Hereditary Gastric and Breast Cancer Syndrome: CDH1: One Genotype with Multiple Phenotypes

Description:

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.

See more ebooks for you at here:

Rates and outcomes of testing for lynch syndrome in a national colorectal cancer screening programme

Building Evidence for Clinical Use of Pharmacogenomics and Reimbursement for Testing

Study on TFF1 and PALB2 gene variants associated with gastric carcinoma risk in the Chinese Han population

Prevalence and factors associated with atrophic gastritis and intestinal metaplasia: A multivariate, hospital-based, statistical analysis

The effect of the Flemish breast cancer screening program on breast cancer-specific mortality: A case-referent study

Gastric cancer epidemiology from 2009 to 2019 in Dnipro Region, Ukraine

Table of contents :

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

……………….

 

Foreword
Any oncologist would agree that the dissimilarity between cancer of the stomach and breast excels all others. Etiology, prognosis, pathophysiology, and treatment, for example, differ in such a way that one can rightfully speak of two entirely different diseases. Besides, they originate in organs far away from each other in the human body with no direct or indirect relationship. The purpose, control, and functions are quite different as well. On top, breasts start to grow at the onset of puberty, where the stomach functions already in utero. Indeed, both are at the ends of the spectrum.
Non-cardiac gastric cancer can be subdivided into two distinct pathologic entities, intestinal and diffuse, which have different epidemiologic and prognostic features. The latter leads to gastric oncogenesis through the E-cadherin–catenin complex, which plays a critical role in the maintenance of normal tissue architecture. Mutation of any of its components results in the loss of cell-to-cell adhesion, thereby contributing to neoplasia. E-cadherin/CDH1 gene germline mutations have been recognized in families with an inherited predisposition to diffuse gastric cancer. Amplification and/or overexpression of putative trophic factors have also been observed in gastric cancer. Finally, Helicobacter pylori (H. pylori) infection is also involved through various mechanisms. Gastric cancer is traditionally linked to poor food preservation and food infections. Apart from refrigeration and freezing, food can be preserved through smoke, salt, and against clostridium with nitrates. All these additives prove carcinogenic in one way or the other. In those regions in the world where refrigeration is possible, gastric cancer declines. Electricity and hygiene are in this sense essential to prevent cancer. Avoidance of helicobacter infection or eradication is another way. Treatment of local cancer is surgery with, in some welldefined cases, radiotherapy. Systemic adjuvant treatment conveys little benefit. In case of metastatic disease, only chemotherapy or, in some cases, targeted therapy can be offered. But prognosis remains universally poor with only 30% of patients surviving the first 5 years.

The epidemiology of breast cancer is entirely different and mainly related to pubertal developmental interferences on the target organ. Ionizing irradiation, calorie-rich nutrition, (xeno-) estrogens, and poor physical activity are all involved and have major influence on the developing organ. Screening and early detection are pivotal and, once occurred, local surgery with or without radiotherapy is the cornerstone of a most effective treatment. The benefit of adjuvant treatments is well established. And for systemic disease a plentitude of treatments is available, depending on the molecular profile. Prognosis is quite good in most patients with a disease-free survival amounting to beyond 80% after 5 years.

And yet, this book deals about similarities.

These two extremes in oncology share an interesting origin that becomes evident during oncogenesis. Both gastric and breast cancer are prevalent and mortalities in absolute numbers score high without much variation in the last decade. Both cancers are a collection of different diseases and will generate alternative signal regulating pathways as many other cancers might do. But the similarity is deeper, at the genomic level. Both share a unique germline mutation that puzzled researchers for already several decades now.

More than any work before, the content of this work illustrates clearly how modern oncologists look at clinically different diseases. Central is the mutation in the CDH1 gene that causes an autosomal-dominant gastric and breast cancer syndrome. The mutational variants can be classified into the usual missense, non-sense, splicing, insertions, and deletions. In diffuse gastric tumors, the predominant defects are exon skipping, which causes in-frame deletions. By contrast, most mutations found in infiltrating lobular breast cancers are out-of-frame mutations, which are predicted to yield secreted truncated E-cadherin fragments.

CDH1 encodes for E-cadherin, which is an essential molecule for epithelial homeostasis and control of cell adhesion. Individuals with germline mutations in the CDH1 gene consistently demonstrated absence of loss of heterozygosity, suggesting the hypothesis that CDH1 promoter methylation might function as the “second genetic hit” in carcinogenesis. Loss or aberrant expression results in disturbed cell-to-cell adhesion, increased cell invasion, and metastasis. Myosin V and F-actin, and many other factors, are required for the formation of a continuous apicolateral E-cadherin layer, the zonula adherens. When this is missing because of mutation in the CDH1 gene, subsequent diseases can develop.

Compelling experimental evidence exists for a potent invasion suppressor role of this cell-to-cell adhesion molecule E-cadherin. In addition, a tumor suppressor effect has been suggested. Partial or complete loss of E-cadherin expression correlates with malignancy. Loss of E-cadherin expression increases diffuse growth pattern in both lobular and ductal types of breast cancer and to some extent in other cancers. Indeed, CDH1 are also found in a small, clinically unimportant, proportion of colorectal cancers. The diffuse growth pattern is well illustrated in typical histological features such as the ”Indian file” growth pattern.

One of the main questions is: Why mostly the breast and stomach are affected while germline mutation confers a risk in all organs? For sure, the relationship between the mutation and cancer is too simplistic to explain oncogenesis in both organs and a “first hit” has to be considered. In the breast, one can think of the hormonal environment with epigenetic imprinting, which is known to be carcinogenic. In the stomach, CDH1 promoter methylation is the second hit in more than half of the sporadic diffuse gastric carcinoma cases harboring CDH1 mutations. This “second hit” theory is well received when considering that initiation precedes promotion in which cell dis-adhesion typically plays a prominent role…