Prophylactic Gastrectomy Research Articles

Hereditary Diffuse Gastric Cancer: Surveillance Endoscopy is Not Enough to Save Lives

Hereditary Diffuse Gastric Cancer: Surveillance Endoscopy is Not Enough to Save Lives

Identification of an intronic single nucleotide polymorphism leading to allele dropout during validation of a CDH1 sequencing assay: implications for designing polymerase chain reaction-based assays

PurposeThe CDH1 gene encodes the cell adhesion protein E-cadherin, and CDH1 germline mutations are associated with hereditary diffuse gastric cancer. Identification of individuals at high risk of developing diffuse gastric cancer affords the opportunity for endoscopic screening or elective prophylactic gastrectomy. We set out to develop a CDH1 sequencing assay for clinical use. MethodsAll exons of the CDH1 gene were amplified and sequenced with published and modified primers. ResultsWhile validating the assay, we encountered a case in which a single nucleotide polymorphism located in intron 15 led to allele dropout and therefore to a false-negative result. The polymorphism leading to allele dropout was located within a primer-binding sequence, five bases away from the 3′ end of the primer. A frameshift mutation in exon 15 was detected by an alternative primer that binds away from the polymorphic site. A search of the University of California Santa Cruz single nucleotide polymorphism database revealed other polymorphisms located within primer-binding sites. A total of 12 primers in nine primer sets were modified to minimize allele dropout risk. ConclusionThe approach of designing primers to avoid known single nucleotide polymorphisms can be generalized to the design of any polymerase chain reaction-based assay and should be employed whenever possible.

Hereditary Gastric Carcinoma: At Management Cross Roads

Introduction: Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominant cancer susceptibility syndrome characterized by early onset diffuse gastric cancer and lobular breast cancer. Germ-line truncating mutations in the E-cadherin gene (CDH1) have been shown to underlie about 30% of HDGC families of various ethnic backgrounds. Here, we report a family with HDGC.FigureCase 1: A 69- year-old, female with a history of familial gastric and breast carcinoma, was diagnosed with lobular carcinoma of right breast at 43 years of age. Genetic screening for BRCA1 and BRCA2 was negative. Full sequencing of CDH1 gene done last year was positive for 2287G>T deleterious mutation. Since then she is under chromoendoscopic surveillance at six monthly interval, as she is still weighing the offer of prophylactic gastrectomy. Detailed family history was obtained and pedigree constructed (Fig. 1). Case 2: A 55-year-old, female presented for consultation about being tested positive for CDH1 gene mutation. She was found to be the first cousin of case 1 and having same deleterious mutation of CDH1 gene at the same locus. She under went EGD and was discovered to have linitis plastica with histology revealing invasive, poorly differentiated adenocarcinoma, signet cell type. Patient is now ongoing evaluation for total gastric resection. Discussion: Germline CDH1-associated gastric cancer develops diffusely throughout the stomach wall and foci of malignant cells often underlie a grossly and histologically normal surface epithelium. Therefore serial conventional EGD, chromoendoscopy or endoscopic ultrasound may not be a useful screen for this patient population. Our cases illustrate the controversies surrounding the optimal management of germline E-cadherin mutation patients and their families. The average age of onset of gastric cancer in germline CDH1- positive families is 38 years, but it has been documented in teens as well. The question arises as to what is the ideal timing for surgical intervention and screening, given our case 1 has been asymptomatic up till now but on the other hand, case 2 being already positive for malignancy.[figure1]

Hereditary diffuse gastric cancer: Natural history, pathology, screening limitations, and prophylactic total gastrectomy in CDH1 mutation carriers

