Hereditary diffuse gastric cancer (HDGC) is the only known cancer syndrome that is dominated by gastric adenocarcinoma. HDGC is caused by germline mutation of the CDH1 gene that encodes the cell ...adhesion protein E-cadherin. Mutation carriers have a more than 70% lifetime risk of developing DGC and an elevated risk of lobular breast cancer. Intestinaltype gastric cancer is not part of the syndrome. Clinical management of HDGC involves predictive genetic testing beginning at or near 16 years of age. It is recommended that mutation carriers undergo prophylactic gastrectomy after about 20 years of age. Anatomical mapping has demonstrated that mutation carriers develop multifocal stage T1a signet ring cell carcinomas, with up to several hundred foci being observed in single stomachs. These foci develop following the somatic inactivation of the second CDH1 allele by mechanisms that include DNA promoter hypermethylation.
The importance of loss of the cell-cell adhesion molecule E-cadherin (encoded by CDH1) to tumor progression is well established. However, CDH1 germ-line mutations predispose to the cancer ...susceptibility syndrome hereditary diffuse gastric cancer (HDGC), suggesting a role for E-cadherin in tumor initiation. The earliest indications of cancer in the stomachs of CDH1 mutation carriers are microscopic foci of intramucosal signet-ring cell carcinoma (SRCC; designated "eHDGC"). Here, we used N-methyl-N-nitrosourea (MNU) to promote gastric carcinogenesis in wild-type (wt) and cdh1(+/-) mice. MNU induced a variety of gastric tumors; however, intramucosal SRCC developed with an 11 times higher incidence in cdh1(+/-) mice compared with wt mice. The murine SRCC resembled the human eHDGCs in that they were hypoproliferative, lacked nuclear beta-catenin accumulation, and had reduced membrane localization of E-cadherin and its interacting junctional proteins. The down-regulation of E-cadherin in the murine SRCCs confirmed the importance of the second CDH1 hit to the initiation of diffuse gastric cancer. CDH1 promoter hypermethylation has been proposed to be a major second hit in advanced HDGC; however, its contribution to eHDGC was unknown. We thus examined a series of human eHDGC and detected CDH1 promoter methylation in 50% of foci. Promoter methylation was accompanied by reduced wt CDH1 mRNA levels in the foci and had a monoclonal pattern, consistent with an epigenetic initiation of disease. Together, these findings provide compelling evidence for a deficiency in cell-to-cell adhesion being sufficient to initiate diffuse gastric cancer in the absence of hyperproliferation and beta-catenin activation.
Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused ...by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.
This article focuses on the diagnosis and management of familial gastric cancer, particularly hereditary diffuse gastric cancer (HDGC). First, existing consensus guidelines are discussed and then the ...pathology and genetics of HDGC are reviewed. Second, patient management is covered, including surveillance gastroscopy, prophylactic total gastrectomy, and management of the risk of breast cancer.
The initial development of diffuse gastric cancer (DGC) is poorly understood. The study of E-cadherin (CDH1) germ line mutation carriers predisposed to DGC provides a rare opportunity to elucidate ...the genetic and biological events surrounding disease initiation. Samples from various stages of hereditary and sporadic DGC were investigated to determine general mechanisms underlying early DGC development. Paraffin-embedded tissues from 13 CDH1 mutation carriers and from 10 sporadic early DGC cases were analyzed. Immunofluorescence and immunohistochemistry using differentiation, proliferation, and adhesion markers showed that DGC initiation seems to occur at the proliferative zone (the upper neck) of the gastric epithelium and correlates with absent or reduced expression of junctional proteins (beta-actin, p120, Lin-7). Slow proliferation of neoplastic cells at the upper gastric neck leads to the formation of intramucosal signet-ring cell carcinoma (SRCC) displaying differentiated features. As shown by immunolabeling, invasion from SRCC lesions beyond the gastric mucosa is associated with poor differentiation, increased proliferation, activation of the c-Src system, and an epithelial-mesenchymal transition. Our results provide a molecular description of the early development of DGC and explain the relationship between the two main DGC types, poorly differentiated carcinoma and SRCC: both share their origin, but SRCC develops following cancer cell differentiation and seems relatively indolent in its intramucosal stage.
