CDH1 Germline Mutations Research Articles

Family History As a Positive Prognostic Factor in Gastric Cancer

Family History As a Positive Prognostic Factor in Gastric Cancer

Frequency of CDH1 germline mutations in gastric carcinoma coming from high- and low-risk areas: metanalysis and systematic review of the literature

BackgroundThe frequency of E-cadherin germline mutations in countries with different incidence rates for gastric carcinoma has not been well established. The goal of this study was to assess the worldwide frequency of CDH1 germline mutations in gastric cancers coming from low- and high-risk areas.MethodsEnglish articles using MEDLINE access (from 1998 to 2011). Search terms included CDH1, E-cadherin, germline mutation, gastric cancer, hereditary, familial and diffuse histotype.The study included all E-cadherin germline mutations identified in gastric cancer patients; somatic mutations and germline mutations reported in other tumors were excluded.The method of this study was scheduled in accordance with the "PRISMA statement for reporting systematic reviews and meta-analyses". Countries were classified as low- or middle/high risk-areas for gastric carcinoma incidence. Statistical analysis was performed to correlate the CDH1 mutation frequency with gastric cancer incidence areas.ResultsA total of 122 E-cadherin germline mutations have been identified; the majority (87.5%) occurred in gastric cancers coming from low-risk areas. In high-risk areas, we identified 16 mutations in which missense mutations were predominant. (68.8%). We verified a significant association between the mutation frequency and the gastric cancer risk area (p < 0.001: overall identified mutations in low- vs. middle/high-risk areas).ConclusionsE-cadherin genetic screenings performed in low-risk areas for gastric cancer identified a higher frequency of CDH1 germline mutations. This data could open new approaches in the gastric cancer prevention test; before proposing a proband candidate for the CDH1 genetic screening, geographic variability, alongside the family history should be considered.

Pancreatic ductal adenocarcinoma in hereditary diffuse gastric cancer. A case report

Hereditary diffuse gastric cancer is an autosomal dominant cancer syndrome characterized by highly penetrant diffuse gastric cancer. It is caused by germ line mutations in CDH1, encoding the cell-cell adhesion protein E-cadherin. Pancreatic ductal adenocarcinoma is one of the most dismal malignancies in humans. Although absent E-cadherin expression in pancreatic ductal adenocarcinoma is related to a higher tumor grade and a worse prognosis, there have been no reports of pancreatic ductal adenocarcinoma associated with hereditary diffuse gastric cancer. Here, we describe a patient with hereditary diffuse gastric cancer who was subsequently diagnosed with pancreatic ductal adenocarcinoma. To investigate if the previously identified CDH1 germ line mutation initiated pancreatic ductal adenocarcinoma development, we performed mutational and proteomic analyses. We conclude that the pancreatic ductal adenocarcinoma did not occur in the context of the germ line CDH1 mutation but rather appeared as a sporadic event. Immunohistochemistry ultimately proved to be the most valuable tool of investigation as persistent CDH1 staining in the pancreatic ductal adenocarcinoma unequivocally revealed E-cadherin expression.

De novo CDH1 mutation in a family presenting with early‐onset diffuse gastric cancer

In this report, we describe the first concluded case of a de novo germline mutation in CDH1 in a hereditary diffuse gastric cancer (HDGC) kindred. The incident case was a woman with a personal history of Hodgkin's lymphoma and diffuse gastric cancer, who was then confirmed to have a CDH1 mutation (c.1792 C>T (R598X)). The patient's mother was found to have the same CDH1 germline mutation; however, neither maternal grandparent was found to carry the mutation, thus leading to a conclusion that the proband's mother's mutation is of de novo origin. This case highlights the importance of recognition of the HDGC syndrome and of testing for CDH1 germline mutations in young individuals with diffuse gastric cancer without a family history of the disease.

The identification and management of hereditary diffuse gastric cancer in a large Jordanian family

The management of families with hereditary diffuse gastric cancer is challenging as screening for cancer in CDH1 mutation carriers is insufficiently sensitive and the commonly recommended option, prophylactic total gastrectomy, is associated with certain morbidity and even potential mortality. We describe the particular challenges associated with the diagnosis and management of a large Jordanian family with hereditary diffuse gastric cancer. A preliminary pedigree enabled DNA testing for CDH1 mutation, denoted as c.1137G→A, on 4 family members; all were identified as mutation carriers. A family information service was then conducted in Amman, Jordan, where 40 family members gathered and we provided education and counseling. Signed permission enabled DNA collection for CDH1 germline mutation studies. Non-attendees were contacted and provided detailed information. Twenty-three family members have been tested for CDH1; 13 were positive and 10 were negative. The proband, a CDH1 mutation carrier, has undergone successful prophylactic total gastrectomy. We are hopeful that this model can be repeated throughout Jordan as well as other emerging countries where knowledge and action about hereditary cancer is lacking.

