
- Medical Microbiology Research Center, Qazvin University of Medical Science, Qazvin, Iran.
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17
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Wang F, Zhang X, Tang L, Wu Q, Cai M, Li Y, Qu X, Qiu H, Zhang Y, Ying J, Zhang J, Sun L, Lin R, Wang C, Liu H, Qiu M, Guan W, Rao S, Ji J, Xin Y, Sheng W, Xu H, Zhou Z, Zhou A, Jin J, Yuan X, Bi F, Liu T, Liang H, Zhang Y, Li G, Liang J, Liu B, Shen L, Li J, Xu R. The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023. Cancer Commun (Lond) 2024; 44:127-172. [PMID: 38160327 PMCID: PMC10794017 DOI: 10.1002/cac2.12516] [Citation(s) in RCA: 75] [Impact Index Per Article: 75.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 12/17/2023] [Accepted: 12/18/2023] [Indexed: 01/03/2024] Open
Abstract
The 2023 update of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China, reflecting the latest advancements in evidence-based medicine, healthcare resource availability, and precision medicine. These updates address the differences in epidemiological characteristics, clinicopathological features, tumor biology, treatment patterns, and drug selections between Eastern and Western gastric cancer patients. Key revisions include a structured template for imaging diagnosis reports, updated standards for molecular marker testing in pathological diagnosis, and an elevated recommendation for neoadjuvant chemotherapy in stage III gastric cancer. For advanced metastatic gastric cancer, the guidelines introduce new recommendations for immunotherapy, anti-angiogenic therapy and targeted drugs, along with updated management strategies for human epidermal growth factor receptor 2 (HER2)-positive and deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) patients. Additionally, the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer. The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice, particularly in the heterogeneous healthcare landscape of China, while maintaining a commitment to scientific rigor, impartiality, and timely revisions.
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Affiliation(s)
- Feng‐Hua Wang
- Department of Medical OncologySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
| | - Xiao‐Tian Zhang
- Department of Gastrointestinal OncologyKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer HospitalBeijingP. R. China
| | - Lei Tang
- Department of RadiologyPeking University Cancer HospitalBeijingP. R. China
| | - Qi Wu
- Department of Endoscopy CenterPeking University Cancer HospitalBeijingP. R. China
| | - Mu‐Yan Cai
- Department of PathologySun Yat‐sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer MedicineGuangzhouGuangdongP. R. China
| | - Yuan‐Fang Li
- Department of Gastric SurgerySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
| | - Xiu‐Juan Qu
- Department of Medical OncologyThe First Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Hong Qiu
- Department of Medical OncologyTongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and TechnologyWuhanHubeiP. R. China
| | - Yu‐Jing Zhang
- Department of RadiotherapySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
| | - Jie‐Er Ying
- Department of Medical OncologyZhejiang Cancer HospitalHangzhouZhejiangP. R. China
| | - Jun Zhang
- Department of Medical OncologyRuijin HospitalShanghai Jiaotong University School of MedicineShanghaiP. R. China
| | - Ling‐Yu Sun
- Department of Surgical OncologyThe Fourth Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangP. R. China
| | - Rong‐Bo Lin
- Department of Medical OncologyFujian Cancer HospitalFuzhouFujianP. R. China
| | - Chang Wang
- Tumor CenterThe First Hospital of Jilin UniversityChangchunJilinP. R. China
| | - Hao Liu
- Department of General SurgeryNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Miao‐Zhen Qiu
- Department of Medical OncologySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
| | - Wen‐Long Guan
- Department of Medical OncologySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
| | - Sheng‐Xiang Rao
- Department of RadiologyZhongshan HospitalFudan UniversityShanghaiP. R. China
| | - Jia‐Fu Ji
- Department of Gastrointestinal SurgeryPeking University Cancer HospitalBeijingP. R. China
| | - Yan Xin
- Pathology Laboratory of Gastrointestinal TumorThe First Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Wei‐Qi Sheng
- Department of PathologyZhongshan Hospital Affiliated to Shanghai Fudan UniversityShanghaiP. R. China
| | - Hui‐Mian Xu
- Department of Gastrointestinal Oncology Surgery. The First Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Zhi‐Wei Zhou
- Department of Gastric SurgerySun Yat‐sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer MedicineGuangzhouGuangdongP. R. China
| | - Ai‐Ping Zhou
- Department of OncologyNational Cancer CenterNational Clinical Research Center for CancerCancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Jing Jin
- Department of Radiation OncologyShenzhen hospitalCancer Hospital of Chinese Academy of Medical SciencesBeijingP. R. China
| | - Xiang‐Lin Yuan
- Department of OncologyTongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and TechnologyWuhanHubeiP. R. China
| | - Feng Bi
- Department of Abdominal OncologyWest China Hospital of Sichuan UniversityChengduSichuanP. R. China
| | - Tian‐Shu Liu
- Department of Medical OncologyZhongshan Hospital Affiliated to Fudan UniversityShanghaiP. R. China
| | - Han Liang
- Department of Gastric SurgeryTianjin Medical University Cancer Institute & HospitalTianjinP. R. China
| | - Yan‐Qiao Zhang
- Department of Medical OncologyCancer Hospital of Harbin Medical UniversityHarbinHeilongjiangP. R. China
| | - Guo‐Xin Li
- Department of General SurgeryNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Jun Liang
- Department of Medical OncologyPeking University International HospitalBeijingP. R. China
| | - Bao‐Rui Liu
- Department of Medical OncologyNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingP. R. China
| | - Lin Shen
- Department of GI OncologyKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer HospitalBeijingP. R. China
| | - Jin Li
- Department of OncologyEaster Hospital affiliated to Shanghai Tongji UniversityShanghaiP. R. China
| | - Rui‐Hua Xu
- Department of Medical OncologySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
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18
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Shah D, Bentrem D. Environmental and Genetic Risk Factors for Gastric Cancer. Cancer Treat Res 2024; 192:1-17. [PMID: 39212913 DOI: 10.1007/978-3-031-61238-1_1] [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] [Indexed: 09/04/2024]
Abstract
Gastric cancer is a heterogeneous and prevalent disease. The traditional environmental exposures associated with elevated risk of gastric cancer are less prevalent in the USA today. Genetic risks and risks associated with inflammation remain. Most cases are sporadic, and familial clustering is observed in about 10% of the cases. Hereditary gastric cancer accounts for a very low percentage of cases. Here we review the genetic and environmental risk factors associated with the disease. In addition, we will review screening guidelines and current modalities that are available for screening in high-risk populations.
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Affiliation(s)
- Dhavan Shah
- Northwestern Quality Improvement, Research, and Education in Surgery, Department of Surgery, Feinberg School of Medicine, Northwestern University, Evanston, USA
| | - David Bentrem
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Evanston, USA.
- Jesse Brown VA Medical Center, Chicago, USA.
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19
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Yang Y, Li S, Li Y, Lv L, Ye D, Kang J, Yu T, Wang Y, Wu H. α-Catenin acetylation is essential for its stability and blocks its tumor suppressor effects in breast cancer through Yap1. Cancer Gene Ther 2023; 30:1624-1635. [PMID: 37679528 DOI: 10.1038/s41417-023-00665-4] [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: 06/09/2023] [Revised: 08/23/2023] [Accepted: 08/29/2023] [Indexed: 09/09/2023]
Abstract
α-Catenin plays a critical role in tissue integrity, repair, and embryonic development. However, the post-translational modifications of α-catenin and the correlative roles in regulating cancer progression remain unclear. Here, we report that α-catenin is acetylated by p300, and identify three acetylation sites, K45, K866, and K881. Conversely, α-catenin acetylation can be reversed by deacetylase HDAC6. Mechanistically, α-catenin acetylation releases the transcriptional coactivator Yes-associated protein 1 (Yap1) by blocking the interaction between α-catenin and Yap1, and promotes the accumulation of Yap1 in the nucleus. Through this mechanism, acetylation weakens the capacity of α-catenin to inhibit breast cancer cell proliferation and tumor growth in mice. Meanwhile, we show that CDDP induces acetylation of α-catenin, and acetylated α-catenin resists the apoptosis under CDDP conditions. Additionally, acetylation inhibits the proteasome-dependent degradation of α-catenin, thus enhancing the stability of α-catenin for storage. Taken together, our results demonstrate that α-catenin can be acetylated, an event that is key for the subcellular distribution of Yap1 and subsequent facilitation of breast tumorigenesis.
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Affiliation(s)
- Yuxi Yang
- School of Bioengineering & Key Laboratory of Protein Modification and Disease, Liaoning Province, Dalian University of Technology, Dalian, China
| | - Shujing Li
- School of Bioengineering & Key Laboratory of Protein Modification and Disease, Liaoning Province, Dalian University of Technology, Dalian, China
| | - Yulin Li
- School of Bioengineering & Key Laboratory of Protein Modification and Disease, Liaoning Province, Dalian University of Technology, Dalian, China
| | - Linlin Lv
- School of Bioengineering & Key Laboratory of Protein Modification and Disease, Liaoning Province, Dalian University of Technology, Dalian, China
- The first affiliated Hospital of Dalian Medical University, Dalian, China
| | - Dongman Ye
- Cancer Hospital of Dalian University of Technology, Shenyang, China
| | - Jie Kang
- School of Bioengineering & Key Laboratory of Protein Modification and Disease, Liaoning Province, Dalian University of Technology, Dalian, China
| | - Tao Yu
- Cancer Hospital of Dalian University of Technology, Shenyang, China.
| | - Yaming Wang
- The first affiliated Hospital of Dalian Medical University, Dalian, China.
| | - Huijian Wu
- School of Bioengineering & Key Laboratory of Protein Modification and Disease, Liaoning Province, Dalian University of Technology, Dalian, China.