4500 Background: Hereditary diffuse gastric cancer (HDGC) is a potentially fatal disease that occurs due to mutations in the E- cadherin (CDH1) gene, as discovered in 1998. Its penetrance ranges between 70–80%. Its morbidity and mortality can be altered favorably through genetic counseling, germline mutation testing, and highly-targeted management that includes prophylactic total gastrectomy. Lobular breast cancer has been identified as an integral lesion in HDGC. Methods: This international collaborative group on HDGC is comprised of 56 mutation-positive families, which is the world’s largest resource of such families. Cancer diagnoses were verified with pathology slides/tissue block review when possible, or reports. Genetic counseling covering the pros and cons of mutation testing, screening and its limitations, and the option of prophylactic total gastrectomy was provided. Results: Findings on 56 HDGC mutation-positive families show carrier testing to have been performed on 267 individuals, of which 123 were CDH1 mutation positive. Prophylactic gastrectomies were performed on 14 families involving 50 individuals. Occult cancer was diagnosed in 31 (31/39=79.5%; results are pending on the remaining 11), based upon pathology and verbal reports. Five individuals underwent prophylactic gastrectomy prior to genetic counseling, 3 of whom later tested negative for mutations. In one of these remarkable HDGC families, 11 first cousins who tested positive for the CDH1 mutation underwent prophylactic total gastrectomy. On a post-surgery questionnaire, they each stated that the decision for the prophylactic procedure was the “right one” for them. In each case, a parent had died of HDGC sequelae, adding to the cousins’ acceptance of DNA testing and surgery. They considered their post-operative nutritional programs to have been acceptable. Conclusion: HDGC and its life-threatening sequelae were significantly ameliorated in CDH1 mutation carriers through total prophylactic gastrectomy in patients at enormous lifetime risk for HDGC. Decision for mutation testing and surgery may be more acceptable through intensive education in concert with a compassionate management team. No significant financial relationships to disclose.

Preemptive Total Gastrectomy for Hereditary Gastric Cancer

Hereditary gastric cancer is a recently described clinical syndrome, associated with truncating mutation of the E-cadherin gene, named CDH1. It is characterized by autosomal dominant transmission, presentation at an early age, and with diffuse type of gastric adenocarcinoma. Clinical management of these patients is challenging and includes intense endoscopic surveillance or prophylactic gastrectomy, which is associated with short- and long-term morbidity. We report four patients submitted to a prophylactic gastrectomy performed in members of three families with hereditary gastric cancer in a tertiary referral center in Mexico City. These are the first Hispanic families with hereditary gastric cancer reported in the literature.

Preoperative Work-up in Asymptomatic Patients Undergoing Roux-en-Y Gastric Bypass: Is Endoscopy Mandatory?

We aimed to determine before Roux-en-Y gastric bypass (RYGBP) in asymptomatic morbidly obese patients: 1) the prevalence of abnormal findings at upper gastrointestinal (UGI) endoscopy; 2) Helicobacter pylori (HP) status; 3) clinical consequences of these findings; and 4) associated costs. We retrospectively reviewed 468 consecutive patients, excluded those with UGI symptoms, drug intake or previous UGI endoscopy/surgery, and analyzed findings in the 319 remaining patients (68%). There were abnormal findings in 147 patients (46%), including 54 hiatal hernias and 146 parietal (i.e. mucosal or submucosal) lesions. The most significant were 7 ulcers and 2 gastric polyposis. HP was detected (using CLO-test) in 124 patients (39%). Histopathological examination of biopsies was abnormal in 109/161 patients (68%), and disclosed mainly chronic gastritis (n=98). Abnormal findings were more frequent in HP-positive compared to HP-negative patients (94 vs 51%, P<0.001). Findings had clinical implications in only 4% of patients: delayed surgery (7 ulcers), prophylactic gastrectomy (2 gastric polyposis), unnecessary work-up (3 irrelevant/false-positive diagnoses), and inclusion in a screening program (1 Barrett's esophagus). Mean cost of complete UGI work-up was 389 euro/patient. Asymptomatic morbidly obese patients frequently harbour UGI lesions warranting UGI work-up before RYGBP. However, routine endoscopy presents drawbacks. We propose a less invasive strategy which reduces costs and limits false-positive results and the subsequent investigations that they require. In our series, it would have missed two gastric polyposis only, for which no formal recommendation has yet been issued. This strategy could be a valuable alternative to routine UGI endoscopy before RYGBP in asymptomatic patients.

Cancer gastrique héréditaire diffus

Some diffuse type gastric cancers are of hereditary origin. Their histological characteristics are poor cell differentiation and the presence of signet-ring cells. The cause is a mutation of the CDH1 gene which is responsible for abnormal E-cadherin. The transmission mode is autosomal dominant. Because of serious prognosis of symptomatic hereditary diffuse gastric cancer (HDGC), the high penetrance of the gene (67% in men and 83% in women) and the young age of onset of these tumors (before the age of 40), a prophylactic gastrectomy is recommended to the mutation carriers. The search for the genetic mutation should be recommended to families corresponding to clinical criteria such as the number of affected family members, degree of relationship and age of onset of these tumors.