Abstract 2202: Identification of CDH1 mutations in patients with lobular carcinoma with and without a family history of gastric cancer

Abstract Background: The E-cadherin (CDH1) gene is involved in cell adhesion and maintenance of tissue architecture. Loss of expression of CDH1 has been found in both invasive lobular carcinoma (ILCA) of the breast as well as hereditary diffuse gastric cancer (HDGC). While mutations in CDH1 have been found in patients with hereditary diffuse gastric cancer, less is known about the role of CDH1 mutations in patients with breast cancer, thus mutation status was determined in a breast cancer cohort with and without family histories of gastric cancer. Methods: The Clinical Breast Care Project database was queried to identify all patients with ILCA with or without a family history of gastric or stomach cancer as well as those with non-lobular invasive cancer with a family history of gastric or stomach cancer. Genomic DNA was isolated from peripheral blood samples. DNA variants were detected for each exon using high-resolution melting technology and the underlying change identified by direct sequencing. Results: Of the 72 patients with ILCA, five had a first degree relative with stomach cancer; 14 patients with non-lobular invasive cancer (12 IDCA, one mixed lobular and ductal, and one tubular) had first degree relatives with stomach or gastric cancer. Three mutations previously associated with gastric cancer were identified: A617T and V832M were identified in a patient with ILCA with no history of gastric cancer and in a patient with IDCA with a family history of gastric cancer, respectively, while one patient with ILCA and no family history harbored the splice site mutation 1137G-T. Three novel variants were also identified: G879S, in a patient with ILCA and no family history, P825Q in a patient with mixed lobular and ductal features with a family history of stomach cancer and L230F in a patient with IDCA and a family history of stomach cancer. Conclusions: The frequency of CDH1 mutations in this patient population was low (∼7%) and were split between patients with ILCA and no family history of gastric cancer and those with non-lobular cancers and at least one family member with gastric or stomach cancer. Identification of known mutations in patients with non-lobular carcinomas suggests that while these specific CDH1 mutations are associated with increased risk of hereditary diffuse gastric cancer, they do not confer increased risk for lobular cancer. In those patients with ILCA, the low frequency of germline mutations in CDH1 suggests alternate methods, such as epigenetic modification or miRNA silencing, may be driving the suppression of expression of E-cadherin and the development of ILCA. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2202. doi:10.1158/1538-7445.AM2011-2202

Histopathology of familial and early-onset gastric cancer

Early-onset gastric cancer (EOGC) is defined as gastric cancer presenting at the age of 45 or younger. Approximately 10% of gastric cancer patients fall into the EOGC category. Furthermore, 10% of young gastric cancer patients have a positive family history, some of which are accounted for by inherited gastric cancer predisposition syndromes. Although the underlying genetic events are not always known, it can involve CDH1 germline mutations, encoding an aberrant form of E-cadherin, resulting in Hereditary diffuse gastric cancer (HDGC) and this occurs in 25–40% of tested families. Management options for asymptomatic mutation carriers are fraught, since endoscopic surveillance can miss cancer foci and prophylactic gastrectomy has profound clinical sequelae. This review serves to bring us up-to-date with the latest findings in EOGC and HDGC including implications for the clinician, geneticist and pathologist.

Germline mutations of the E‐cadherin gene in families with inherited invasive lobular breast carcinoma but no diffuse gastric cancer

Present data are highly suggestive but do not unequivocally prove the cosegregation of germ-line CDH1 mutations with inherited invasive lobular breast cancer (ILBC). Two Caucasian families with 6 pathologically confirmed ILBC cases but no diffuse gastric cancer (DGC) were identified in our oncogenetics consultations. Screening for mutations of CDH1, BRCA1, and BRCA2 genes was performed on blood samples. When available, loss of heterozygosity (LOH) and immunohistochemistry (IHC) analyses were performed on tumor samples. No BRCA1 or BRCA2 mutation was found. Deleterious CDH1 germ-line mutations c.283C>T and c.1582del were found in all the 4 living women with ILBC in family 1 and family 2, respectively. The mutation c.283C>T was also present in a healthy 71-year-old male and 2 obligate carriers in family 1. No DGC was observed in the 2 families. Loss of the wild-type CDH1 allele in 1 of the breast tumors was confirmed by LOH and IHC studies, in accordance with the "2-hit" model of tumor suppressor genes. Germline CDH1 mutation can be cosegregated with ILBC in the absence of DGC. Present data do not support recommendation of prophylactic gastrectomy in CDH1 germline mutation carriers with ILBC. Cancer 2011. © 2011 American Cancer Society.