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20
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Le V, Abdelmessih G, Dailey WA, Pinnock C, Jobczyk V, Rashingkar R, Drenser KA, Mitton KP. Mechanisms Underlying Rare Inherited Pediatric Retinal Vascular Diseases: FEVR, Norrie Disease, Persistent Fetal Vascular Syndrome. Cells 2023; 12:2579. [PMID: 37947657 PMCID: PMC10647367 DOI: 10.3390/cells12212579] [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: 09/14/2023] [Revised: 10/28/2023] [Accepted: 10/30/2023] [Indexed: 11/12/2023] Open
Abstract
Familial Exudative Vitreoretinopathy (FEVR), Norrie disease, and persistent fetal vascular syndrome (PFVS) are extremely rare retinopathies that are clinically distinct but are unified by abnormal retinal endothelial cell function, and subsequent irregular retinal vascular development and/or aberrant inner blood-retinal-barrier (iBRB) function. The early angiogenesis of the retina and its iBRB is a delicate process that is mediated by the canonical Norrin Wnt-signaling pathway in retinal endothelial cells. Pathogenic variants in genes that play key roles within this pathway, such as NDP, FZD4, TSPAN12, and LRP5, have been associated with the incidence of these retinal diseases. Recent efforts to further elucidate the etiology of these conditions have not only highlighted their multigenic nature but have also resulted in the discovery of pathological variants in additional genes such as CTNNB1, KIF11, and ZNF408, some of which operate outside of the Norrin Wnt-signaling pathway. Recent discoveries of FEVR-linked variants in two other Catenin genes (CTNND1, CTNNA1) and the Endoplasmic Reticulum Membrane Complex Subunit-1 gene (EMC1) suggest that we will continue to find additional genes that impact the neural retinal vasculature, especially in multi-syndromic conditions. The goal of this review is to briefly highlight the current understanding of the roles of their encoded proteins in retinal endothelial cells to understand the essential functional mechanisms that can be altered to cause these very rare pediatric retinal vascular diseases.
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Affiliation(s)
- Vincent Le
- Eye Research Institute, Oakland University, Rochester, MI 48309, USA
- Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA
| | | | - Wendy A. Dailey
- Eye Research Institute, Oakland University, Rochester, MI 48309, USA
| | - Cecille Pinnock
- Eye Research Institute, Oakland University, Rochester, MI 48309, USA
| | - Victoria Jobczyk
- Eye Research Institute, Oakland University, Rochester, MI 48309, USA
| | - Revati Rashingkar
- Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA
| | - Kimberly A. Drenser
- Eye Research Institute, Oakland University, Rochester, MI 48309, USA
- Associated Retinal Consultants P.C., Royal Oak, MI 48073, USA
| | - Kenneth P. Mitton
- Eye Research Institute, Oakland University, Rochester, MI 48309, USA
- Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA
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21
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Wang F, Chen S, Peng S, Zhou X, Tang H, Liang H, Zhong X, Yang H, Ke X, Lü M, Cui H. PRMT1 promotes the proliferation and metastasis of gastric cancer cells by recruiting MLXIP for the transcriptional activation of the β-catenin pathway. Genes Dis 2023; 10:2622-2638. [PMID: 37554218 PMCID: PMC10404965 DOI: 10.1016/j.gendis.2023.02.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 02/03/2023] [Indexed: 03/30/2023] Open
Abstract
Protein arginine methyltransferase 1 (PRMT1), a type I PRMT, is overexpressed in gastric cancer (GC) cells. To elucidate the function of PRMT1 in GC, PRMT1 expression in HGC-27 and MKN-45 cells was knocked down by short hairpin RNA (shRNA) or inhibited by PRMT1 inhibitors (AMI-1 or DCLX069), which resulted in inhibition of GC cell proliferation, migration, invasion, and tumorigenesis in vitro and in vivo. MLX-interacting protein (MLXIP) and Kinectin 1 (KTN1) were identified as PRMT1-binding proteins. PRMT1 recruited MLXIP to the promoter of β-catenin, which induced β-catenin transcription and activated the β-catenin signaling pathway, promoting GC cell migration and metastasis. Furthermore, KTN1 inhibited the K48-linked ubiquitination of PRMT1 by decreasing the interaction between TRIM48 and PRMT1. Collectively, our findings reveal a mechanism by which PRMT1 promotes cell proliferation and metastasis mediated by the β-catenin signaling pathway.
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Affiliation(s)
- Feng Wang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
| | - Shitong Chen
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
| | - Shihan Peng
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
| | - Xujun Zhou
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
| | - Houyi Tang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
| | - Hanghua Liang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
| | - Xi Zhong
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
| | - He Yang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
| | - Xiaoxue Ke
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
| | - MuHan Lü
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan 646000, China
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
- Jinfeng Laboratory, Chongqing 401329, China
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22
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São José C, Garcia-Pelaez J, Ferreira M, Arrieta O, André A, Martins N, Solís S, Martínez-Benítez B, Ordóñez-Sánchez ML, Rodríguez-Torres M, Sommer AK, Te Paske IBAW, Caldas C, Tischkowitz M, Tusié MT, Hoogerbrugge N, Demidov G, de Voer RM, Laurie S, Oliveira C. Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer. Gastric Cancer 2023; 26:653-666. [PMID: 37249750 PMCID: PMC10361908 DOI: 10.1007/s10120-023-01395-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 04/30/2023] [Indexed: 05/31/2023]
Abstract
BACKGROUND Germline CDH1 pathogenic or likely pathogenic variants cause hereditary diffuse gastric cancer (HDGC). Once a genetic cause is identified, stomachs' and breasts' surveillance and/or prophylactic surgery is offered to asymptomatic CDH1 carriers, which is life-saving. Herein, we characterized an inherited mechanism responsible for extremely early-onset gastric cancer and atypical HDGC high penetrance. METHODS Whole-exome sequencing (WES) re-analysis was performed in an unsolved HDGC family. Accessible chromatin and CDH1 promoter interactors were evaluated in normal stomach by ATAC-seq and 4C-seq, and functional analysis was performed using CRISPR-Cas9, RNA-seq and pathway analysis. RESULTS We identified a germline heterozygous 23 Kb CDH1-TANGO6 deletion in a family with eight diffuse gastric cancers, six before age 30. Atypical HDGC high penetrance and young cancer-onset argued towards a role for the deleted region downstream of CDH1, which we proved to present accessible chromatin, and CDH1 promoter interactors in normal stomach. CRISPR-Cas9 edited cells mimicking the CDH1-TANGO6 deletion display the strongest CDH1 mRNA downregulation, more impacted adhesion-associated, type-I interferon immune-associated and oncogenic signalling pathways, compared to wild-type or CDH1-deleted cells. This finding solved an 18-year family odyssey and engaged carrier family members in a cancer prevention pathway of care. CONCLUSION In this work, we demonstrated that regulatory elements lying down-stream of CDH1 are part of a chromatin network that control CDH1 expression and influence cell transcriptome and associated signalling pathways, likely explaining high disease penetrance and very young cancer-onset. This study highlights the importance of incorporating scientific-technological updates and clinical guidelines in routine diagnosis, given their impact in timely genetic diagnosis and disease prevention.
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Affiliation(s)
- Celina São José
- i3S-Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- Doctoral Programme in Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
| | - José Garcia-Pelaez
- i3S-Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- Doctoral Programme in Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Marta Ferreira
- i3S-Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- Department Computer Science Faculty of Science, University of Porto, Porto, Portugal
| | - Oscar Arrieta
- Thoracic Oncology Unit, Department of Thoracic Oncology, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Ana André
- i3S-Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
| | - Nelson Martins
- i3S-Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- Master Programme in Molecular Medicine and Oncology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Samantha Solís
- INCMNSZ/Instituto de Investigaciones Biomédicas, Unidad de Biología Molecular y Medicina Genómica Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, UNAM Mexico City, Mexico
| | - Braulio Martínez-Benítez
- Pathology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, INCMNSZ Mexico City, Mexico
| | - María Luisa Ordóñez-Sánchez
- INCMNSZ/Instituto de Investigaciones Biomédicas, Unidad de Biología Molecular y Medicina Genómica Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, UNAM Mexico City, Mexico
| | - Maribel Rodríguez-Torres
- INCMNSZ/Instituto de Investigaciones Biomédicas, Unidad de Biología Molecular y Medicina Genómica Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, UNAM Mexico City, Mexico
| | - Anna K Sommer
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany
| | - Iris B A W Te Paske
- Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Carlos Caldas
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK
- Department of Oncology, University of Cambridge, Cambridge, UK
- Cambridge Experimental Cancer Medicine Centre (ECMC), CRUK Cambridge Centre, NIHR Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Marc Tischkowitz
- Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
| | - Maria Teresa Tusié
- INCMNSZ/Instituto de Investigaciones Biomédicas, Unidad de Biología Molecular y Medicina Genómica Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, UNAM Mexico City, Mexico
| | - Nicoline Hoogerbrugge
- Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - German Demidov
- Institute of Medical Genetics and Applied Genomics, Tübingen, Germany
| | - Richarda M de Voer
- Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Steve Laurie
- The Barcelona Institute of Science and Technology, CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona, Spain
| | - Carla Oliveira
- i3S-Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal.
- FMUP-Faculty of Medicine of the University of Porto, Porto, Portugal.
