Outcomes of Endoscopic Surveillance in Individuals With Genetic Predisposition to Hereditary Diffuse Gastric Cancer.

BACKGROUND & AIMS: Pathogenic germline variants in CDH1 are associated with risk for diffuse gastric cancer (DGC) and lobular breast cancer. The reported high incidence of DGC and limited sensitivity of endoscopy in detection have prompted recommendation for total prophylactic gastrectomy for carriers of pathogenic or likely pathogenic (PLP) germline variants of CDH1. Multigene panel tests have identified increasing numbers of carriers of PLP variants in CDH1 who lack a family history of DGC. We evaluated outcomes of endoscopic surveillance for carriers of PLP variants of CDH1 with and without family history of DGC. METHODS: Individuals from 13 families with germline PLP variants of CDH1 were evaluated at the Michigan Medicine Cancer Genetics Clinic from January 1998 through May 2018. Outcomes of esophagogastroduodenoscopy examinations, histopathology analyses, and surgery were compared between individuals with and without a family history of DGC. RESULTS: We identified 20 carriers of germline CDH1 PLP variants; they underwent endoscopic examinations and/or gastrectomy. None had abnormal findings visible during endoscopy. Signet ring cell carcinoma (SRCC) was detected in 12 of 20 subjects. All but 1 of the carcinomas were tiny and confined to the lamina propria, and 1 was transmural. Seven of 12 subjects who had SRCC reported no diagnoses of DGC in first-degree relatives and did not meet established criteria for CDH1 analysis based on a 3-generation family pedigree. CONCLUSIONS: More than half of individuals with germlines variants of CDH1 that are PLP had histopathologic evidence for DGC on endoscopy and/or gastrectomy. Family history of DGC and endoscopic findings therefore do not appear to be reliable determinants of risk of SRCC in individuals with genetic predisposition to DGC.

Therapeutic and prophylactic gastrectomy in a family with hereditary diffuse gastric cancer secondary to a CDH1 mutation: a case series.

BACKGROUND: Gastric cancer is the fifth most prevalent and the third most lethal cancer worldwide, causing approximately 720,000 deaths annually. Although most cases of gastric cancers are sporadic, one of its inherited forms, hereditary diffuse gastric cancer (HDGC), constitutes about 1-3% of cases. Interestingly, females in families with HDGC are also predisposed to developing lobular breast cancer (LBC). Recent analyses have identified loss-of-function germline mutations in cadherein-1 (CDH1) as a culprit in HDGC and LBC. This discovery fueled several sequencing analyses and case series reports analyzing the pattern of inheritance of CDH1 and its propensity to induce HDGC. In 2015, a multinational and multidisciplinary task force updated the guidelines and criteria for screening, diagnosing, and managing HDGC. CASE PRESENTATION: Here, we present a case series of three siblings with family history of HDGC who tested positive for the CDH1 mutation and describe their surgical treatment course, post-operative management, and follow-up as they pertain to the updated guidelines. CONCLUSIONS: Despite recent updates in guidelines in the diagnosis and management of HDGC, the disease remains challenging to address with patients given the high level of uncertainty and the comorbidities associated with prophylactic intervention. We strongly recommend that an interdisciplinary team inclusive of clinical and surgical oncologists, along with geneticists, social work, and psychological support, should follow the patients in a longitudinal and comprehensive manner in order to achieve full recovery and return to normalcy, as with our patients.

Total Gastrectomy for Hereditary Diffuse Gastric Cancer at a Single Center: Postsurgical Outcomes in 41 Patients.

