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1
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Li D, Morgan DR, Corral JE, Montgomery EA, Riquelme A, Shah SC. Gastric Cancer Screening in the United States: A Review of Current Evidence, Challenges, and Future Perspectives. Am J Gastroenterol 2025; 120:765-777. [PMID: 40072512 DOI: 10.14309/ajg.0000000000003301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 12/18/2024] [Indexed: 03/14/2025]
Abstract
Gastric cancer remains a leading cause of cancer-related mortality worldwide. In the United States, gastric cancer incidence and mortality are substantially higher among non-White racial and ethnic groups and new immigrants from high-incidence countries. This is in large part related to the higher prevalence of Helicobacter pylori -associated gastric premalignant changes in these populations. Apart from primary prevention, early detection of gastric cancer is the principal strategy to reduce gastric cancer mortality and improve survival. Extensive evidence in Asian countries has demonstrated the benefits of endoscopic screening in detecting early-stage gastric cancer and reducing gastric cancer-related mortality. By contrast, direct, high-quality US-based data, such as from large clinical trials or observational studies, on important outcomes of gastric cancer screening are still lacking. In this review, we evaluate and summarize the latest global evidence on the epidemiology and predisposing factors of gastric cancer as well as the efficacy, benefits vs. risks, and cost-effectiveness of gastric cancer screening. We further discuss the critical knowledge gaps and challenges in promoting gastric cancer screening in the United States. Dedicated research is urgently needed to enrich the US-based data on gastric cancer primary and secondary prevention to inform clinical practice and reduce gastric cancer-related morbidity and mortality in a cost and resource efficient manner.
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Affiliation(s)
- Dan Li
- Department of Gastroenterology, Kaiser Permanente Medical Center, Santa Clara, California, USA
- Kaiser Permanente Northern California Division of Research, Oakland, California, USA
| | - Douglas R Morgan
- Division of Gastroenterology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Juan E Corral
- Division of Gastroenterology, Prisma Health, Greenville, South Carolina, USA
| | - Elizabeth A Montgomery
- Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Arnoldo Riquelme
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Center for Control and Prevention of Cancer (CECAN), Santiago, Chile
| | - Shailja C Shah
- Division of Gastroenterology, University of California, San Diego, La Jolla, California, USA
- Gastroenterology Section, Jennifer Moreno Department of Veterans Affairs Medical Center, La Jolla, California, USA
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2
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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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3
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Llach J, Salces I, Guerra A, Peñas B, Rodriguez-Alcalde D, Redondo PD, Cubiella J, Murcia Ó, Escalante M, Gratacós-Ginès J, Pocurull A, Daca-Alvarez M, Luzko I, Sánchez A, Herrera-Pariente C, Ocaña T, Carballal S, Elizalde I, Castellví-Bel S, Fernández-Esparrach G, Castells A, Balaguer F, Moreira L. Endoscopic surveillance for familial intestinal gastric cancer in low-incidence areas: An effective strategy. Int J Cancer 2024; 154:124-132. [PMID: 37676082 DOI: 10.1002/ijc.34714] [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: 06/25/2023] [Revised: 08/16/2023] [Accepted: 08/17/2023] [Indexed: 09/08/2023]
Abstract
While clinical practice guidelines for hereditary diffuse gastric cancer are well established, there is no consensus on the approach for familial intestinal gastric cancer (FIGC). In low-incidence gastric cancer (GC) areas such as the United States or most European countries, there are no evidence-based recommendations on endoscopic assessment in FIGC families. We aim to describe the yield of GC surveillance in these families, and to identify epidemiological risk factors for the development of GC and its precursor lesions. This is a multicenter observational study involving nine tertiary Spanish hospitals, in which all individuals fulfilling FIGC criteria who underwent endoscopic surveillance were included between 1991 and 2020. Forty-one healthy individuals of 31 families were recruited. The median number of upper gastrointestinal endoscopies per individual was 3 (interquartile range, IQR, 1-4). The median interval time between tests was 2 years (IQR 1.5-2.5), and the median follow-up was 9 years (IQR 3-14.5). In 18 (43.9%) subjects, a precursor lesion of GC was found during follow-up, and in 2 (4.9%), an early GC was identified, in which curative treatment was offered. Helicobacter pylori (Hp) infection proved to be independently associated with an increased risk of developing precursor lesions or GC, adjusted by age, gender and follow-up, with an Odds Ratio of 6.443 (1.36-30.6, P value .019). We present the first outcomes that support endoscopic surveillance with biopsies and detection of Hp in FIGC families, although the periodicity has yet to be defined.