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23
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Guerra J, Pinto C, Pinto P, Pinheiro M, Santos C, Peixoto A, Escudeiro C, Barbosa A, Porto M, Francisco I, Lopes P, Isidoro AR, Cunha AL, Albuquerque C, Claro I, Oliveira C, Silva J, Teixeira MR. Frequency of CDH1, CTNNA1 and CTNND1 Germline Variants in Families with Diffuse and Mixed Gastric Cancer. Cancers (Basel) 2023; 15:4313. [PMID: 37686589 PMCID: PMC10486404 DOI: 10.3390/cancers15174313] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/23/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
The most well-characterized hereditary form of gastric cancer is hereditary diffuse gastric cancer (HDGC), an autosomal dominant syndrome characterized by an increased risk of diffuse gastric and lobular breast cancer. HDGC is predominantly caused by germline pathogenic variants in the CDH1 gene, and more rarely in the CTNNA1 gene. Furthermore, the International Gastric Cancer Linkage Consortium (IGCLC) guidelines do not clarify whether or not mixed gastric cancer (with a diffuse component) should be considered in the HDGC genetic testing criteria. We aimed to evaluate the contribution of CTNNA1 and CTNND1 germline variants to HDGC. Additionally, we also intended to compare the frequencies of CDH1 and CTNNA1 (and eventually CTNND1) germline variants between patients with diffuse and mixed gastric carcinomas to evaluate if genetic testing for these genes should or should not be considered in patients with the latter. We analyzed the CDH1 gene in 67 cases affected with early-onset/familial mixed gastric carcinomas and the CTNNA1 and CTNND1 genes in 208 cases with diffuse or mixed gastric cancer who had tested negative for CDH1 pathogenic germline variants. A deleterious CTNNA1 germline variant was found in 0.7% (1/141) of diffuse gastric cancer patients meeting the 2020 IGCLC criteria, as compared to the rate of 2.8% of CDH1 deleterious variants found by us in this setting. No deleterious variants were found in CTNND1, but six variants of uncertain significance were identified in this gene. We did not find any pathogenic CDH1, CTNNA1 or CTNND1 variant in index patients with early-onset/familial mixed gastric cancer, so there is no evidence that supports including this tumor type in the testing criteria for germline variants in these genes. The role of the CTNND1 gene in inherited gastric cancer predisposition is still unclear.
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Affiliation(s)
- Joana Guerra
- Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal; (J.G.); (C.P.); (P.P.); (M.P.); (C.S.); (A.P.); (C.E.); (A.B.); (M.P.); (J.S.)
- Doctoral Programme in Biomedical Sciences, School Medicine and Biomedical Sciences, University of Porto (ICBAS-UP), 4050-313 Porto, Portugal
| | - Carla Pinto
- Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal; (J.G.); (C.P.); (P.P.); (M.P.); (C.S.); (A.P.); (C.E.); (A.B.); (M.P.); (J.S.)
- Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal
- Department of Pathological, Cytological and Thanatological Anatomy, School of Health, Polytechnic Institute of Porto, 4200-072 Porto, Portugal
| | - Pedro Pinto
- Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal; (J.G.); (C.P.); (P.P.); (M.P.); (C.S.); (A.P.); (C.E.); (A.B.); (M.P.); (J.S.)
| | - Manuela Pinheiro
- Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal; (J.G.); (C.P.); (P.P.); (M.P.); (C.S.); (A.P.); (C.E.); (A.B.); (M.P.); (J.S.)
| | - Catarina Santos
- Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal; (J.G.); (C.P.); (P.P.); (M.P.); (C.S.); (A.P.); (C.E.); (A.B.); (M.P.); (J.S.)
- Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal
| | - Ana Peixoto
- Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal; (J.G.); (C.P.); (P.P.); (M.P.); (C.S.); (A.P.); (C.E.); (A.B.); (M.P.); (J.S.)
- Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal
| | - Carla Escudeiro
- Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal; (J.G.); (C.P.); (P.P.); (M.P.); (C.S.); (A.P.); (C.E.); (A.B.); (M.P.); (J.S.)
- Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal
| | - Ana Barbosa
- Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal; (J.G.); (C.P.); (P.P.); (M.P.); (C.S.); (A.P.); (C.E.); (A.B.); (M.P.); (J.S.)
- Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal
| | - Miguel Porto
- Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal; (J.G.); (C.P.); (P.P.); (M.P.); (C.S.); (A.P.); (C.E.); (A.B.); (M.P.); (J.S.)
| | - Inês Francisco
- Molecular Pathobiology Research Unit, Portuguese Oncology Institute of Lisbon, 1099-023 Lisbon, Portugal; (I.F.); (C.A.)
| | - Paula Lopes
- Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal; (P.L.); (A.R.I.); (A.L.C.)
| | - Ana Raquel Isidoro
- Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal; (P.L.); (A.R.I.); (A.L.C.)
| | - Ana Luísa Cunha
- Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal; (P.L.); (A.R.I.); (A.L.C.)
| | - Cristina Albuquerque
- Molecular Pathobiology Research Unit, Portuguese Oncology Institute of Lisbon, 1099-023 Lisbon, Portugal; (I.F.); (C.A.)
| | - Isabel Claro
- Gastroenterology Department, Portuguese Oncology Institute of Lisbon, 1099-023 Lisbon, Portugal;
- Familiar Cancer Risk Clinic, Portuguese Oncology Institute of Lisbon, 1099-023 Lisbon, Portugal
| | - Carla Oliveira
- i3S-Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, Portugal;
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, 4200-135 Porto, Portugal
- FMUP-Faculty of Medicine of the University of Porto, 4100-179 Porto, Portugal
| | - João Silva
- Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal; (J.G.); (C.P.); (P.P.); (M.P.); (C.S.); (A.P.); (C.E.); (A.B.); (M.P.); (J.S.)
- Medical Genetics Department, Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal
| | - Manuel R. Teixeira
- Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal; (J.G.); (C.P.); (P.P.); (M.P.); (C.S.); (A.P.); (C.E.); (A.B.); (M.P.); (J.S.)
- Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal
- School of Medicine and Biomedical Sciences (ICBAS), University of Porto, 4050-313 Porto, Portugal
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24
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Harrold E, Latham A, Pemmaraju N, Lieu CH. Early-Onset GI Cancers: Rising Trends, Genetic Risks, Novel Strategies, and Special Considerations. Am Soc Clin Oncol Educ Book 2023; 43:e398068. [PMID: 37235819 DOI: 10.1200/edbk_398068] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Cancers in young adults (commonly described as early-onset [EO] cancer) represent a group of malignancies that have unique and challenging biology and genetic, treatment, social, and psychological implications. Even more concerning is a rising trend of EO cancers in multiple tumor types. Research and investigation in EO cancers will help elucidate mechanisms of carcinogenesis, differences in biology and response to treatment, and the need for multidisciplinary care to ensure comprehensive treatment and support for young patients.
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Affiliation(s)
- Emily Harrold
- Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Alicia Latham
- Memorial Sloan-Kettering Cancer Center, New York, NY
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25
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Knipper K, Fuchs HF, Alakus H, Bruns CJ, Schmidt T. [Hereditary diffuse gastric cancer]. CHIRURGIE (HEIDELBERG, GERMANY) 2023; 94:400-405. [PMID: 36700973 DOI: 10.1007/s00104-023-01806-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 12/22/2022] [Indexed: 01/27/2023]
Abstract
Due to the increasing research into familial clustering of cancer entities, more and more genes are being identified in which mutations explain this clustering. Mutations in the cadherin 1 (CDH1) and catenin alpha 1 (CTNNA1) genes are considered to be causative for the occurrence of hereditary diffuse gastric cancer. Those affected show an incidence of gastric cancer of around 40% up to the age of 80 years and affected women show an incidence of 55% for the occurrence of lobular breast cancer. In 2020 updated international guidelines were published for the clinical management of patients with hereditary diffuse gastric cancer. When the specific test criteria are fulfilled, patients should undergo genetic testing for mutations in the CDH1 and CTNNA1 genes. In cases of the familial occurrence of diffuse gastric cancer and detection of a pathological mutation, a prophylactic total gastrectomy with D1 lymphadenectomy is recommended. Alternatively, or when pathological mutations are not detected, a gastroscopy should be performed annually with targeted and random biopsies. The occurrence of lobular breast cancer should be monitored annually by magnetic resonance imaging (MRI) from the age of 30 years onwards. A bilateral mastectomy for risk reduction should be discussed in a multidisciplinary setting.
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Affiliation(s)
- Karl Knipper
- Klinik für Allgemein‑, Viszeral‑, Tumor- und Transplantationschirurgie, Uniklinik Köln, Kerpener Str. 62, 50937, Köln, Deutschland
| | - Hans F Fuchs
- Klinik für Allgemein‑, Viszeral‑, Tumor- und Transplantationschirurgie, Uniklinik Köln, Kerpener Str. 62, 50937, Köln, Deutschland
| | - Hakan Alakus
- Klinik für Allgemein‑, Viszeral‑, Tumor- und Transplantationschirurgie, Uniklinik Köln, Kerpener Str. 62, 50937, Köln, Deutschland
| | - Christiane J Bruns
- Klinik für Allgemein‑, Viszeral‑, Tumor- und Transplantationschirurgie, Uniklinik Köln, Kerpener Str. 62, 50937, Köln, Deutschland
| | - Thomas Schmidt
- Klinik für Allgemein‑, Viszeral‑, Tumor- und Transplantationschirurgie, Uniklinik Köln, Kerpener Str. 62, 50937, Köln, Deutschland.
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26
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Abstract
miRNAs are a type of small endogenous noncoding RNA composed of 20-22 nucleotides that can regulate gene expression by targeting the 3' untranslated region of mRNA. Many investigations have discovered that miRNAs have a role in the development and progression of human cancer. Several aspects of tumor development are affected by miR-425, including growth, apoptosis, invasion, migration, epithelial-mesenchymal transition, and drug resistance. In this article, we discuss the properties and research development of miR-425, focusing on the regulation and function of miR-425 in various cancers. Furthermore, we discuss the clinical implications of miR-425. This review may broaden our horizon for better understanding the role of miR-425 as biomarkers and therapeutic targets in human cancer.
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Affiliation(s)
- Zhichao Wang
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wenjie Xie
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hongzai Guan
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, China
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27
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Decourtye-Espiard L, Guilford P. Hereditary Diffuse Gastric Cancer. Gastroenterology 2023; 164:719-735. [PMID: 36740198 DOI: 10.1053/j.gastro.2023.01.038] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 02/07/2023]
Abstract
Hereditary diffuse gastric cancer (HDGC) is a dominantly inherited cancer syndrome characterized by a high incidence of diffuse gastric cancer (DGC) and lobular breast cancer (LBC). HDGC is caused by germline mutations in 2 genes involved in the epithelial adherens junction complex, CDH1 and CTNNA1. We discuss the genetics of HDGC and the variability of its clinical phenotype, in particular the variable penetrance of advanced DGC and LBC, both within and between families. We review the pathology of the disease, the mechanism of tumor initiation, and its natural history. Finally, we describe current best practice for the clinical management of HDGC, including emerging genetic testing criteria for the identification of new families, methods for endoscopic surveillance, the complications associated with prophylactic surgery, postoperative quality of life, and the emerging field of HDGC chemoprevention.