Prophylactic Laparoscopic Total Gastrectomy for Hereditary Diffuse Gastric Cancer

Introduction: Ten percent of gastric cancer (GC) cases are familial. Of the familial cases, one-third results from a mutation in the tumor suppressor gene CDH1, which normally encodes for a transmembrane protein, E-cadherin. The loss of E-cadherin leaves patients at high risk for developing diffuse gastric cancer. These individuals with 'hereditary diffuse gastric cancer' (HDGC) have a high mortality if early diagnosis is not made. Despite its clear genetic origin, optimal management of HDGC family members is controversial. The utility and efficacy of current cancer screening programs for mutation carriers are unproven, which has given credence to the recommendation for prophylactic gastrectomy. We report the first prophylactic laparoscopic total gastrectomy. Case Report: A 53 year-old Caucasian woman was referred to our clinic for a family history of gastric cancer. After an extensive pedigree analysis, it was apparent that her family had an autosomal dominant form of diffuse gastric cancer. The patient was asymptomatic, had no past medical history and her exam was unremarkable. She had the CDH1 gene mutation. Previous upper endoscopies with gastric biopsies were normal. After genetic counseling, she elected to undergo a prophylactic laparoscopic hand-assisted total gastrectomy. The gross specimen appeared normal. Microscopically there were 11 foci of invasive adenocarcinoma limited to the lamina propria in a background of diffuse (signet ring cell) adenocarcinoma in-situ. She had return of bowel function by day 3 and was discharged home on postoperative day 4. More than one-year after the surgery she is disease free and doing well. Discussion: Genomics is playing a greater role in clinical medicine, as exemplified by our case, in which a patient with a CDH1 mutation within a family of HDGC underwent prophylactic laparoscopic gastrectomy. Despite the normal-appearing stomach, there were many microscopic foci of adenocarcinoma. Thus, the surgery was curative. Our case highlights the importance of taking a thorough family history and obtaining a pedigree analysis. In addition, it is evident that endoscopic screening in HDGC cannot rule out diffuse GC, as the stomach and biopsies can be normal despite the presence of adenocarcinoma. Therefore, our case supports the recommendation for prophylactic gastrectomy in HDGC. Furthermore, we report that successful prophylactic gastrectomy can be accomplished laparoscopically.

A model to infer the pathogenic significance of CDH1 germline missense variants

Germline mutations of the E-cadherin gene (CDH1) are involved in the tumorigenesis of hereditary diffuse gastric cancer (HDGC). Recent studies have highlighted the lifesaving potential of total prophylactic gastrectomy for CDH1 germline mutation carriers. In this regard, CDH1 germline mutations of the missense type represent a clinical burden in genetic counseling, as their pathogenic relevance is not straightforward. In this work, we have outlined a possible multivariate approach to infer the significance of such variants. We reviewed all HDGC-associated E-cadherin germline missense mutations reported to date. The information collected included: co-segregation of the mutation within pedigrees, frequency in healthy population control, recurrence in independent families, and functional in vitro and in silico data. We used the neighbor-joining method to group mutations according to the collected information and assessed the robustness of mutation clusters with a bootstrap test. CDH1 germline missense variants were classified according to the parameters defined in the multivariate analysis. This analysis allowed the distribution of the variants into two distinct groups: neutral variants vs mutations. The model described in this study provides an important tool that can ultimately improve the genetic counseling offered to the carriers of the germline CDH1 missense variants.

Genetics of Hereditary Diffuse Gastric Cancer: Progress and Future Challenges

Hereditary diffuse gastric cancer (HDGC) is a rare cancer susceptibility syndrome. One third of HDGC syndrome families carry germline mutations of the E-cadherin gene. Owing to the limitation of the current endoscopic screening techniques and since no chemoprevention is yet available, total prophylactic gastrectomy is the only option offered to carriers of inactivating mutations in genetic counseling. In this regard, 30% of the E-cadherin germline mutations reported to date are of the missense type, and since their pathogenic significance is not straightforward, the management of carriers of such mutations is suboptimal. In the absence of definitive clinical evidence, functional in vitro studies together with in silico analysis have been used to infer the pathogenic significance of germline missense mutations. Since most of the HDGC families reported to date are negative for E-cadherin germline mutations, the identification of alternative genes underlying the tumorigenesis of diffuse gastric has become an important target for research.

