In this book the editors and authors provide a comprehensive overview on basic research and clinical aspects of hereditary breast and gastric tumors. In particular, this updated editorial work aims to suggest guidelines for the clinical management of patients with hereditary diffuse gastric and lobular breast cancer. Special attention is given to E-cadherin (CDH1 gene) germline mutations, genetic screening approaches, the underlying molecular mechanisms and pathological and microscopic features. In addition, the book aims to define clinical criteria for genetic screening, and highlights current surgical treatment and clinical approaches for asymptomatic mutation carriers. Other inherited predispositions involving gastric and breast carcinoma are discussed as well.
Divided into eight sections, the book starts by providing an epidemiological overview of gastric and breast cancers, followed by a section dealing with new descriptions of genetic pathways in hereditary cancer predispositions. The third section focuses on pathological features of the diseases, in an effort to bridge the gap between discovery and cancer therapy development. Subsequent sections of the book are dedicated to endoscopy and breast imaging, as well as risk-reducing surgeries to curb the risk of developing cancer. The sixth section focuses on the generation of ideas for the identification of targets and novel treatment strategies. Finally, in the seventh section the authors share the story of two patients and their experiences with the diagnosis and treatment of hereditary cancer.
This multidisciplinary book brings together multiple disciplines in science and technology; specifically, medicine, surgery and biology. The majority of authors are members of the International Gastric Cancer Linkage Consortium (IGCLC) and of the European Cancer Prevention Organization (EJCPO), with relevant experience in this context. Offering in-depth insights into hereditary cancers, this book represents essential reading for students, researchers, and specialists who want to extend their knowledge on hereditary gastric and breast cancers.
Author(s): Giovanni Corso, Paolo Veronesi, Franco Roviello
Publisher: Springer
Year: 2023
Language: English
Pages: 411
City: Cham
Foreword
Contents
About the Editors
Part I: Epidemiology
1: Family History and the Risk of Breast and Gastric Cancer
1.1 Familial Breast Cancer
1.2 Familial Gastric Cancer
References
2: Worldwide CDH1 Germline Mutation Frequency
2.1 Introduction
2.2 Gastric Cancer Epidemiology
2.3 Frequency of E-Cadherin Germline Mutations
2.4 Conclusion
References
3: Hereditary Lobular Breast Cancer: A Newly Defined Syndrome
3.1 Introduction
3.2 History of HDGC Guidelines
3.3 Criteria for Screening the CDH1 Gene in LBC
3.4 Other Breast Cancer Predisposition Genes Associated with LBC
3.5 LBC and Family History But No PV Detected
3.6 Classification and Pathogenesis
3.7 Conclusion
References
Part II: Genetics
4: Genetic Counselling and Prevention in Families at High Risk for HDGC and Other Hereditary Syndromes
4.1 Introduction
4.2 Hereditary Diffuse Gastric Cancer
4.3 Other Hereditary Cancer Syndromes
4.4 Genetic Testing Evaluation
4.5 Surveillance
4.6 Conclusion
References
5: CTNNA1, a New HDGC Gene: Inactivating Mechanisms and Driven Phenotypes
5.1 Introduction
5.2 Brief Overview on CTNNA1/αE-catenin
5.3 αE-catenin Connects the Adherens Junction Complex with the Actin Cytoskeleton
5.3.1 αE-catenin and the Adherens Junction Complex
5.3.2 αE-catenin and the Actin Cytoskeleton
5.3.3 Direct vsIndirect Binding of the Adherens Junction Complex to the Actin Cytoskeleton
5.4 CTNNA1 Germline Variants Predispose to HDGC
5.4.1 Brief Overview of HDGC
5.4.2 HDGC Guidelines for CTNNA1 Germline Variant Carriers
5.4.3 Clinical Classification of CTNNA1 Germline Variants and Distribution in HDGC Ascertained and Non-ascertained Cohorts
5.4.4 Distribution of CTNNA1 Germline Variants in HDGC and Non-HDGC Families
5.4.5 Genotype-Phenotype Correlations in CTNNA1 Germline Variant Carriers
5.5 CTNNA1 Germline Missense Variants Predispose to MDPT2, But Not HDGC
5.6 Possible Mechanisms Underlying Tumor Formation and Development Due to CTNNA1/αE-catenin Impairment
5.6.1 Wnt/beta-catenin Signaling Pathway
5.6.2 NF-kappaB Signaling Pathway
5.6.3 Hippo-YAP Signaling Pathway
5.6.4 Hedgehog Signaling Pathway
5.7 Concluding Remarks
References
6: Revisiting the Biological and Clinical Impact of CDH1 Missense Variants
6.1 Introduction
6.2 CDH1 Missense Variants in Distinct Clinical Phenotypes
6.3 Insights from Population Variation and Geographic Distribution of Variants
6.4 Integrative Pipeline to Determine Variant Functional Significance
6.4.1 Familial and Population Data
6.4.2 In Silico Models
6.4.3 In Vitro Assays
6.4.4 In Vivo Approaches
6.5 Molecular Mechanisms Triggered by CDH1 Variants
6.6 Conclusion and Future Challenges
References
7: Other Syndromes and Genes Associated with Gastric Cancer Predisposition
7.1 Introduction
7.2 HDGC
7.3 GAPPS
7.4 FIGC
7.5 Non-polyposis Syndromes
7.5.1 Lynch Syndrome
7.5.2 Li-Fraumeni Syndrome
7.5.3 BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer
7.6 Polyposis Syndromes
7.6.1 Familial Adenomatous Polyposis
7.6.2 MUTYH-Associated Polyposis
7.6.3 Juvenile Polyposis Syndrome
7.6.4 Peutz-Jeghers Syndrome
7.6.5 PTEN Hamartoma Tumor Syndrome
7.7 Conclusions
References
8: Computer-Assisted Interpretation of Cancer-Predisposing Variants
8.1 The Problem of Variant Interpretation in Genetics
8.1.1 Clinical Databases
8.1.2 Standard Guidelines for the Interpretation of Sequence Variations
8.1.3 Computer-Assisted Prioritization of Variants
8.1.4 Machine Learning-Assisted Prioritization
References
Part III: Pathology
9: Histopathology of Hereditary Diffuse Gastric Cancer: From Grossing and 3D Microscopy to Immunophenotypic and Molecular Prof...