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Affiliation(s)
- Lyvianne Decourtye-Espiard
- Cancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Parry Guilford
- Cancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin, New Zealand.
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28
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Javed A, Yarmohammadi M, Korkmaz KS, Rubio-Tomás T. The Regulation of Cyclins and Cyclin-Dependent Kinases in the Development of Gastric Cancer. Int J Mol Sci 2023; 24:2848. [PMID: 36769170 PMCID: PMC9917736 DOI: 10.3390/ijms24032848] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Revised: 01/23/2023] [Accepted: 01/28/2023] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer predominantly occurs in adenocarcinoma form and is characterized by uncontrolled growth and metastases of gastric epithelial cells. The growth of gastric cells is regulated by the action of several major cell cycle regulators including Cyclins and Cyclin-dependent kinases (CDKs), which act sequentially to modulate the life cycle of a living cell. It has been reported that inadequate or over-activity of these molecules leads to disturbances in cell cycle dynamics, which consequently results in gastric cancer development. Manny studies have reported the key roles of Cyclins and CDKs in the development and progression of the disease in either in vitro cell culture studies or in vivo models. We aimed to compile the evidence of molecules acting as regulators of both Cyclins and CDKs, i.e., upstream regulators either activating or inhibiting Cyclins and CDKs. The review entails an introduction to gastric cancer, along with an overview of the involvement of cell cycle regulation and focused on the regulation of various Cyclins and CDKs in gastric cancer. It can act as an extensive resource for developing new hypotheses for future studies.
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Affiliation(s)
- Aadil Javed
- Department of Bioengineering, Faculty of Engineering, Cancer Biology Laboratory, Ege University, Izmir 35040, Turkey
| | - Mahdieh Yarmohammadi
- Department of Biology, Faculty of Sciences, Central Tehran Branch, Islamic Azad University, Tehran 33817-74895, Iran
| | - Kemal Sami Korkmaz
- Department of Bioengineering, Faculty of Engineering, Cancer Biology Laboratory, Ege University, Izmir 35040, Turkey
| | - Teresa Rubio-Tomás
- School of Medicine, University of Crete, 70013 Herakleion, Crete, Greece
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29
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Giunta EF, Arrichiello G, Pappalardo A, Federico P, Petrillo A. Transversal Perspectives of Integrative Oncology Care in Gastric and Lobular Breast Cancer. Cancer Treat Res 2023; 188:89-104. [PMID: 38175343 DOI: 10.1007/978-3-031-33602-7_4] [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] [Indexed: 01/05/2024]
Abstract
The occurrence of gastric cancer has been associated with an increased risk of lobular breast tumors in a subset of patients harboring selected germline mutations. Among all, the germline alteration of the gene coding for E-Cadherin (CDH1) was associated with an increased risk of gastric cancer diffuse-histotype and lobular breast cancer. However, the risk assessment of breast neoplasms and the role of multiple prophylactic procedures in these patients has never been systematically addressed. In addition, the performance of the common screening procedures for lobular breast cancer like mammography is suboptimal. Therefore, recalling the need for a better articulation of the patient-centered strategies of surveillance for individuals with germline CDH1 and other similar alterations, to offer comprehensive approaches for prevention, early diagnosis, and treatment. Accordingly, this chapter aims to discuss the value and the role of integrated oncological care in the era of oncology sub-specializations. Additionally, it sheds light on how the harmonization across the health providers can enhance patient care in this setting.
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Affiliation(s)
- Emilio Francesco Giunta
- Department of Precision Medicine, School of Medicine, University of Study of Campania, 80131, Naples, Italy
| | - Gianluca Arrichiello
- Department of Precision Medicine, School of Medicine, University of Study of Campania, 80131, Naples, Italy
| | | | - Piera Federico
- Medical Oncology Unit, Ospedale del Mare, Via E. Russo, 80147, Naples, Italy
| | - Angelica Petrillo
- Medical Oncology Unit, Ospedale del Mare, Via E. Russo, 80147, Naples, Italy.
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30
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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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31
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Li B, Zhang F, Niu Q, Liu J, Yu Y, Wang P, Zhang S, Zhang H, Wang Z. A molecular classification of gastric cancer associated with distinct clinical outcomes and validated by an XGBoost-based prediction model. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 31:224-240. [PMID: 36700042 PMCID: PMC9843270 DOI: 10.1016/j.omtn.2022.12.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022]
Abstract
Gastric cancer (GC) is a heterogeneous disease and a leading cause of cancer-related deaths. Discovering robust, clinically relevant molecular classifications is critical for guiding personalized therapies for GC. Here, we propose a refined molecular classification scheme for GC using integrated optimal algorithms and multi-omics data. Based on the important features of mRNA, microRNA, and DNA methylation data selected by the multivariate Cox regression model, three subtypes linked to distinct clinical outcomes were identified by combining similarity network fusion and consensus clustering methods. Three subtypes were validated by an extreme gradient boosting machine learning prediction model with 125 differentially expressed genes in multiple independent cohorts. The molecular characteristics of mutation signatures, characteristic gene sets, driver genes, and chemotherapy sensitivity for each subtype were also identified: subtype 1 was associated with favorable prognosis and characterized by high ARID1A and PIK3CA mutations, subtype 2 was associated with a poor prognosis and harbored high recurrent TP53 mutations, and subtype 3 was associated with high CHD1, APOA1 mutations, and a poor prognosis. The proposed three-subtype scheme achieved a better clinical prediction performance (area under the curve value = 0.71) than The Cancer Genome Atlas classification, which may provide a practical subtyping framework to improve the treatment of GC.
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Affiliation(s)
- Bing Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Fengbin Zhang
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China
| | - Qikai Niu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Jun Liu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yanan Yu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Pengqian Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Siqi Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Huamin Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China,Corresponding author: Huamin Zhang, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Zhong Wang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China,Corresponding author: Zhong Wang, Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
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32
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Hereditary Diffuse Gastric Cancer: A 2022 Update. J Pers Med 2022; 12:jpm12122032. [PMID: 36556253 PMCID: PMC9783673 DOI: 10.3390/jpm12122032] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 11/21/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer is ranked fifth among the most commonly diagnosed cancers, and is the fourth leading cause of cancer-related deaths worldwide. The majority of gastric cancers are sporadic, while only a small percentage, less than 1%, are hereditary. Hereditary diffuse gastric cancer (HDGC) is a rare malignancy, characterized by early-onset, highly-penetrant autosomal dominant inheritance mainly of the germline alterations in the E-cadherin gene (CDH1) and β-catenin (CTNNA1). In the present study, we provide an overview on the molecular basis of HDGC and outline the essential elements of genetic counseling and surveillance. We further provide a practical summary of current guidelines on clinical management and treatment of individuals at risk and patients with early disease.
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33
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Coudert M, Drouet Y, Delhomelle H, Svrcek M, Benusiglio PR, Coulet F, Clark DF, Katona BW, van Hest LP, van der Kolk LE, Cats A, van Dieren JM, Nehoray B, Slavin T, Spier I, Hüneburg R, Lobo S, Oliveira C, Boussemart L, Masson L, Chiesa J, Schwartz M, Buecher B, Golmard L, Bouvier AM, Bonadona V, Stoppa-Lyonnet D, Lasset C, Colas C. First estimates of diffuse gastric cancer risks for carriers of CTNNA1 germline pathogenic variants. J Med Genet 2022; 59:1189-1195. [PMID: 36038258 DOI: 10.1136/jmg-2022-108740] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 08/02/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND Pathogenic variants (PV) of CTNNA1 are found in families fulfilling criteria for hereditary diffuse gastric cancer (HDGC) but no risk estimates were available until now. The aim of this study is to evaluate diffuse gastric cancer (DGC) risks for carriers of germline CTNNA1 PV. METHODS Data from published CTNNA1 families were updated and new families were identified through international collaborations. The cumulative risk of DGC by age for PV carriers was estimated with the genotype restricted likelihood (GRL) method, taking into account non-genotyped individuals and conditioning on all observed phenotypes and genotypes of the index case to obtain unbiased estimates. A non-parametric (NP) and the Weibull functions were used to model the shape of penetrance function with the GRL. Kaplan-Meier incidence curve and standardised incidence ratios were also computed. A 'leave-one-out' strategy was used to evaluate estimate uncertainty. RESULTS Thirteen families with 46 carriers of PV were included. The cumulative risks of DGC at 80 years for carriers of CTNNA1 PV are 49% and 57%, respectively with the Weibull GRL and NP GRL methods. Risk ratios to population incidence reach particularly high values at early ages and decrease with age. At 40 years, they are equal to 65 and 833, respectively with the Weibull GRL and NP GRL. CONCLUSION This is the largest series of CTNNA1 families that provides the first risk estimates of GC. These data will help to improve management and surveillance for these patients and support inclusion of CTNNA1 in germline testing panels.