OBJECTIVE: The aim of this study was to describe postoperative outcomes of total gastrectomy at our institution for patients with hereditary diffuse gastric cancer (HDGC). BACKGROUND: HDGC, which is mainly caused by germline mutations in the E-cadherin gene (CDH1), renders a lifetime risk of gastric cancer of up to 70%, prompting a recommendation for prophylactic total gastrectomy. METHODS: A prospective gastric cancer database identified 41 patients with CDH1 mutation who underwent total gastrectomy during 2005 to 2015. Perioperative, histopathologic, and long-term data were collected. RESULTS: Of the 41 patients undergoing total gastrectomy, median age was 47 years (range 20 to 71). There were 14 men and 27 women, with 25 open operations and 16 minimally invasive operations. Median length of stay was 7 days (range 4 to 50). In total, 11 patients (27%) experienced a complication requiring intervention, and there was 1 peri-operative mortality (2.5%). Thirty-five patients (85%) demonstrated 1 or more foci of intramucosal signet ring cell gastric cancer in the examined specimen. At 16 months median follow-up, the median weight loss was 4.7 kg (15% of preoperative weight). By 6 to 12 months postoperatively, weight patterns stabilized. Overall outcome was reported to be "as expected" by 40% of patients and "better than expected" by 45%. Patient-reported outcomes were similar to those of other patients undergoing total gastrectomy. CONCLUSION: Total gastrectomy should be considered for all CDH1 mutation carriers because of the high risk of invasive diffuse-type gastric cancer and lack of reliable surveillance options. Although most patients have durable weight loss after total gastrectomy, weights stabilize at about 6 to 12 months postoperatively, and patients report outcomes as being good to better than their preoperative expectations. No patients have developed gastric cancer recurrence after resections.

Prophylactic Laparoscopic Total Gastrectomy with Jejunal Pouch Reconstruction in Patients Carrying a CDH1 Germline Mutation.

BACKGROUND: For patients with an identified germline E-cadherin-1 (CDH1) mutation, prophylactic gastrectomy is the treatment of choice to eliminate the high risk of developing diffuse gastric cancer. Laparoscopic total gastrectomy with jejunal pouch reconstruction is a novel approach that may be especially suitable in these patients. METHODS: Patients with a germline CDH1 mutation who underwent prophylactic laparoscopic total gastrectomy with jejunal pouch were included in our prospective database. RESULTS: A total of 11 patients with a median age of 40 (22-61) years were included. The average operative time was 4:26 ± 0:49 h and the average blood loss was 219 ± 155 ml. Median length of hospital stay was 10 (7-27) days. In two patients, an esophagojejunal anastomotic leakage occurred (grade 4). The leakages were seen in patient numbers 2 and 3, which may be a result of a learning curve. The latter eight patients did not develop anastomotic leakage. Pulmonary complications occurred in one patient with atelectasis and in one patient with pneumonia (grade 2). The 60-day mortality rate was 0 %. Multiple foci of intramucosal diffuse gastric signet ring cell carcinoma were found in the resection specimen of 9/11 (82 %) patients. All 11/11 (100 %) resections were microscopically radical. CONCLUSIONS: Prophylactic laparoscopic total gastrectomy with jejunal pouch reconstruction in patients with a CDH1 germline mutation is feasible and safe. In 82 % of patients, foci of intramucosal diffuse gastric signet ring cell carcinoma in the resection specimen were found.

Hereditary gastric cancer.

In 1998, Guilford et al. identified the hereditary diffuse gastric cancer (HDGC) syndrome, caused by germline alterations at the CDH1 (E-cadherin) gene. To date, 141 probands harboring more than 100 different germline CDH1 alterations, mainly point mutations and large deletions, have been described. In mutation-positive individuals prophylactic total gastrectomy is recommended. The systematic histological study of prophylactic gastrectomies shows intramucosal signet-ring cell carcinoma and pre-invasive lesions including in situ signet ring carcinoma with pagetoid spread of signet ring cells. In 2011, a new hereditary gastric cancer syndrome was identified: gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). GAPPS is a unique gastric polyposis syndrome with a significant risk of gastric adenocarcinoma, characterized by the autosomal dominant transmission of fundic gland polyposis, with areas of dysplasia or intestinal-type GC, restricted to the proximal stomach, with no evidence of colorectal or duodenal polyposis or other heritable gastrointestinal cancer syndromes.

Hereditary diffuse gastric cancer: translation of CDH1 germline mutations into clinical practice.

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. Intestinal-type 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.

Germline mutation of the E-cadherin gene in three sibling cases with advanced gastric cancer: clinical consequences for the other family members.

BACKGROUND AND AIMS: Germline mutations in the E-cadherin (CDH1) gene have been found in families with hereditary diffuse gastric cancer (HDGC). These families are characterized by a highly penetrant susceptibility to diffuse gastric cancer with an autosomal dominant pattern of inheritance. We describe the clinical presentation of three sibling cases with advanced gastric cancer, the way of confirming the suspicion of underlying HDGC and the clinical management of the other healthy family members. METHODS: Screening for CDH1 germline mutation was carried out by denaturing high-performance liquid chromatography and automated DNA sequencing. The clinical suspicion of HDGC has been confirmed by identifying a frameshift mutation in exon 9 (1302_1303insA, 1306_1307delTT) of the E-cadherin gene. RESULTS: Eight of nine tested family members were positive for the CDH1 germline mutation. Prophylactic laparoscopic gastrectomies were performed in five mutation carriers. After pathological examination, we could identify intramucosal malignant signet-ring cell carcinoma in all resected stomachs. CONCLUSION: This report underlines that prophylactic gastrectomy remains the only option to eliminate the high risk for gastric cancer in CDH1 mutation carriers.