Prophylactic Gastrectomy for Hereditary Diffuse Gastric Cancer Syndrome

Germline mutations in the E-cadherin gene, CDH1, were recently identified in families with hereditary diffuse gastric cancer. The efficacy of endoscopic surveillance by current methods is largely ineffective because most tumors spread diffusely. There has been little evidence that prophylactic gastrectomy should be performed in patients with the genetic mutation, and few data are available on the outcomes of operations in patients with the CDH1 mutation undergoing prophylactic gastrectomy. We report the outcomes of patients with the CDH1 mutation who have undergone prophylactic gastrectomy in the year 2003 to 2004. After genetic counseling and informed consent, two patients underwent total gastrectomy with Roux-en-Y reconstruction. Demographic information, pedigree analysis, preoperative screening results, operative course, and postoperative data, including complications, were collected and reviewed for each patient. Pathologic examination of the stomach revealed no evidence of in situ or invasive carcinoma. There were no operative complications. Both patients reported diarrhea and moderate weight loss. There were no other postoperative complications. Prophylactic gastrectomy can be performed safely, without mortality or severe morbidity, in patients with CDH1 mutations, and should be curative in this population of patients.

Familial gastric cancer – clinical management

The clinical management of familial gastric cancer is the same as that for sporadic gastric cancer at the current time. As the causative mutations for these cases are identified this should lead to the development of specific treatments which target the molecular abnormality. The only germline mutations identified so far occur within the E-cadherin gene (CDHI) and they account for approximately 30% of familial gastric cancer cases. When index patients fulfilling the clinical criteria for hereditary diffuse gastric cancer syndrome have a CDHI mutation identified then genetic testing of asymptomatic relatives should be considered. The clinical sequelae of testing positive for such a mutation are profound and therefore it is essential that counselling is given prior to genetic testing. The management options are surveillance endoscopy and prophylactic gastrectomy. In this chapter the practicalities of genetic testing are discussed as well as the pros and cons of the two management options. It is essential that experience of these rare families is pooled so that surveillance and treatment can be optimised in the future.

E-cadherin mutation-associated diffuse gastric adenocarcinoma: penetrance and non-penetrance

According to the published medical literature to date, prophylactic gastrectomy undertaken in the context of carriage of a germline truncating E-cadherin mutation and an appropriate positive family history will lead to the discovery of occult foci of adenocarcinoma in all gastrectomy specimens. We describe the first published case of a patient whose prophylactic gastrectomy in this setting failed to reveal any dysplastic or malignant foci. Furthermore the patient's nephew, who was found to carry an identical E-cadherin mutation on family screening and also underwent prophylactic gastrectomy, was shown to have multi-focal diffuse adenocarcinoma after analysis of the gastrectomy specimen. Both patients were also found to have penetrant genetic haemochromatosis. Within this case, we discuss the clinical manifestations and penetrance of germline E-cadherin mutations and the difficult decisions facing both clinicians and families with this mutation. We also speculate on how these patients' undiagnosed genetic haemochromatosis may have influenced the pathology encountered.

Prophylaktische Chirurgie des Magens

A premalignant condition with high risk of gastric cancer is the basis for prophylactic gastric surgery. The germline mutation carrier in the E-cadherin gene has a lifetime risk of 70-80% for diffuse-type gastric cancer, and high-grade intraepithelial neoplasia has a 60-70% gastric cancer risk. Other premalignant conditions such as HNPCC syndrome (5% gastric cancer) and low-grade intraepithelial neoplasia (10% risk) are moderate risk factors for developing gastric cancer. They do not justify prophylactic surgery, but surveillance is required. In case high-grade intraepithelial neoplasia or early gastric cancer is detected, an option is extended radicality with total gastrectomy instead of subtotal gastric resection. Positive family history and early-onset of gastric cancer are risk factors to consider when discussing prophylactic gastrectomy or extended radicality.