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Affiliation(s)
- Marie Coudert
- Département de Génétique, Institut Curie, Paris, France
| | - Youenn Drouet
- CNRS UMR 5558 LBBE, Université de Lyon, Villeurbanne, France.,Département Prévention et Santé Publique, Centre Léon Bérard, Lyon, France
| | | | - Magali Svrcek
- AP-HP, Saint-Antoine Hospital, Department of Pathology, Sorbonne Université, Paris, France
| | - Patrick R Benusiglio
- Département de Génétique Médicale, AP-HP, Hôpital Pitié-Salpêtrière, Sorbonne Université, Paris, France
| | - Florence Coulet
- Département de Génétique Médicale, AP-HP, Hôpital Pitié-Salpêtrière, Sorbonne Université, Paris, France
| | - Dana Farengo Clark
- Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Bryson W Katona
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Liselotte P van Hest
- Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | | | - Annemieke Cats
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jolanda M van Dieren
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Bita Nehoray
- Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA
| | - Thomas Slavin
- Departments of Medical Oncology and Population Sciences, City of Hope, Duarte, California, USA
| | - Isabel Spier
- Institute of Human Genetics/National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Robert Hüneburg
- Department of Internal Medicine/National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Silvana Lobo
- IPATIMUP-Institut of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,i3s, Universidade do Porto Instituto de Investigação e Inovação em Saúde, Porto, Portugal
| | - Carla Oliveira
- Instituto de Investigação e Inovação em Saúde & Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,Faculty of Medicine, University of Porto, Porto, Portugal
| | | | | | - Jean Chiesa
- Génétique, Hopital Universitaire Caremeau, Nimes, France
| | | | - Bruno Buecher
- Département de Génétique, Institut Curie, Paris, France
| | - Lisa Golmard
- Département de Génétique, Institut Curie, Paris, France
| | - Anne-Marie Bouvier
- Digestive Cancer Registry of Burgundy, UMR 1231, Réseau FRANCIM (réseau Français des registres du cancer), Burgundy Franche-Comté University, Dijon, France
| | - Valérie Bonadona
- CNRS UMR 5558 LBBE, Université de Lyon, Villeurbanne, France.,Unité Clinique d'Oncologie génétique, Centre Leon Berard, Lyon, France
| | - Dominique Stoppa-Lyonnet
- Département de Génétique, Institut Curie, Paris, France.,INSERM U830, Université de Paris, Paris, France
| | - Christine Lasset
- CNRS UMR 5558 LBBE, Université de Lyon, Villeurbanne, France.,Département Prévention et Santé Publique, Centre Léon Bérard, Lyon, France
| | - Chrystelle Colas
- Département de Génétique, Institut Curie, Paris, France .,INSERM U830, Université de Paris, Paris, France
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34
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Liu ZX, Zhang XL, Zhao Q, Chen Y, Sheng H, He CY, Sun YT, Lai MY, Wu MQ, Zuo ZX, Wang W, Zhou ZW, Wang FH, Li YH, Xu RH, Qiu MZ. Whole-Exome Sequencing Among Chinese Patients With Hereditary Diffuse Gastric Cancer. JAMA Netw Open 2022; 5:e2245836. [PMID: 36484990 PMCID: PMC9856492 DOI: 10.1001/jamanetworkopen.2022.45836] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
IMPORTANCE The E-cadherin gene, CDH1, and the α-E-catenin gene, CTNNA1, were previously identified as hereditary diffuse gastric cancer (HDGC) susceptibility genes, explaining 25% to 50% of HDGC cases. The genetic basis underlying disease susceptibility in the remaining 50% to 75% of patients with HDGC is still unknown. OBJECTIVE To assess the incidence rate of CDH1 germline alterations in HDGC, identify new susceptibility genes that can be used for screening of HDGC, and provide a genetic landscape for HDGC. DESIGN, SETTING, AND PARTICIPANTS This cohort study conducted retrospective whole-exome and targeted sequencing of 284 leukocyte samples and 186 paired tumor samples from Chinese patients with HDGC over a long follow-up period (median, 21.7 [range, 0.6-185.9] months). Among 10 431 patients diagnosed with gastric cancer between January 1, 2002, and August 31, 2018, 284 patients who met the criteria for HDGC were included. Data were analyzed from August 1 to 30, 2020. MAIN OUTCOMES AND MEASURES Incidence rate of CDH1 germline alterations, identification of new HDGC susceptibility genes, and genetic landscape of HDGC. RESULTS Among 284 Chinese patients, 161 (56.7%) were female, and the median age was 35 (range, 20-75) years. The frequency of CDH1 germline alterations was 2.8%, whereas the frequency of CDH1 somatic alterations was 25.3%. The genes with the highest incidence (>10%) of private germline alterations (including insertions and deletions) in the HDGC cohort were MUC4, ABCA13, ZNF469, FCGBP, IGFN1, RNF213, and SSPO, whereas previously reported germline alterations of CTNNA1, BRCA2, STK11, PRSS1, ATM, MSR1, PALB2, BRCA1, and RAD51C were observed at low frequencies (median, 4 [range, 1-12] cases). Furthermore, enrichment of the somatic variant signature of exposure to aflatoxin suggested potential interaction between genetics and environment in HDGC. Double-hit events in genes such as CACNA1D were observed, which suggested that these events might serve as important mechanisms for HDGC tumorigenesis. In addition, germline variants of FSIP2, HSPG2, and NCKAP5 and somatic alterations of FGFR3, ASPSCR1, CIC, DGCR8, and LZTR1 were associated with poor overall survival among patients with HDGC. CONCLUSIONS AND RELEVANCE This study provided a genetic landscape for HDGC. The study's findings challenged the previously reported high germline alteration rate of CDH1 in HDGC and identified new potential susceptibility genes. Analyses of variant signatures and double-hit events revealed potentially important mechanisms for HDGC tumorigenesis. Findings from the present study may provide helpful information for further investigations of HDGC.
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Affiliation(s)
- Ze-Xian Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Xiao-Long Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Qi Zhao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Yungchang Chen
- Department of Medical Oncology, The First People’s Hospital of Foshan, Chancheng District, Foshan, People’s Republic of China
| | - Hui Sheng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Cai-Yun He
- Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China
| | - Yu-Ting Sun
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China
| | - Ming-Yu Lai
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China
| | - Min-Qing Wu
- Department of Cancer Prevention, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Zhi-Xiang Zuo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Wei Wang
- Department of Medical Oncology, The First People’s Hospital of Foshan, Chancheng District, Foshan, People’s Republic of China
| | - Zhi-Wei Zhou
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China
| | - Feng-Hua Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China
| | - Yu-Hong Li
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China
| | - Rui-Hua Xu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, People’s Republic of China
| | - Miao-Zhen Qiu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China
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35
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Long JM, Ebrahimzadeh J, Stanich PP, Katona BW. Endoscopic Surveillance in Patients with the Highest Risk of Gastric Cancer: Challenges and Solutions. Cancer Manag Res 2022; 14:2953-2969. [PMID: 36238953 PMCID: PMC9553156 DOI: 10.2147/cmar.s277898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 09/22/2022] [Indexed: 11/23/2022] Open
Abstract
Gastric cancer is one of the most significant causes of cancer-related morbidity and mortality worldwide. Recognized modifiable risk factors include Helicobacter pylori infection, geographic location, select dietary factors, tobacco use and alcohol consumption. In addition, multiple hereditary cancer predisposition syndromes are associated with significantly elevated gastric cancer risk. Endoscopic surveillance in hereditary gastric cancer predisposition syndromes has the potential to identify gastric cancer at earlier and more treatable stages, as well as to prevent development of gastric cancer through identification of precancerous lesions. However, much uncertainty remains regarding use of endoscopic surveillance in hereditary gastric cancer predisposition syndromes, including whether or not it should be routinely performed, the surveillance interval and age of initiation, cost-effectiveness, and whether surveillance ultimately improves survival from gastric cancer for these high-risk individuals. In this review, we outline the hereditary gastric cancer predisposition syndromes associated with the highest gastric cancer risks. Additionally, we cover current evidence and guidelines addressing hereditary gastric cancer risk and surveillance in these syndromes, along with current challenges and limitations that emphasize a need for continued research in this field.
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Affiliation(s)
- Jessica M Long
- Division of Hematology and Oncology, Penn Medicine, Philadelphia, PA, USA
| | | | - Peter P Stanich
- Division of Gastroenterology, Hepatology & Nutrition, The Ohio State University, Wexner Medical Center, Columbus, OH, USA
| | - Bryson W Katona
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA,Correspondence: Bryson W Katona, Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, 751 South Pavilion, Philadelphia, PA, 19104, USA, Tel +1-215-349-8222, Fax +1-215-349-5915, Email
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Hereditary Diffuse Gastric Cancer: Molecular Genetics, Biological Mechanisms and Current Therapeutic Approaches. Int J Mol Sci 2022; 23:ijms23147821. [PMID: 35887173 PMCID: PMC9319245 DOI: 10.3390/ijms23147821] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 07/01/2022] [Accepted: 07/06/2022] [Indexed: 12/14/2022] Open
Abstract
Hereditary diffuse gastric cancer is an autosomal dominant syndrome characterized by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is caused by inactivating mutations in the tumor suppressor gene CDH1. Genetic testing technologies have become more efficient over the years, also enabling the discovery of other susceptibility genes for gastric cancer, such as CTNNA1 among the most important genes. The diagnosis of pathogenic variant carriers with an increased risk of developing gastric cancer is a selection process involving a multidisciplinary team. To achieve optimal long-term results, it requires shared decision-making in risk management. In this review, we present a synopsis of the molecular changes and current therapeutic approaches in HDGC based on the current literature.
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Shah D, Bentrem D. Environmental and genetic risk factors for gastric cancer. J Surg Oncol 2022; 125:1096-1103. [PMID: 35481919 PMCID: PMC9322002 DOI: 10.1002/jso.26869] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/10/2022] [Accepted: 03/12/2022] [Indexed: 12/11/2022]
Abstract
Gastric cancer is a heterogeneous and prevalent disease. The traditional environmental exposures associated with an elevated risk of gastric cancer are less prevalent in the United States today. Genetic risks and risks associated with inflammation remain. Most cases are sporadic and familial clustering is observed in about 10% of the cases. Hereditary gastric cancer accounts for a very low percentage of cases. Here we review the genetic and environmental risk factors associated with the disease.