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Affiliation(s)
- Joan Llach
- Department of Gastroenterology, Hospital Clínic Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain
| | | | - Ana Guerra
- Complejo Hospitalario de Navarra, Navarra, Spain
| | - Beatriz Peñas
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Hospital Universitario Ramón y Cajal, Madrid, Spain
| | | | | | - Joaquin Cubiella
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Grupo de Investigación en Oncología Digestiva-Ourense, Hospital Universitario de Ourense, Ourense, Spain
| | - Óscar Murcia
- Hospital General Universitario de Alicante, Valencia, Spain
| | | | - Jordi Gratacós-Ginès
- Department of Gastroenterology, Hospital Clínic Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain
| | - Anna Pocurull
- Department of Gastroenterology, Hospital Clínic Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain
| | - Maria Daca-Alvarez
- Department of Gastroenterology, Hospital Clínic Barcelona, Barcelona, Spain
- IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain
| | - Irina Luzko
- Department of Gastroenterology, Hospital Clínic Barcelona, Barcelona, Spain
| | - Ariadna Sánchez
- Department of Gastroenterology, Hospital Clínic Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain
| | - Cristina Herrera-Pariente
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain
| | - Teresa Ocaña
- Department of Gastroenterology, Hospital Clínic Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain
| | - Sabela Carballal
- Department of Gastroenterology, Hospital Clínic Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain
| | - Ignasi Elizalde
- Department of Gastroenterology, Hospital Clínic Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain
| | - Sergi Castellví-Bel
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain
| | - Glòria Fernández-Esparrach
- Department of Gastroenterology, Hospital Clínic Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain
- Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain
| | - Antoni Castells
- Department of Gastroenterology, Hospital Clínic Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain
- Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain
| | - Francesc Balaguer
- Department of Gastroenterology, Hospital Clínic Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain
- Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain
| | - Leticia Moreira
- Department of Gastroenterology, Hospital Clínic Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain
- Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain
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4
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Thrift AP, Wenker TN, El-Serag HB. Global burden of gastric cancer: epidemiological trends, risk factors, screening and prevention. Nat Rev Clin Oncol 2023; 20:338-349. [PMID: 36959359 DOI: 10.1038/s41571-023-00747-0] [Citation(s) in RCA: 291] [Impact Index Per Article: 145.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/21/2023] [Indexed: 03/25/2023]
Abstract
Gastric cancer remains a major cause of cancer-related mortality worldwide. The temporal trends for this malignancy, however, are dynamic, and reports from the past decade indicate important declines in some regions and demographic groups, as well as a few notable exceptions in which gastric cancer rates are either stable or increasing. Two main anatomical subtypes of gastric cancer exist, non-cardia and cardia, with different temporal trends and risk factors (such as obesity and reflux for cardia gastric cancer and Helicobacter pylori infection for non-cardia gastric cancer). Shifts in the distribution of anatomical locations have been detected in several high-incidence regions. H. pylori is an important aetiological factor for gastric cancer; importantly, the anticipated long-term findings from studies examining the effect of H. pylori eradication on the risk of (re)developing gastric cancer have emerged in the past few years. In this Review, we highlight the latest trends in incidence and mortality using an evidence-based approach. We make the best possible inferences, including clinical and public health inference, on the basis of the quality of the evidence available, and highlight burning questions as well as gaps in knowledge and public health practice that need to be addressed to reduce gastric cancer burden worldwide.
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Affiliation(s)
- Aaron P Thrift
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Theresa Nguyen Wenker
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA
| | - Hashem B El-Serag
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
- Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA.