9.1 Introduction
9.2 The Indolent Phenotype of HDGC: 3D Modelling, Morphological, Immunohistochemical and Molecular Features
9.3 Prophylactic Total Gastrectomy in CDH1 Carriers
9.4 HDGC Progression: Aggressive Gastric Phenotype in CDH1 Carriers
9.5 Conclusion
References
10: HER2 Testing in Breast and Gastric Cancer with CDH1 Germline Mutations
10.1 Introduction
10.2 The Biological Nature of HER2
10.3 HER2 Testing: Current Testing Guidelines
10.3.1 Breast Cancer
10.3.2 Gastric Cancer
10.4 HER2 Testing in Hereditary Breast and Gastric Cancers
10.4.1 Hereditary Lobular Breast Cancer
10.4.2 Hereditary Diffuse Gastric Cancer
References
11: Pathology and Somatic Alterations in Hereditary Lobular Breast Cancers
11.1 Introduction
11.2 Pathology of Lobular Breast Cancer
11.3 CDH1 Aberrations: The Hallmark of Lobular Breast Cancer
11.4 The Genomic Landscape of Lobular Breast Cancer
11.5 Conclusion
References
Part IV: Endoscopy and Imaging
12: Endoscopy: Is There Anything New?
12.1 Text Content and Description
References
13: Endoscopic Surveillance and Pathology of Biopsies in CDH1, CTNNA1, and HDGC-Like Families
13.1 Endoscopic Surveillance in CDH1 and CTNNA1
13.2 Type of Lesions Found in Gastroscopic Surveillance in CDH1 (Panel Fig. 13.1)
13.3 Considerations on the Goals of Surveillance Endoscopy
13.4 Considerations on Biopsies (Random Versus Targeted) During Surveillance
13.5 Endoscopic Surveillance in CTNNA1 Mutation Carriers
13.6 What Is Known on Gastric Inlet Patches in Mutation Carriers?
13.7 What Is Known on Helicobacter pylori Infection in HDGC?
13.8 Endoscopic Surveillance in HDGC-Like Families
References
14: Lobular Carcinoma of the Breast: Spectrum of Imaging Findings and New Emerging Technologies on the Horizon
14.1 Introduction
14.2 Imaging Findings of ILC
References
Part V: Surgery
15: Prophylactic Total Gastrectomy: Techniques
15.1 Introduction
15.2 Timing
15.3 Technique
15.4 Lymphaadenectomy
15.5 Other Issues
15.6 Adverse Effects
15.7 Conclusions
References
16: Prophylactic Total Gastrectomy: How Many?