Characterization of a Recurrent Germ Line Mutation of the E-Cadherin Gene: Implications for Genetic Testing and Clinical Management

To identify germ line CDH1 mutations in hereditary diffuse gastric cancer (HDGC) families and develop guidelines for management of at risk individuals. We ascertained 31 HDGC previously unreported families, including 10 isolated early-onset diffuse gastric cancer (DGC) cases. Screening for CDH1 germ line mutations was done by denaturing high-performance liquid chromatography and automated DNA sequencing. We identified eight inactivating and one missense CDH1 germ line mutation. The missense mutation conferred in vitro loss of protein function. Two families had the previously described 1003C>T nonsense mutation. Haplotype analysis revealed this to be a recurrent and not a founder mutation. Thirty-six percent (5 of 14) of the families with a documented DGC diagnosed before the age of 50 and other cases of gastric cancer carried CDH1 germ line mutations. Two of 10 isolated cases of DGC in individuals ages <35 years harbored CDH1 germ line mutations. One mutation positive family was ascertained through a family history of lobular breast cancer (LBC) and another through an individual with both DGC and LBC. Occult DGC was identified in five of six prophylactic gastrectomies done on asymptomatic, endoscopically negative 1003C>T mutation carriers. In addition to families with a strong history of early-onset DGC, CDH1 mutation screening should be offered to isolated cases of DGC in individuals ages <35 years and for families with multiple cases of LBC, with any history of DGC or unspecified GI malignancies. Prophylactic gastrectomy is potentially a lifesaving procedure and clinical breast screening is recommended for asymptomatic mutation carriers.

Gastric cancer: New genetic developments

Gastric cancer's (GC) incidence shows large geographic differences worldwide with the lowest rates occurring in most Western industrialized countries including the United States and the United Kingdom; in contrast, relatively high rates of GC occur in Japan, Korea, China, and South America, particularly Chile. The Laurén classification system classifies GC under two major histopathological variants: 1) an intestinal type and 2) a diffuse type. The intestinal type is more common in the general population, more likely to be sporadic and related to environmental factors such as diet, particularly salted fish and meat as well as smoked foods, cigarette smoking, and alcohol use. It exhibits components of glandular, solid, or intestinal architecture, as well as tubular structures. On the other hand, the diffuse type is more likely to have a primary genetic etiology, a subset of which, known as hereditary diffuse gastric cancer (HDGC), is due to the E-cadherin (CDH1) germline mutation. The diffuse type pathology is characterized by poorly cohesive clusters of cells which infiltrate the gastric wall, leading to its widespread thickening and rigidity of the gastric wall, known as linitis plastica. Helicobacter pylori infection is associated with risk for both the intestinal and diffuse varieties of gastric cancer. Germline truncating mutations of the CDH1 gene, which codes for the E-cadherin protein, were initially identified in three Maori families from New Zealand that were predisposed to diffuse GC. Since then, similar mutations have been described in more than 40 additional HDGC families of diverse ethnic backgrounds. It is noteworthy that two-thirds of HDGC families reported to date have proved negative for the CDH1 germline mutation. A number of candidate genes have been identified through analysis of the molecular biology of E-cadherin. Patients with evidence of the CDH1 germline mutation in the context of a family history of HDGC must be considered as candidates for prophylactic gastrectomy, given the extreme difficulty in its early diagnosis and its exceedingly poor prognosis when there is regional or distant spread. Specifically, the E-cadherin cytoplasmic tail interacts with catenins, assembling the cell-adhesion complex involved with E-cadherin mediated cell:cell adhesion. Beta-catenin and gamma-catenin compete for the same binding site on the E-cadherin cytoplasmic tail, directly linking the adhesion complex to the cytoskeleton through alpha-catenin. Beta-catenin gene (CTNNB1) mutations have been described predominantly in intestinal-type gastric cancers and CTNNB1 gene amplification and overexpression have recently been described in a mixed-type gastric cancer. This paper reviews the genetics of both intestinal and diffuse types of gastric carcinoma, their differential diagnosis, molecular genetics, pathology, and, when known, their mode of genetic transmission within families.