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5
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Backert S, Linz B, Tegtmeyer N. Helicobacter pylori-Induced Host Cell DNA Damage and Genetics of Gastric Cancer Development. Curr Top Microbiol Immunol 2023; 444:185-206. [PMID: 38231219 DOI: 10.1007/978-3-031-47331-9_7] [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: 01/18/2024]
Abstract
Gastric cancer is a very serious and deadly disease worldwide with about one million new cases every year. Most gastric cancer subtypes are associated with genetic and epigenetic aberrations caused by chromosome instability, microsatellite instability or Epstein-Barr virus infection. Another risk factor is an infection with Helicobacter pylori, which also triggers severe alterations in the host genome. This pathogen expresses an extraordinary repertoire of virulence determinants that take over control of important host cell signaling functions. In fact, H. pylori is a paradigm of persistent infection, chronic inflammation and cellular destruction. In particular, H. pylori profoundly induces chromosomal DNA damage by introducing double-strand breaks (DSBs) followed by genomic instability. DSBs appear in response to oxidative stress and pro-inflammatory transcription during the S-phase of the epithelial cell cycle, which mainly depends on the presence of the bacterial cag pathogenicity island (cagPAI)-encoded type IV secretion system (T4SS). This scenario is closely connected with the T4SS-mediated injection of ADP-glycero-β-D-manno-heptose (ADP-heptose) and oncoprotein CagA. While ADP-heptose links transcription factor NF-κB-induced innate immune signaling with RNA-loop-mediated DNA replication stress and introduction of DSBs, intracellular CagA targets the tumor suppressor BRCA1. The latter scenario promotes BRCAness, a disease characterized by the deficiency of effective DSB repair. In addition, genetic studies of patients demonstrated the presence of gastric cancer-associated single nucleotide polymorphisms (SNPs) in immune-regulatory and other genes as well as specific pathogenic germline variants in several crucial genes involved in homologous recombination and DNA repair, all of which are connected to H. pylori infection. Here we review the molecular mechanisms leading to chromosomal DNA damage and specific genetic aberrations in the presence or absence of H. pylori infection, and discuss their importance in gastric carcinogenesis.
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Affiliation(s)
- Steffen Backert
- Division of Microbiology, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058, Erlangen, Germany.
| | - Bodo Linz
- Division of Microbiology, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058, Erlangen, Germany
| | - Nicole Tegtmeyer
- Division of Microbiology, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058, Erlangen, Germany.
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6
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Jelassi R, Dhouioui S, Ben Salah H, Saidi N, Mzoughi N, Ammi R, Bouratbine A, Aoun K, Zidi I, Chelbi H. rs401502 and rs11575934 Polymorphisms of the IL-12 Receptor Beta 1 Gene are Protective Against Colorectal Carcinogenesis. Front Genet 2022; 13:864419. [PMID: 35646062 PMCID: PMC9136319 DOI: 10.3389/fgene.2022.864419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Colorectal cancer (CRC) is a major public health problem worldwide and in Tunisia. It ranks among the main cancers in terms of incidence and cancer-related cause of death. Its pathogenesis is currently considered to be multifactorial involving genetic and environmental factors. Recent studies have suggested that the gene encoding the β1 subunit of the IL-12 receptor, an important pro-inflammatory cytokine of the anti-tumor response, could be involved in the susceptibility to inherited CRC. Hence, it would be interesting to study the role of single nucleotide polymorphisms (SNPs) within the IL-12RB1 gene (rs401502 and rs11575934) in CRC susceptibility. Aim: Our purpose was to assess whether genetic variants IL-12RB1 +1196G/C (rs401502) and IL-12RB1 +705A/G (rs11575934) within the IL-12RB1 gene are associated with the sporadic CRC risk. Methods: A total of 110 Tunisian patients with sporadic CRC and 141 healthy control subjects were included in this study. Genotyping was performed by high-resolution melting (HRM) analysis. All results were confirmed by direct DNA sequencing or PCR-RFLP methods. Later, the allele frequencies and genotype distribution were established and compared between the control group and CRC patients. Results: The obtained results showed that the two target SNPs were in Hardy–Weinberg equilibrium (HWE) in both patients and controls. Minor allele frequencies of rs401502 SNP were 16.4% in CRC cases and 23.8% in controls. Mutant allele of rs11575934 SNP was present with 21.4% in CRC patients and 29.8% in control group. An association study showed a significant association of two target polymorphisms with CRC, according to the dominant genetic model with OR = 0.577, 95% CI = [0.343 to 0.972], p = 0.038 and OR = 0.547, 95% CI = [0.328 to 0.911], p = 0.02, respectively. Conclusion: In this study, we found, for the first time, a potential protective effect of two SNPs in the IL-12RB1 gene, namely rs401502 and rs11575934, in sporadic colorectal cancer in Tunisians.