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Affiliation(s)
- Dhavan Shah
- Department of Surgery, Surgical Outcome and Quality Improvement Center, Feinberg School of MedicineNorthwestern UniversityChicagoIllinoisUSA
| | - David Bentrem
- Department of Surgery, Feinberg School of MedicineNorthwestern UniversityChicagoIllinoisUSA
- Jesse Brown VA Medical CenterChicagoIllinoisUSA
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38
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Carneiro F. Familial and hereditary gastric cancer, an overview. Best Pract Res Clin Gastroenterol 2022; 58-59:101800. [PMID: 35988963 DOI: 10.1016/j.bpg.2022.101800] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 04/11/2022] [Accepted: 04/24/2022] [Indexed: 02/08/2023]
Abstract
There are three major hereditable syndromes that affect primarily the stomach: hereditary diffuse gastric cancer (HDGC), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) and familial intestinal gastric cancer (FIGC). HDGC is caused by germline mutations in CDH1 gene that occur in 10-40% of HDGC families and, in a minority of cases, by mutations in CTNNA1 gene. GAPPS is caused by germline mutations in the promoter 1B of APC gene, and the genetic cause of FIGC is not fully elucidated. Gastric cancer can also be observed as part of other inherited cancer disorders, namely in familial adenomatous polyposis, MUTYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, Lynch syndrome, Li-Fraumeni syndrome, Cowden syndrome, and hereditary breast and ovarian cancer syndrome. In this article, the state of the art of familial gastric cancer regarding the clinical, molecular and pathology features is reviewed, as well as the practical aspects for a correct diagnosis and clinical management.
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Affiliation(s)
- Fátima Carneiro
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho,45, 4200-135, Porto, Portugal; Department of Pathology, Faculty of Medicine of the University of Porto, Alameda Prof. Hernâni Monteiro, 4100-319, Porto, Portugal; Centro Hospitalar Universitário São João, Alameda Prof. Hernani Monteiro, 4100-319, Porto, Portugal.
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Hereditary diffuse gastric cancer (HDGC). An overview. Clin Res Hepatol Gastroenterol 2022; 46:101820. [PMID: 34656755 DOI: 10.1016/j.clinre.2021.101820] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/02/2021] [Accepted: 09/25/2021] [Indexed: 02/06/2023]
Abstract
It is estimated that up to 10% of gastric carcinomas show familial aggregation. In contrast, around 1-3 % (approximately 33,000 yearly) are genuinely hereditary. Hereditary diffuse gastric cancer (HDGC) is a rare malignancy characterized by autosomal dominant inheritance of pathological variants of the CDH1 and CTNNA1 genes encoding the adhesion molecules E-cadherin and α-catenin, respectively. The multifocal nature of the disease and the difficulty of visualizing precursor lesions by endoscopy underscore the need to be aware of this malignancy as surgical prevention can be fully protective. Here, we provide an overview of the main epidemiological, clinical, genetic, and pathological features of HDGC, as well as updated guidelines for its diagnosis, genetic testing, counseling, surveillance, and management. We conclude that HDGC is a rare, highly penetrant disease that is difficult to diagnose and manage, so it is necessary to correctly identify it to offer patients and their families' adequate management following the recommendations of the IGCL. A critical point is identifying a mutation in HDGC families to determine whether unaffected relatives are at risk for cancer.
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Treese C, Siegmund B, Daum S. Hereditary Diffuse Gastric Cancer—Update Based on the Current Consort Recommendations. Curr Oncol 2022; 29:2454-2460. [PMID: 35448173 PMCID: PMC9029010 DOI: 10.3390/curroncol29040199] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 03/22/2022] [Accepted: 03/24/2022] [Indexed: 12/18/2022] Open
Abstract
Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant inherited cancer syndrome that has been associated with a mutation of the CDH1, and rarely the CTNNA1 gene, respectively. HDGC is characterized histologically by multifocal growth and signet ring cells in the gastric mucosa and lobular type breast cancer. In cases of a proven pathogenic CDH1 mutation, a prophylactic gastrectomy, or alternatively, an annual surveillance gastroscopy in expert centers is recommended. Additionally, MR imaging of the breast should be performed annually starting from the age of 30, to detect lobular breast cancer. In 2020, the International Gastric Cancer Linkage Consortium (IGCLC) additionally defined new clinical groups with specific recommendations: (1) the group of patients with a proven mutation in the CDH1 gene, but exclusive manifestation as lobular breast cancer, was defined as hereditary lobular breast cancer (HLBC); (2) the group, which clinically fulfills familial HDGC criteria, in the absence of a relevant mutation, was designated as HDGC-like. This update summarizes relevant aspects of hereditary gastric cancer and the current recommendation criteria of the IGCLC published in 2020.
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Affiliation(s)
| | | | - Severin Daum
- Correspondence: ; Tel.: +49-30-450-51-43-22; Fax: +49-30-450-51-49-90
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Diffuse gastric cancer: Emerging mechanisms of tumor initiation and progression. Biochim Biophys Acta Rev Cancer 2022; 1877:188719. [PMID: 35307354 DOI: 10.1016/j.bbcan.2022.188719] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 02/07/2023]
Abstract
Gastric cancer is globally the fourth leading cause of cancer-related deaths. Patients with diffuse-type gastric cancer (DGC) particularly have a poor prognosis that only marginally improved over the last decades, as conventional chemotherapies are frequently ineffective and specific therapies are unavailable. Early-stage DGC is characterized by intramucosal lesions of discohesive cells, which can be present for many years before the emergence of advanced DGC consisting of highly proliferative and invasive cells. The mechanisms underlying the key steps of DGC development and transition to aggressive tumors are starting to emerge. Novel mouse- and organoid models for DGC, together with multi-omic analyses of DGC tumors, revealed contributions of both tumor cell-intrinsic alterations and gradual changes in the tumor microenvironment to DGC progression. In this review, we will discuss how these recent findings are leading towards an understanding of the cellular and molecular mechanisms responsible for DGC initiation and malignancy, which may provide opportunities for targeted therapies.
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Ajaz S, Zaidi SEZ, Ali S, Siddiqa A, Memon MA. Germline Mutation Analysis in Sporadic Breast Cancer Cases With Clinical Correlations. Front Genet 2022; 13:820610. [PMID: 35356428 PMCID: PMC8959921 DOI: 10.3389/fgene.2022.820610] [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: 11/23/2021] [Accepted: 02/08/2022] [Indexed: 11/15/2022] Open
Abstract
Demographics for breast cancers vary widely among nations. The frequency of germline mutations in breast cancers, which reflects the hereditary cases, has not been investigated adequately and accurately in highly-consanguineous Pakistani population. In the present discovery case series, germ-line mutations in twenty-seven breast cancer candidate genes were investigated in eighty-four sporadic breast cancer patients along with the clinical correlations. The germ-line variants were also assessed in two healthy gender-matched controls. The clinico-pathological features were evaluated by descriptive analysis and Pearson χ2 test (with significant p-value <0.05). The most frequent parameters associated with hereditary cancer cases are age and ethnicity. Therefore, the analyses were stratified on the basis of age (≤40 years vs. >40 years) and ethnicity. The breast cancer gene panel assay was carried out by BROCA, which is a genomic capture, massively parallel next generation sequencing assay on Illumina Hiseq2000 with 100bp read lengths. Copy number variations were determined by partially-mapped read algorithm. Once the mutation was identified, it was validated by Sanger sequencing. The ethnic analysis stratified on the basis of age showed that the frequency of breast cancer at young age (≤40 years) was higher in Sindhis (n = 12/19; 64%) in contrast to patients in other ethnic groups. Majority of the patients had stage III (38.1%), grade III (50%), tumor size 2–5 cm (54.8%), and invasive ductal carcinoma (81%). Overall, the analysis revealed germ-line mutations in 11.9% of the patients, which was not significantly associated with younger age or any particular ethnicity. The mutational spectrum was restricted to three genes: BRCA1, BRCA2, and TP53. The identified mutations consist of seven novel germ-line mutations, while three mutations have been reported previously. All the mutations are predicted to result in protein truncation. No mutations were identified in the remaining twenty-four candidate breast cancer genes. The present study provides the framework for the development of hereditary-based preventive and treatment strategies against breast cancers in Pakistani population.
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Affiliation(s)
- Sadia Ajaz
- Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, Pakistan
- Department of Human Genetics and Molecular Biology, University of Health Sciences, Lahore, Pakistan
- *Correspondence: Sadia Ajaz, ,
| | - Sani-e-Zehra Zaidi
- Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, Pakistan
| | - Saleema Ali
- Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, Pakistan
| | - Aisha Siddiqa
- Atomic Energy Medical Centre (AEMC), Jinnah Postgraduate Medical Centre (JPMC), Karachi, Pakistan
| | - Muhammad Ali Memon
- Atomic Energy Medical Centre (AEMC), Jinnah Postgraduate Medical Centre (JPMC), Karachi, Pakistan
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Ben Aissa-Haj J, Kabbage M, Othmen H, Saulnier P, Kettiti HT, Jaballah-Gabteni A, Ferah A, Medhioub M, Khsiba A, Mahmoudi M, Maaloul A, Ben Nasr S, Chelbi E, Abdelhak S, Boubaker MS, Azzouz MM, Rouleau E. CDH1 Germline Variants in a Tunisian Cohort with Hereditary Diffuse Gastric Carcinoma. Genes (Basel) 2022; 13:genes13030400. [PMID: 35327954 PMCID: PMC8950196 DOI: 10.3390/genes13030400] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 02/08/2022] [Accepted: 02/10/2022] [Indexed: 12/24/2022] Open
Abstract
Mutational screening of the CDH1 gene is a standard treatment for patients who fulfill Hereditary Diffuse Gastric Cancer (HDGC) testing criteria. In this framework, the classification of variants found in this gene is a crucial step for the clinical management of patients at high risk for HDGC. The aim of our study was to identify CDH1 as well as CTNNA1 mutational profiles predisposing to HDGC in Tunisia. Thirty-four cases were included for this purpose. We performed Sanger sequencing for the entire coding region of both genes and MLPA (Multiplex Ligation Probe Amplification) assays to investigate large rearrangements of the CDH1 gene. As a result, three cases, all with the HDGC inclusion criteria (8.82% of the entire cohort), carried pathogenic and likely pathogenic variants of the CDH1 gene. These variants involve a novel splicing alteration, a missense c.2281G > A detected by Sanger sequencing, and a large rearrangement detected by MLPA. No pathogenic CTNNA1 variants were found. The large rearrangement is clearly pathogenic, implicating a large deletion of two exons. The novel splicing variant creates a cryptic site. The missense variant is a VUS (Variant with Uncertain Significance). With ACMG (American College of Medical Genetics and Genomics) classification and the evidence available, we thus suggest a revision of its status to likely pathogenic. Further functional studies or cosegregation analysis should be performed to confirm its pathogenicity. In addition, molecular exploration will be needed to understand the etiology of the other CDH1- and CTNNA1-negative cases fulfilling the HDGC inclusion criteria.