Hereditary diffuse gastric cancer (HDGC) is the only known predisposition syndrome dominated by carcinoma of the stomach and with a recognised genetic cause. Germline mutations in the E-cadherin gene ...(CDH1) co-segregate with the disease in about half of the families with multiple diffuse gastric cancer. In these families, identification of the CDH1 mutation allows for clinical measures to be taken. Importantly, clinical intervention is likely to be therapeutic and associated with tolerable morbidity. This review is thus aimed at providing a current overview of the clinical management and the underlying biology of HDGC.
Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, ...surgery, surveillance strategies, pathology reporting and the patient's perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.
25-30% of families fulfilling the criteria for hereditary diffuse gastric cancer have germline mutations of the CDH1 (E-cadherin) gene. In light of new data and advancement of technologies, a ...multidisciplinary workshop was convened to discuss genetic testing, surgery, endoscopy and pathology reporting. The updated recommendations include broadening of CDH1 testing criteria such that: histological confirmation of diffuse gastric criteria is only required for one family member; inclusion of individuals with diffuse gastric cancer before the age of 40 years without a family history; and inclusion of individuals and families with diagnoses of both diffuse gastric cancer (including one before the age of 50 years) and lobular breast cancer. Testing is considered appropriate from the age of consent following counselling and discussion with a multidisciplinary team. In addition to direct sequencing, large genomic rearrangements should be sought. Annual mammography and breast MRI from the age of 35 years is recommended for women due to the increased risk for lobular breast cancer. In mutation positive individuals prophylactic total gastrectomy at a centre of excellence should be strongly considered. Protocolised endoscopic surveillance in centres with endoscopists and pathologists experienced with these patients is recommended for: those opting not to have gastrectomy, those with mutations of undetermined significance, and in those families for whom no germline mutation is yet identified. The systematic histological study of prophylactic gastrectomies almost universally shows pre-invasive lesions including in situ signet ring carcinoma with pagetoid spread of signet ring cells. Expert histopathological confirmation of these early lesions is recommended.
Persisting ethnic disparities in cancer incidence and outcomes exist between Māori and non‐Māori in Aotearoa/New Zealand. It is difficult to disentangle the complex interplay of environmental and ...genetic factors that contribute to the variation in cancer statistics between these two groups. In Māori, the sites of highest cancer incidence are the prostate in men, breast in women and lung in both – the next most common cancers in Māori are colorectal and stomach cancer. This paper discusses colorectal, prostate and stomach cancer in Māori to illustrate selected issues that impact on cancer care. Colorectal cancer is discussed to illustrate the importance of accurate cancer statistics to focus management strategies. Prostate cancer in Māori is reviewed – an area where cultural factors impact on care delivery. Sporadic stomach cancer in New Zealand is used to show how sub‐classification of different types of cancer can be important and illustrate the breadth of putative causal factors. Then follows an overview of developments in hereditary gastric cancer in New Zealand in the last 15 years, showing how successful clinical and research partnerships can improve patient outcomes. One example is the Kimi Hauora Clinic, which provides support to cancer patients, mutation carriers and their families, helping them navigate the interface with the many health‐care professionals involved in the multidisciplinary care of cancer patients in the 21st century.
Early mobilisation of orthopaedic patients undergoing elective surgery is driven by increasing pressure for early discharge. To facilitate this, the use of femoral nerve blocks (FNB) in joint ...replacement surgery i.e. arthroplasty has become increasingly popular as an effective analgesic modality. This is directly linked to a reduction in drug related side effects experienced by the patient, but femoral nerve blocks are not without patient related risks and complications. Residual nerve blocks not effectively assessed by nurses using a valid and reliable neurovascular assessment tool can result in a patient falling or having a ’near miss’. This paper as a result aims to re-examine the role of the practising orthopaedic nurse in using a neurovascular assessment tool for FNB and review the related problems experienced within one paradigm of clinical practice. The paper then concludes by recognising potential interventions that may aid and ensure patient safety.
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