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Affiliation(s)
- Refka Jelassi
- Laboratory of Medical Parasitology, Biotechnology, and Biomolecules, Pasteur Institute of Tunis, University Tunis El Manar, Tunis, Tunisia
- Faculty of Sciences Bizerte, University of Carthage, Tunis, Tunisia
| | - Sabrine Dhouioui
- Laboratory Microorganisms and Active Biomolecules, Faculty of Sciences of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Hamza Ben Salah
- Laboratory of Medical Parasitology, Biotechnology, and Biomolecules, Pasteur Institute of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Nasreddine Saidi
- Laboratory of Medical Parasitology, Biotechnology, and Biomolecules, Pasteur Institute of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Nabiha Mzoughi
- Laboratory of Medical Parasitology, Biotechnology, and Biomolecules, Pasteur Institute of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Radhia Ammi
- External Consultants Service Pasteur Institute of Tunis, Tunis, Tunisia
| | - Aida Bouratbine
- Laboratory of Medical Parasitology, Biotechnology, and Biomolecules, Pasteur Institute of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Karim Aoun
- Laboratory of Medical Parasitology, Biotechnology, and Biomolecules, Pasteur Institute of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Ines Zidi
- Laboratory Microorganisms and Active Biomolecules, Faculty of Sciences of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Hanen Chelbi
- Laboratory of Medical Parasitology, Biotechnology, and Biomolecules, Pasteur Institute of Tunis, University Tunis El Manar, Tunis, Tunisia
- *Correspondence: Hanen Chelbi,
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7
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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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8
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Gullo I, van der Post RS, Carneiro F. Recent advances in the pathology of heritable gastric cancer syndromes. Histopathology 2020; 78:125-147. [PMID: 33382491 DOI: 10.1111/his.14228] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 08/04/2020] [Indexed: 02/06/2023]
Abstract
Despite the relative rarity of hereditary gastric cancer syndromes, the prompt recognition of their specific clinical features and histopathological characteristics is pivotal in offering patients the most appropriate treatment. In this article, we address the three major inherited syndromes that primarily affect the stomach: hereditary diffuse gastric cancer (HDGC), caused by germline variants in CDH1 and CTNNA1; gastric adenocarcinoma and proximal polyposis of the stomach, caused by germline mutations in promoter 1B of APC; and familial intestinal gastric cancer, which has a poorly defined genetic cause. The main focus will be on HDGC, in light of the recent publication of updated clinical practice guidelines and emerging concepts regarding HDGC histopathology. In particular, we describe the broad morphological spectrum of HDGC lesions, stressing the importance of recognising indolent and aggressive phenotypes. Moreover, we discuss the increased risk of gastric (pre)malignancies developing in patients with other well-defined hereditary cancer syndromes, such as familial adenomatous polyposis, Lynch syndrome, Peutz-Jeghers syndrome, juvenile polyposis, Li-Fraumeni syndrome, and hereditary breast and ovarian cancer syndrome.
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Affiliation(s)
- Irene Gullo
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ), Porto, Portugal.,Department of Pathology, Faculty of Medicine of the University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal
| | - Rachel S van der Post
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Fátima Carneiro
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ), Porto, Portugal.,Department of Pathology, Faculty of Medicine of the University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal
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9
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Belhadj S, Terradas M, Munoz-Torres PM, Aiza G, Navarro M, Capellá G, Valle L. Candidate genes for hereditary colorectal cancer: Mutational screening and systematic review. Hum Mutat 2020; 41:1563-1576. [PMID: 32449991 DOI: 10.1002/humu.24057] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 01/30/2020] [Accepted: 05/19/2020] [Indexed: 12/19/2022]
Abstract
Genome-wide approaches applied for the identification of new hereditary colorectal cancer (CRC) genes, identified several potential causal genes, including RPS20, IL12RB1, LIMK2, POLE2, MRE11, POT1, FAN1, WIF1, HNRNPA0, SEMA4A, FOCAD, PTPN12, LRP6, POLQ, BLM, MCM9, and the epigenetic inactivation of PTPRJ. Here we attempted to validate the association between variants in these genes and nonpolyposis CRC by performing a mutational screening of the genes and PTPRJ promoter methylation analysis in 473 familial/early-onset CRC cases, a systematic review of the published cases, and assessment of allele frequencies in control population. In the studied cohort, 24 (5%) carriers of (predicted) deleterious variants in the studied genes and no constitutional PTPRJ epimutations were identified. Assessment of allele frequencies in controls compared with familial/early-onset patients with CRC showed association with increased nonpolyposis CRC risk of disruptive variants in RPS20, IL12RB1, POLE2, MRE11 and POT1, and of FAN1 c.149T>G (p.Met50Arg). Lack of association was demonstrated for LIMK2, PTPN12, LRP6, PTPRJ, POLQ, BLM, MCM9 and FOCAD variants. Additional studies are required to provide conclusive evidence for SEMA4A, WIF1, HNRNPA0 c.-110G>C, and FOCAD large deletions.