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Affiliation(s)
- Jihenne Ben Aissa-Haj
- Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia; (M.K.); (H.T.K.); (A.J.-G.); (A.M.); (M.S.B.)
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia;
- Correspondence:
| | - Maria Kabbage
- Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia; (M.K.); (H.T.K.); (A.J.-G.); (A.M.); (M.S.B.)
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia;
| | - Houcemeddine Othmen
- Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg 2000, South Africa;
| | - Patrick Saulnier
- Genomic Platform Molecular Biopathology Unit, URA3655 Inserm, US23 CNRS, Gustave Roussy, 94805 Villejuif, France;
| | - Haifa Tounsi Kettiti
- Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia; (M.K.); (H.T.K.); (A.J.-G.); (A.M.); (M.S.B.)
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia;
| | - Amira Jaballah-Gabteni
- Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia; (M.K.); (H.T.K.); (A.J.-G.); (A.M.); (M.S.B.)
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia;
| | - Azer Ferah
- Laboratory of Venoms and Therapeutic Biomolecules, LR16IPT08 Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia;
| | - Mouna Medhioub
- Gastroenterology Department, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia; (M.M.); (A.K.); (M.M.); (M.M.A.)
- Faculty of Medicine Tunis, University of Tunis El Manar, Tunis 1068, Tunisia
| | - Amal Khsiba
- Gastroenterology Department, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia; (M.M.); (A.K.); (M.M.); (M.M.A.)
- Faculty of Medicine Tunis, University of Tunis El Manar, Tunis 1068, Tunisia
| | - Moufida Mahmoudi
- Gastroenterology Department, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia; (M.M.); (A.K.); (M.M.); (M.M.A.)
- Faculty of Medicine Tunis, University of Tunis El Manar, Tunis 1068, Tunisia
| | - Afifa Maaloul
- Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia; (M.K.); (H.T.K.); (A.J.-G.); (A.M.); (M.S.B.)
| | - Sonia Ben Nasr
- Oncology Department, Military Hospital of Tunis, Tunis 1008, Tunisia;
| | - Emna Chelbi
- Department of Pathology, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia;
| | - Sonia Abdelhak
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia;
| | - M. Samir Boubaker
- Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia; (M.K.); (H.T.K.); (A.J.-G.); (A.M.); (M.S.B.)
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia;
| | - Mohamed Mousaddak Azzouz
- Gastroenterology Department, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia; (M.M.); (A.K.); (M.M.); (M.M.A.)
- Faculty of Medicine Tunis, University of Tunis El Manar, Tunis 1068, Tunisia
| | - Etienne Rouleau
- Department of Biology and Pathology-Cancer Genetics Laboratory-Gustave Roussy, 94805 Villejuif, France;
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Abstract
Gastric cancer (GC) is a leading contributor to global cancer incidence and mortality. Pioneering genomic studies, focusing largely on primary GCs, revealed driver alterations in genes such as ERBB2, FGFR2, TP53 and ARID1A as well as multiple molecular subtypes. However, clinical efforts targeting these alterations have produced variable results, hampered by complex co-alteration patterns in molecular profiles and intra-patient genomic heterogeneity. In this Review, we highlight foundational and translational advances in dissecting the genomic cartography of GC, including non-coding variants, epigenomic aberrations and transcriptomic alterations, and describe how these alterations interplay with environmental influences, germline factors and the tumour microenvironment. Mapping of these alterations over the GC life cycle in normal gastric tissues, metaplasia, primary carcinoma and distant metastasis will improve our understanding of biological mechanisms driving GC development and promoting cancer hallmarks. On the translational front, integrative genomic approaches are identifying diverse mechanisms of GC therapy resistance and emerging preclinical targets, enabled by technologies such as single-cell sequencing and liquid biopsies. Validating these insights will require specifically designed GC cohorts, converging multi-modal genomic data with longitudinal data on therapeutic challenges and patient outcomes. Genomic findings from these studies will facilitate 'next-generation' clinical initiatives in GC precision oncology and prevention.
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Affiliation(s)
- Khay Guan Yeoh
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore
- Singapore Gastric Cancer Consortium, Singapore, Singapore
| | - Patrick Tan
- Singapore Gastric Cancer Consortium, Singapore, Singapore.
- Cancer and Stem Cell Biology, Duke-NUS Medical School Singapore, Singapore, Singapore.
- Genome Institute of Singapore, Singapore, Singapore.
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
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Abstract
Gastric cancer (GC) is a major health concern in many countries. GC is a heterogeneous disease stratified by histopathological differences. However, these variations are not used to determine GC management. Next-generation sequencing (NGS) technologies have become widely used, and cancer genomic analysis has recently revealed the relationships between various malignant tumors and genomic information. In 2014, studies using whole-exome sequencing (WES) and whole-genome sequencing (WGS) for GC revealed the entire structure of GC genomics. Genomics with NGS has been used to identify new therapeutic targets for GC. Moreover, personalized medicine to provide specific therapy for targets based on multiplex gene panel testing of tumor tissues has become of clinical use. Recently, immune checkpoint inhibitors (ICIs) have been used for GC treatment; however, their response rates are limited. To predict the anti-tumor effects of ICIs for GC and to select patients suitable for ICI treatment, genomics also provides informative data not only of tumors but also of tumor microenvironments, such as tumor-infiltrating lymphocytes. In therapeutic strategies for unresectable or recurrent malignant tumors, the target is not only the primary lesion but also metastatic lesions, and metastatic lesions are often resistant to chemotherapy. Unlike colorectal carcinoma, there is a heterogeneous status of genetic variants between the primary and metastatic lesions in GC. Liquid biopsy analysis is also helpful for predicting the genomic status of both primary and metastatic lesions. Genomics has become an indispensable tool for GC treatment and is expected to be further developed in the future.
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Affiliation(s)
- Takumi Onoyama
- Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Tottori University Faculty of Medicine, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan
| | - Shumpei Ishikawa
- Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
| | - Hajime Isomoto
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Tottori University Faculty of Medicine, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan
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Kheirollahi M, Saneipour M, Moridnia A. Germline likely pathogenic variants in ataxia-telangiectasia-mutated gene in an Iranian family with hereditary diffuse gastric cancer without CDH1 mutation. J Cancer Res Ther 2021; 17:1434-1437. [PMID: 34916374 DOI: 10.4103/jcrt.jcrt_344_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Background Gastric cancer (GC) is the fourth common cancer in the world and the second cause of cancer-related mortality. Germline mutations in the E-cadherin gene (CDH1) are the most common cause of hereditary diffuse GC (HDGC) and explain 25%-30% of cases. In HDGC families without the pathogenic CDH1 variant, there is poor management and therapeutic strategies, and detect other genetic defects in HDGC, except CDH1 gene will be useful for further clarification of the disease mechanisms and risk-reducing strategies. Here, we reported an Iranian pedigree with familial HDGC to assess the fundamental genetic causes by whole-exome sequencing (WES). Materials and Methods WES performed in an Iranian with a history of familial GC in whom no pathogenic variants or indels has been found in CDH1 and CTNNA1 genes with Sanger sequencing and multiplex ligation-dependent probe amplification methods. Results Prioritizing genes associate with HDGC recognized several variants include c.2572T>C, and c.3161C>G in ataxia-telangiectasia mutated (ATM), c.1114A>C in BRCA2, and finally c.1173A>G in PIK3CA. Protein function prediction software tools reveal that c.3161C>G in ATM is likely pathogen. Conclusion The results of this study suggested a role for the known cancer predisposition gene ATM in families with HDGC with no pathogenic variant in CDH1. Our results suggested that mutations in ATM and other genes, particularly the mutations found in this study, should be considered even in one case of positive familial status of HDGC disease. The presence of these mutations in patients with familial history raises important issues regarding genetic counseling.
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Affiliation(s)
- Majid Kheirollahi
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maryam Saneipour
- Department of Genetics and Molecular Biology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran
| | - Abbas Moridnia
- Department of Genetics and Molecular Biology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran
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Garcia-Pelaez J, Barbosa-Matos R, São José C, Sousa S, Gullo I, Hoogerbrugge N, Carneiro F, Oliveira C. Gastric cancer genetic predisposition and clinical presentations: Established heritable causes and potential candidate genes. Eur J Med Genet 2021; 65:104401. [PMID: 34871783 DOI: 10.1016/j.ejmg.2021.104401] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 11/10/2021] [Accepted: 11/28/2021] [Indexed: 12/12/2022]
Abstract
Tumour risk syndromes (TRS) are characterized by an increased risk of early-onset cancers in a familial context. High cancer risk is mostly driven by loss-of-function variants in a single cancer-associated gene. Presently, predisposition to diffuse gastric cancer (DGC) is explained by CDH1 and CTNNA1 pathogenic and likely pathogenic variants (P/LP), causing Hereditary Diffuse Gastric Cancer (HDGC); while APC promoter 1B single nucleotide variants predispose to Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS). Familial Intestinal Gastric Cancer (FIGC), recognized as a GC-predisposing disease, remains understudied and genetically unsolved. GC can also occur in the spectrum of other TRS. Identification of heritable causes allows defining diagnostic testing criteria, helps to clinically classify GC families into the appropriate TRS, and allows performing pre-symptomatic testing identifying at-risk individuals for downstream surveillance, risk reduction and/or treatment. However, most of HDGC, some GAPPS, and most FIGC patients/families remain unsolved, expecting a heritable factor to be discovered. The missing heritability in GC-associated tumour risk syndromes (GC-TRS) is likely explained not by a single major gene, but by a diversity of genes, some, predisposing to other TRS. This would gain support if GC-enriched small families or apparently isolated early-onset GC cases were hiding a family history compatible with another TRS. Herein, we revisited current knowledge on GC-TRS, and searched in the literature for individuals/families bearing P/LP variants predisposing for other TRS, but whose probands display a clinical presentation and/or family history also fitting GC-TRS criteria. We found 27 families with family history compatible with HDGC or FIGC, harbouring 28 P/LP variants in 16 TRS-associated genes, mainly associated with DNA repair. PALB2 or BRCA2 were the most frequently mutated candidate genes in individuals with family history compatible with HDGC and FIGC, respectively. Consolidation of PALB2 and BRCA2 as HDGC- or FIGC-associated genes, respectively, holds promise and worth additional research. This analysis further highlighted the influence, that proband's choice and small or unreported family history have, for a correct TRS diagnosis, genetic screening, and disease management. In this review, we provide a rational for identification of particularly relevant candidate genes in GC-TRS.