16.1 Introduction
16.2 Criteria for CDH1 Genetic Test
16.3 Penetrance Risk
16.4 Indication
16.5 Geographic Distribution
16.6 Conclusion
References
17: Hereditary Lobular Breast Cancer Syndrome: Role of Surgery
17.1 Introduction
17.2 Hereditary Lobular Breast Cancer
17.3 CDH1 Gene Mutation Carriers´ Management
17.4 Prophylactic Surgery
17.5 Technical and Clinical Implications of Prophylactic Mastectomy
17.6 Conclusions
References
18: Breast Reconstruction
18.1 Prophylactic Mastectomies in Healthy Women
18.1.1 Submuscular Implant-Based Reconstructions
18.1.2 Submuscular ADM-Assisted Reconstructions
18.1.3 Skin-Reducing Pattern in Large and Ptotic Breasts
18.1.4 Prepectoral Reconstructions
18.1.5 Reconstruction After Nipple-Areola-Sparing Robotic Surgery
18.1.6 Combined Procedures (Fat Grafting) for Conservative Implant-Based Reconstructions
18.2 Cancer Patients Requiring Mastectomy at the Tumor Site and Prophylactic Mastectomy on the Healthy Breast
18.3 Risk-Reducing Surgery After the Treatment of Primary Cancer
18.3.1 Autologous Reconstruction: DIEP Flap for Bilateral Reconstructions
18.3.2 Latissimus Dorsi Flap and Implant
18.3.3 ADM-Assisted Implant-Based Reconstructions and Prepectoral Reconstructions
References
Part VI: New Issues
19: Psychological Burden and Preferences in CDH1 Mutation Carriers: Beyond the Cancer Diagnosis
19.1 From the Body to the Mind: Clinical and Psychological Challenges in Gene Mutation Carriers
19.1.1 The Uncertainty Hole in Cancer Genetic Testing
19.1.1.1 Emotional Responses and Psychological Consequences of Genetic Susceptibility Testing
19.2 Inner and External Mechanisms Behind the Construction of the Mutation Carriers´ Preferences
19.2.1 A Landmark in the Management of CDH1 Mutation Carriers: Introducing Psychological Consultation into Clinical Practice
19.3 Conclusions
References
20: Drug Repurposing in Gastric Cancer: Current Status and Future Perspectives
20.1 Gastric Cancer Facts
20.2 Therapeutic Agents Currently Approved for Gastric Cancer
20.3 Drug Repurposing as a Complementary Strategy to the Traditional De Novo Drug Development
20.4 Strategies for DR
20.5 Non-cancer Repurposed Drugs in Gastric Cancer: Pre-clinical Studies and Clinical Trials
20.6 Concluding Remarks and Future Perspectives
References
21: The Chemoprevention of Hereditary Diffuse Gastric Cancer
21.1 Introduction
21.2 HDGC Pathology
21.3 Is HDGC Amenable to Chemoprevention?
21.4 Targeting CDH1-Null Epithelial Cells
21.5 A Model of E-Cadherin-Null Cell Vulnerability
21.6 Synthetic Lethal Drug Screens
21.7 Candidate Chemoprevention Drugs
21.8 Minimisation of Drug Side Effects
21.9 Future Development Path
21.10 Conclusion
References
22: Malformations and Malformative Syndromes Associated with CDH1
22.1 Introduction
22.2 CDH1 Association with Cleft Lip/Palate
22.2.1 Clinical Description of CLP
22.2.2 Genetic Causes of CLP
22.2.3 A Literature Review of CDH1 Association with CLP
22.3 CDH1 Association with Blepharocheilodontic Syndrome (BCDS)
22.3.1 Clinical Description of BCDS
22.3.2 Genes Associated with BCDS
22.4 Physiopathology
22.4.1 Function of E-Cadherin
22.4.2 Modifying Factors
22.5 Genotype-Phenotype Correlation
22.6 Conclusion
References
23: Hereditary Breast Cancer Non-CDH1 Associated
23.1 Introduction
23.2 Genetics of BC
23.2.1 High-Penetrance Genes
23.2.1.1 BRCA1-BRCA2: Hereditary Breast and Ovarian Cancer Syndrome
23.2.1.2 TP53: Li-Fraumeni Syndrome
23.2.1.3 PTEN: Cowden Syndrome/PTEN Hamartoma Syndrome
23.2.1.4 PALB2
23.2.1.5 STK11: Peutz-Jeghers Syndrome
23.2.2 Moderate-Penetrance Genes
23.2.2.1 CHEK2
23.2.2.2 ATM (Ataxia Telangectasia Mutated Gene)
23.2.2.3 BARD1
23.2.3 Low-Penetrance Genes
23.2.3.1 RAD51 and RAD51 Related Genes (Including RAD51C, RAD51D, and XRCC2)
23.2.3.2 BRIP1 (BRCA1 Interacting Protein C-Terminal Helicase 1)
23.2.3.3 NF1 (Neurofibromatosis Type 1)
23.2.3.4 MRN Complex (Including MRE11, RAD50, and NBS1)
23.3 Conclusions
References
Part VII: Patient Advocacy
24: My Hereditary Gastric Cancer
25: Hereditary Breast Cancer Syndrome, My Experience
Part VIII: Miscellaneous
26: β-Hemoglobinopathies and Early Onset of Cancers in Adulthood: Epidemiology in Southeastern Asia and Brunei with Emphasis f...
26.1 Introduction
26.2 Population Structure and Cancer Burden in Southeast Asia and Brunei
26.3 Early Age Breast Cancers in Southeastern Asia and Brunei
26.4 Other Cancers with Early Age of Onset in Brunei: Emphasis for Colorectal and Neurological Cancers
26.5 Thalassemia and Hemoglobinopathies in Southeast Asia and Brunei
26.6 Malays Have Breast Cancers with Younger Age of Onset and Worse Prognosis than Chinese
26.7 Genes at 11p15.5 Chromosomal Region Which Associate Both with Early Age Breast Cancers and Neurological Tumors
26.8 Conclusions
References