Hereditary diffuse gastric cancer: surgery, surveillance and unanswered questions.

Hereditary diffuse gastric cancer (HDGC) is an inherited cancer-susceptibility syndrome characterized by autosomal dominance and high penetrance. In 30-50% of cases, a causative germline mutation in CDH1, the E-cadherin gene, may be identified. Female carriers of CDH1 mutations also have an increased (20-40%) risk of lobular breast cancer. Endoscopic surveillance of patients with CDH1 mutations is ineffective because early foci of HDGC are typically small and underlie normal mucosa. CDH1 mutation carriers are therefore offered the option of prophylactic gastrectomy, which commonly reveals early foci of invasive signet-ring cell cancer. We review recommendations for genetic testing, surveillance and prophylactic surgery in HDGC. Areas for future research are discussed, including development of new screening modalities, optimal timing of prophylactic gastrectomy, identification of additional causative mutations in HDGC, management of patients with CDH1 missense mutations and prevention/early detection of lobular breast cancer in CDH1 mutation carriers.

[Hereditary diffuse gastric cancer]. / 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.

Carcinoembryonic antigen antibody inhibits lung metastasis and augments chemotherapy in a human colonic carcinoma xenograft.

PURPOSE: In addition to its use as a blood marker for many carcinomas, elevated expression of carcinoembryonic antigen (CEA, CD66e, CEACAM5) has been implicated in various biological aspects of neoplasia, especially tumor cell adhesion, metastasis, the blocking of cellular immune mechanisms, and having antiapoptosis functions. However, it is not known if treatment with anti-CEA antibodies can affect tumor metastasis or alter the effects of cytotoxic drugs. METHODS: In vitro, human colon cancer cell lines were treated with anti-CEA MAb IgG1, hMN-14 (labetuzumab), to assess direct effects on proliferation, as well as antibody-dependent cellular cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). In vivo studies were undertaken in nude mice bearing s.c. (local growth) or i.v. (metastatic model) GW-39 and LS174T human colon cancer grafts, to evaluate the MAb alone and in combination with either CPT-11 or 5-fluorouracil (5FU). RESULTS: In vitro, labetuzumab did not induce apoptosis, nor did it affect tumor cell proliferation directly or by CDC, but it did inhibit tumor cell proliferation by ADCC. In vivo, labetuzumab did not increase median survival in the GW-39 metastatic model unless the mice were pretreated with GM-CSF to increase their peripheral WBC counts; GM-CSF alone was ineffective. Also, if GW-39 tumors were pretreated with IFN-gamma to up-regulate CEA expression threefold prior to i.v. injection, labetuzumab significantly increased median survival of the mice. When nude mice received labetuzumab with CPT-11 or 5FU, median survival increased significantly as compared to the drug or antibody alone. CONCLUSIONS: Labetuzumab, a CEA-specific MAb, induces effector-cell function in vitro against CEA-positive colonic tumor cells, and also inhibits growth of lung metastasis when CEA expression is up-regulated or if peripheral WBCs are increased. The MAb also shows chemosensitizing properties.

[From gene to disease; E-cadherin and hereditary diffuse gastric cancer]. / Van gen naar ziekte; E-cadherine en hereditair diffuus maagcarcinoom.

Hereditary diffuse gastric cancer (HDGC) is a rare autosomal dominant syndrome associated with an early-onset, histologically diffuse, signet ring cell type gastric cancer and the occurrence of cancer at other anatomical sites, i.e. breast, colon, prostate and ovary. Inactivating germline mutations in the CDH1 gene, encoding the cell to cell adhesion protein E-cadherin, predispose to HDGC. About 30% of HDGC families have a proven pathogenic CDH1 mutation. Lifetime penetrance of HDGC is about 70%. In HDGC families the recommendation for prophylactic total gastrectomy is restricted to carriers of an inactivating CDH1 mutation.