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Affiliation(s)
- José Garcia-Pelaez
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; Doctoral Programme in Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Rita Barbosa-Matos
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; International Doctoral Programme in Molecular and Cellular Biotechnology Applied to Health Sciences from Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Celina São José
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; Doctoral Programme in Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Sónia Sousa
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
| | - Irene Gullo
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; FMUP - Faculty of Medicine of the University of Porto, Porto, Portugal; Centro Hospitalar e Universitário S. João, Porto, Portugal
| | - Nicoline Hoogerbrugge
- Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands
| | - Fátima Carneiro
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; FMUP - Faculty of Medicine of the University of Porto, Porto, Portugal; Centro Hospitalar e Universitário S. João, Porto, Portugal
| | - Carla Oliveira
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; FMUP - Faculty of Medicine of the University of Porto, Porto, Portugal.
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Song J, Yu S, Zhong D, Yang W, Jia Z, Yuan G, Li P, Zhang R, Li Y, Zhong G, Chen Z. The circular RNA hsa_circ_000780 as a potential molecular diagnostic target for gastric cancer. BMC Med Genomics 2021; 14:282. [PMID: 34838011 PMCID: PMC8627072 DOI: 10.1186/s12920-021-01096-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 10/08/2021] [Indexed: 01/01/2023] Open
Abstract
Background The present study aimed to identify a specific circular RNA (circRNA) for early diagnosis of gastric cancer (GC). Methods Totally 82 patients with GC, 30 with chronic nonatrophic gastritis and 30 with chronic atrophic gastritis were included in this study. Four of the 82 GC patients were selected for screening. Total RNA from malignant and adjacent tissue samples was extracted, and circRNAs in four patients were screened. According to the screening results, the eight most upregulated and downregulated circRNAs with a statistically significant association with GC were identified by real-time fluorescent quantitative polymerase chain reaction (PCR). Then, the most regulated circRNA was selected for further sensitivity and specificity assessments. CircRNA expression was examined by quantitative reverse transcriptase PCR in 78 GC (21 and 57 early and advanced GC, respectively) and adjacent tissue samples, as well as in gastric fluid samples from 30 patients with chronic nonatrophic gastritis, 30 with chronic atrophic gastritis, and 78 GC. Results A total of 445 circRNAs, including 69 upregulated and 376 downregulated circRNAs, showed significantly altered expression in GC tissue samples. Hsa_circ_000780 was significantly downregulated in 80.77% of GC tissue samples, with levels in GC tissue samples correlating with tumor size, tumor stage, T stage, venous invasion, carcinoembryonic antigen amounts, and carbohydrate antigen 19–9 levels. Strikingly, this circRNA was found in the gastric fluid of patients with early and advanced GC. Conclusions The present study uncovered a new circRNA expression profile in human GC, with hsa_circ_000780 significantly downregulated in GC tissue and gastric fluid specimens. These findings indicate that hsa_circ_000780 should be considered a novel biomarker for early GC screening.
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Affiliation(s)
- Jian Song
- Department of Gastroenterology, The Affiliated Cancer Hospital of Hainan Medical University, Haikou, 570123, China.
| | - Shuyong Yu
- Department of Gastrointestinal Surgery, The Affiliated Cancer Hospital of Hainan Medical University, Haikou, 570123, China
| | - Dunjing Zhong
- Department of Gastroenterology, The Affiliated Cancer Hospital of Hainan Medical University, Haikou, 570123, China
| | - Weizhong Yang
- Department of Digestive Endoscopy, The Affiliated Second Hospital of Hainan Medical University, Haikou, 570100, China
| | - Zhen Jia
- Department of Anesthesiology, The Affiliated Cancer Hospital of Hainan Medical University, Haikou, 570123, China
| | - Guihong Yuan
- Department of Gastroenterology, The Affiliated Cancer Hospital of Hainan Medical University, Haikou, 570123, China
| | - Ping Li
- Department of Gastroenterology, The Affiliated Cancer Hospital of Hainan Medical University, Haikou, 570123, China
| | - Ronglin Zhang
- Department of Gastroenterology, The Affiliated Cancer Hospital of Hainan Medical University, Haikou, 570123, China
| | - Yini Li
- Department of Gastroenterology, The Affiliated Cancer Hospital of Hainan Medical University, Haikou, 570123, China
| | - Guobing Zhong
- Department of Clinical Laboratory, The Affiliated Cancer Hospital of Hainan Medical University, Haikou, 570123, China
| | - Zhaowei Chen
- Department of Gastroenterology, The Affiliated Cancer Hospital of Hainan Medical University, Haikou, 570123, China
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Cristofoli F, Sorrentino E, Guerri G, Miotto R, Romanelli R, Zulian A, Cecchin S, Paolacci S, Miertus J, Bertelli M, Maltese PE, Chiurazzi P, Stuppia L, Castori M, Marceddu G. Variant Selection and Interpretation: An Example of Modified VarSome Classifier of ACMG Guidelines in the Diagnostic Setting. Genes (Basel) 2021; 12:1885. [PMID: 34946832 PMCID: PMC8700904 DOI: 10.3390/genes12121885] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/22/2021] [Accepted: 11/24/2021] [Indexed: 11/18/2022] Open
Abstract
Variant interpretation is challenging as it involves combining different levels of evidence in order to evaluate the role of a specific variant in the context of a patient's disease. Many in-depth refinements followed the original 2015 American College of Medical Genetics (ACMG) guidelines to overcome subjective interpretation of criteria and classification inconsistencies. Here, we developed an ACMG-based classifier that retrieves information for variant interpretation from the VarSome Stable-API environment and allows molecular geneticists involved in clinical reporting to introduce the necessary changes to criterion strength and to add or exclude criteria assigned automatically, ultimately leading to the final variant classification. We also developed a modified ACMG checklist to assist molecular geneticists in adjusting criterion strength and in adding literature-retrieved or patient-specific information, when available. The proposed classifier is an example of integration of automation and human expertise in variant curation, while maintaining the laboratory analytical workflow and the established bioinformatics pipeline.
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Affiliation(s)
- Francesca Cristofoli
- Diagnostics Unit, MAGI EUREGIO, 39100 Bolzano, Italy; (F.C.); (E.S.); (R.M.); (J.M.); (M.B.); (G.M.)
| | - Elisa Sorrentino
- Diagnostics Unit, MAGI EUREGIO, 39100 Bolzano, Italy; (F.C.); (E.S.); (R.M.); (J.M.); (M.B.); (G.M.)
| | - Giulia Guerri
- Diagnostics Unit, MAGI’S LAB, 38068 Rovereto, Italy; (G.G.); (R.R.); (A.Z.); (S.C.); (P.E.M.)
| | - Roberta Miotto
- Diagnostics Unit, MAGI EUREGIO, 39100 Bolzano, Italy; (F.C.); (E.S.); (R.M.); (J.M.); (M.B.); (G.M.)
| | - Roberta Romanelli
- Diagnostics Unit, MAGI’S LAB, 38068 Rovereto, Italy; (G.G.); (R.R.); (A.Z.); (S.C.); (P.E.M.)
| | - Alessandra Zulian
- Diagnostics Unit, MAGI’S LAB, 38068 Rovereto, Italy; (G.G.); (R.R.); (A.Z.); (S.C.); (P.E.M.)
| | - Stefano Cecchin
- Diagnostics Unit, MAGI’S LAB, 38068 Rovereto, Italy; (G.G.); (R.R.); (A.Z.); (S.C.); (P.E.M.)
| | - Stefano Paolacci
- Diagnostics Unit, MAGI’S LAB, 38068 Rovereto, Italy; (G.G.); (R.R.); (A.Z.); (S.C.); (P.E.M.)
| | - Jan Miertus
- Diagnostics Unit, MAGI EUREGIO, 39100 Bolzano, Italy; (F.C.); (E.S.); (R.M.); (J.M.); (M.B.); (G.M.)
- Diagnostics Unit, MAGI’S LAB, 38068 Rovereto, Italy; (G.G.); (R.R.); (A.Z.); (S.C.); (P.E.M.)
| | - Matteo Bertelli
- Diagnostics Unit, MAGI EUREGIO, 39100 Bolzano, Italy; (F.C.); (E.S.); (R.M.); (J.M.); (M.B.); (G.M.)
- Diagnostics Unit, MAGI’S LAB, 38068 Rovereto, Italy; (G.G.); (R.R.); (A.Z.); (S.C.); (P.E.M.)
| | - Paolo Enrico Maltese
- Diagnostics Unit, MAGI’S LAB, 38068 Rovereto, Italy; (G.G.); (R.R.); (A.Z.); (S.C.); (P.E.M.)
| | - Pietro Chiurazzi
- Section of Genomic Medicine, Department of Life Science and Public Health, “Sacro Cuore” Catholic University, 00168 Rome, Italy;
- Policlinic University Foundation “A. Gemelli” IRCCS, UOC Medical Genetics, 00168 Rome, Italy
| | - Liborio Stuppia
- Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, “G. D’Annunzio” University, Chieti-Pescara, 66100 Chieti, Italy;
| | - Marco Castori
- Division of Medical Genetics, IRCCS Foundation “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy;
| | - Giuseppe Marceddu
- Diagnostics Unit, MAGI EUREGIO, 39100 Bolzano, Italy; (F.C.); (E.S.); (R.M.); (J.M.); (M.B.); (G.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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