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Affiliation(s)
- Sami Belhadj
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.,Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - Mariona Terradas
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.,Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - Pau M Munoz-Torres
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.,Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - Gemma Aiza
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.,Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain
| | - Matilde Navarro
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.,Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain
| | - Gabriel Capellá
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.,Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain
| | - Laura Valle
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.,Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain
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10
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Terradas M, Capellá G, Valle L. Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes. J Clin Med 2020; 9:jcm9061954. [PMID: 32585810 PMCID: PMC7355797 DOI: 10.3390/jcm9061954] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/16/2020] [Accepted: 06/18/2020] [Indexed: 12/30/2022] Open
Abstract
In the past two decades, multiple studies have been undertaken to elucidate the genetic cause of the predisposition to mismatch repair (MMR)-proficient nonpolyposis colorectal cancer (CRC). Here, we present the proposed candidate genes according to their involvement in specific pathways considered relevant in hereditary CRC and/or colorectal carcinogenesis. To date, only pathogenic variants in RPS20 may be convincedly linked to hereditary CRC. Nevertheless, accumulated evidence supports the involvement in the CRC predisposition of other genes, including MRE11, BARD1, POT1, BUB1B, POLE2, BRF1, IL12RB1, PTPN12, or the epigenetic alteration of PTPRJ. The contribution of the identified candidate genes to familial/early onset MMR-proficient nonpolyposis CRC, if any, is extremely small, suggesting that other factors, such as the accumulation of low risk CRC alleles, shared environmental exposures, and/or gene-environmental interactions, may explain the missing heritability in CRC.
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Affiliation(s)
- Mariona Terradas
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; (M.T.); (G.C.)
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain
| | - Gabriel Capellá
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; (M.T.); (G.C.)
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Laura Valle
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; (M.T.); (G.C.)
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-93-260-7145
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11
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van der Post RS, Oliveira C, Guilford P, Carneiro F. Hereditary gastric cancer: what's new? Update 2013-2018. Fam Cancer 2019; 18:363-367. [PMID: 30989426 DOI: 10.1007/s10689-019-00127-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Around 10-20% of gastric cancer patients have relatives with a diagnosis of GC and in 1-3% of patients a genetic cause can be confirmed. Histopathologically, GC is classified into intestinal-type, with glandular growth, and diffuse-type with poorly cohesive growth pattern often with signet ring cells. Familial or hereditary GC is classified into hereditary diffuse GC (HDGC), familial intestinal GC (FIGC) and polyposis forms. This review focuses on recent research findings and new concepts of hereditary GC.
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Affiliation(s)
- Rachel S van der Post
- Department of Pathology, Radboud university medical centre, Nijmegen, The Netherlands
| | - Carla Oliveira
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Júlio Amaral de Carvalho, 45, 4200-135, Porto, Portugal.,Ipatimup - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,Faculty of Medicine, University of Porto, Porto, Portugal
| | - Parry Guilford
- Cancer Genetics Laboratory, Department of Biochemistry, Centre for Translational Cancer Research, Te Aho Matatū, University of Otago, Dunedin, Aotearoa, New Zealand
| | - Fátima Carneiro
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Júlio Amaral de Carvalho, 45, 4200-135, Porto, Portugal. .,Ipatimup - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal. .,Faculty of Medicine, University of Porto, Porto, Portugal.