CDH1 associated gastric cancer: a report of a family and review of the literature

Aims Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominant inherited form of gastric cancer associated with inactivating germline mutations in the CDH1 gene. We set out to outline the role of CDH1 in HDGC. Investigation of a family suspected as having HDGC is discussed. The role of surgery in the management of affected individuals is then examined. Methods A search was conducted of Medline and the National Library of Medicine to identify key articles concerning CDH1 gene mutations, familial gastric cancer and gastrectomy. Further, relevant articles were obtained by manual scanning of the reference lists of identified papers. Mutation-specific CDH1 genetic testing was performed on six living family members and on gastric tissue obtained from two deceased members. Results CDH1 mutations cause inactivation of the cell adhesion protein E-cadherin. Carriers of the CDH1 germline gene mutation develop an aggressive, diffuse, submucosal gastric cancer at an early age. Current endoscopic screening is ineffective at detecting HDGC. The presence of a CDH1 germline gene mutation was confirmed in both deceased family members and also in four of the six living members tested. Conclusion Genetic counselling and CDH1 gene mutation testing is indicated in families with suspected HDGC. In the absence of a satisfactory surveillance mechanism, prophylactic total gastrectomy would appear to be an appropriate therapeutic option in mutation carriers.

Gastric Cancer — Keeping It in the Family

Genetic predisposition to gastric cancer was first proven in families with recurrent diffuse gastric cancer, where the disease was found to segregate with germline mutations of the E-cadherin (CDH1) gene. Subsequent guidelines defining the various types of inherited gastric cancer predisposition syndromes have identified that these represent 1–3% of gastric cancer worldwide. Mutational analyses of families worldwide suggest that germline CDH1 mutations account for approximately 40% of hereditary diffuse gastric cancer. A significant proportion of these mutations are associated with functional derangement of the E-cadherin protein. The lifetime risk of gastric cancer in patients with CDH1 mutation has been estimated at 70–80%. Individuals from these families are also at increased risk of other cancers, including colon, ovarian, protate and breast (in particular, lobular carcinoma). In addition to genetic counseling, these patients should be offered prophylactic gastrectomies as currently available screening methods may not be sufficient to identify occult disease. Several other candidate genes are currently being tested for their roles in inherited gastric cancer syndromes.

Model of the early development of diffuse gastric cancer in E-cadherin mutation carriers and its implications for patient screening.

Hereditary diffuse gastric cancer (HDGC) is a familial cancer syndrome caused, in 30-40% of cases, by germline mutations of the E-cadherin/CDH1 gene. The presence of clinically undetectable early gastric cancers has been previously reported in ten of ten prophylactic gastrectomies from germline E-cadherin mutation carriers. In the present study, detailed maps of the distribution of invasive cancers in nine of these ten stomachs were produced and precursor lesions of HDGC searched for. The nine gastrectomy specimens contained from 1 to 161 foci of early diffuse gastric cancer, occupying 0.005-2.96% of the gastric mucosa. Seven specimens contained focal in situ signet ring carcinoma. Pagetoid spread of signet ring cells was observed beneath the epithelial lining of gastric foveolae/glands. Helicobacter pylori organisms and associated pathology were absent from all cases. Two-dimensional maps of the gastrectomy specimens revealed lesions throughout the gastric mucosa without evidence of antral clustering. The distribution and size of the cancers in the gastrectomy specimens indicate that standard endoscopic screening with random or geographically targeted biopsies is unlikely to provide sufficiently sensitive clinical screening for at-risk individuals. An in situ precursor of signet ring carcinoma was identified and a model for neoplastic progression in the setting of HDGC is proposed.

Prophylactic gastrectomy for CDH1 mutation carriers.

Gastric cancer is difficult to diagnose at an early stage. Signs and symptoms of the disease often only occur when advanced or metastatic disease is present. A very small number of gastric cancers are hereditary. The mutation to the E-cadherin gene has high penetrance and confers a lifetime risk of gastric cancer of 80% for carriers. Because of the high penetrance of the mutation and the difficulty of diagnosing gastric cancer at an early stage, carriers of the mutation may be candidates for prophylactic gastrectomy. Although limited data are available about the complications and outcomes associated with prophylactic gastrectomy, nurses should be knowledgeable about prophylactic surgery for hereditary cancers and prepared to answer patients' questions about their prevention.