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12
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Emerging Concepts in Gastric Neoplasia: Heritable Gastric Cancers and Polyposis Disorders. Surg Pathol Clin 2018; 10:931-945. [PMID: 29103540 DOI: 10.1016/j.path.2017.07.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hereditary gastric cancer is a relatively rare disease with specific clinical and histopathologic characteristics. Hereditary gastric cancer of the diffuse type is predominantly caused by germline mutations in CDH1. The inherited cause of familial intestinal gastric cancer is unknown. Gastric adenocarcinoma and proximal polyposis of the stomach is a hereditary cancer syndrome caused by germline mutations in promoter 1B of APC. Other well-defined cancer syndromes, such as Lynch, Li-Fraumeni, and hereditary breast or ovarian cancer syndromes, are associated with increased risk of gastric cancer. This article reviews important histopathologic features and emerging concepts regarding gastric carcinogenesis in these syndromes.
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13
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Chubb D, Broderick P, Dobbins SE, Frampton M, Kinnersley B, Penegar S, Price A, Ma YP, Sherborne AL, Palles C, Timofeeva MN, Bishop DT, Dunlop MG, Tomlinson I, Houlston RS. Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer. Nat Commun 2016; 7:11883. [PMID: 27329137 PMCID: PMC4917884 DOI: 10.1038/ncomms11883] [Citation(s) in RCA: 126] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 05/09/2016] [Indexed: 12/30/2022] Open
Abstract
Colorectal cancer (CRC) displays a complex pattern of inheritance. It is postulated that much of the missing heritability of CRC is enshrined in high-impact rare alleles, which are mechanistically and clinically important. In this study, we assay the impact of rare germline mutations on CRC, analysing high-coverage exome sequencing data on 1,006 early-onset familial CRC cases and 1,609 healthy controls, with additional sequencing and array data on up to 5,552 cases and 6,792 controls. We identify highly penetrant rare mutations in 16% of familial CRC. Although the majority of these reside in known genes, we identify POT1, POLE2 and MRE11 as candidate CRC genes. We did not identify any coding low-frequency alleles (1-5%) with moderate effect. Our study clarifies the genetic architecture of CRC and probably discounts the existence of further major high-penetrance susceptibility genes, which individually account for >1% of the familial risk. Our results inform future study design and provide a resource for contextualizing the impact of new CRC genes.
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Affiliation(s)
- Daniel Chubb
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK
| | - Peter Broderick
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK
| | - Sara E. Dobbins
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK
| | - Matthew Frampton
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK
| | - Ben Kinnersley
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK
| | - Steven Penegar
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK
| | - Amy Price
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK
| | - Yussanne P. Ma
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK
| | - Amy L. Sherborne
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK
| | - Claire Palles
- Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
| | - Maria N. Timofeeva
- Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK
| | - D. Timothy Bishop
- Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds LS9 7TF, UK
| | - Malcolm G. Dunlop
- Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK
| | - Ian Tomlinson
- Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
| | - Richard S. Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK
- Division of Pathology, The Institute of Cancer Research, London SM2 5NG, UK
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14
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Tan RYC, Ngeow J. Hereditary diffuse gastric cancer: What the clinician should know. World J Gastrointest Oncol 2015; 7:153-160. [PMID: 26380059 PMCID: PMC4569593 DOI: 10.4251/wjgo.v7.i9.153] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 08/05/2015] [Indexed: 02/05/2023] Open
Abstract
Hereditary diffuse gastric cancer (HDGC) is an inherited autosomal dominant syndrome with a penetrance of up to 80% affecting diverse geographic populations. While it has been shown to be caused mainly by germline alterations in the E-cadherin gene (CDH1), problematically, the genetic diagnosis remains unknown in up to 60% of patients. Given the important knowledge gaps regarding the syndrome, asymptomatic carriers of CDH1 mutations are advised for a prophylactic total gastrectomy. Intensive annual endoscopic surveillance is the alternative for carriers who decline gastrectomy. As HDGCs have a prolonged indolent phase, this provides a window of opportunity for surveillance and treatment. Recent findings of other gene defects in CTNNA1 and MAP3K6, as well as further characterization of CDH1 mutations and their pathogenicity will change the way HDGC patients are counselled for screening, surveillance and treatment. This review will bring the reader up to date with these changes and discuss future directions for research; namely more accurate risk stratification and surveillance methods to improve clinical care of HDGC patients.
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