Familial gastric cancer: update for practice management

About 90% of gastric carcinoma presents a sporadic setting and only 10% shows a familial cluster; among this group, 1-3% are considered as hereditary syndromes, with a clear genetic pathway. The most important genetic mechanisms are associated with CDH1 germline mutations, causing the hereditary diffuse gastric cancer syndrome. Other inherited predispositions with gastric carcinoma are the hereditary nonpolyposis colorectal cancer, Li-Fraumeni and Peutz-Jeghers syndromes. In this brief update, we described these principal hereditary syndromes offering a simple management to physicians where are these diseases diagnosed.

E-cadherin genetic screening and clinico-pathologic characteristics of early onset gastric cancer

Aim CDH1 germline alterations occur in about 40% of hereditary diffuse gastric cancer (HDGC) families. CDH1 germline mutations are also documented in few early onset diffuse gastric cancer patients (EODGC) without family history, but the real frequency in this setting in unknown. In these patients, the advanced stage at the time of diagnosis remains a clinical burden due to the poor long term survival. Methods The entire coding region and exon flanking sequences of the CDH1 gene was analysed by direct sequencing in 21 EODGC patients aged ⩽50 years. The potential deleterious nature for a new CDH1 missense variant was assessed by cell–cell aggregation and invasion assays. Somatic CDH1 mutation, loss of heterozigosity (LOH) and promoter hypermethylation was explored in the tumour from one CDH1 germline mutation carrier. Results Two novel CDH1 germline variants were identified in 21 EODGC cases, c.670C>T and –63C>A. Functional analysis of the c.670C>T missense variant classified this mutation as non-pathogenic. The analysis of CDH1 somatic second hits failed to demonstrate E-cadherin structural and epigenetic alterations in the tumour sample. Conclusion Data from the present work and a systematic review of the literature revealed that CDH1 germline mutations occurred in 7.2% of EOGC patients invariably with diffuse of mixed histology. From these, proved CDH1 mutation pathogenicity has been assigned only to 2.3% of the cases who were recurrently diagnosed before 35 years old. Germline CDH1 mutation remain the only germline genetic defect described in this type of patients and CDH1 mutation screening should be recommended for patients with these characteristics.

Prophylactic total gastrectomy for individuals with germline CDH1 mutation

Germline mutation of the CDH1 gene, which encodes for the E-cadherin adhesion protein, is rare but confers an estimated lifetime risk of hereditary diffuse gastric cancer of 87%. Fewer than 100 prophylactic total gastrectomies have been reported for this condition. Patients with germline CDH1 mutation who underwent multidisciplinary counseling followed by prophylactic total gastrectomy were reviewed. Ten patients (6 male, 4 female) with a median age of 42 years (range, 26-51) underwent prophylactic total gastrectomy between 2006 and 2009. Of the 6 families represented, there were 4 missense, 1 frameshift, and 1 splice site mutation. Median time from genetic testing to surgery was 3 months (range, 1-7). All patients had an upper endoscopy before surgery, identifying only 1 patient with a focus of diffuse gastric cancer. After prophylactic total gastrectomy, extensive pathologic analysis demonstrated that 9 patients had up to 77 foci of noninvasive cancer, and 2 of these patients had 4-12 foci of T1 invasive cancer. Median operative time was 213 minutes; there were no anastomotic leaks, and the length of stay was 7-8 days. One patient had a complication within 30 days (pulmonary embolism), and 3 patients had late complications (2 small bowel obstructions and 1 anastomotic stricture). Median weight loss at 6 months was 19%. The majority of patients with germline CDH1 mutation have foci of noninvasive or invasive gastric cancer by middle age. Serial upper endoscopies provide inadequate screening. Prophylactic total gastrectomy is the procedure of choice for definitive treatment.

73 Inherited invasive lobular breast carcinomas without diffuse gastric cancer as a special phenotype of CDH-1 germ-line mutation

73 Inherited invasive lobular breast carcinomas without diffuse gastric cancer as a special phenotype of CDH-1 germ-line mutation

A novel truncating mutation in the E-cadherin gene in the first Iranian family with hereditary diffuse gastric cancer

Aims Hereditary Diffuse Gastric Cancer (HDGC) is a dominantly inherited familial cancer syndrome resulting from germline mutations of the E-cadherin (CDH1) gene. The first Iranian family with HDGC is herein reported. Methods The family fulfilled the International Gastric Cancer Linkage Consortium (IGCLC) criteria for HDGC. The entire coding region of the CDH1 gene was analysed by direct sequencing in an obligatory carrier. Subsequent molecular genetic tests were done on other at risk individuals to identify mutation carriers. Results A novel heterozygous 2275G>T mutation in exon 14 of the CDH1 gene was detected. This nonsense mutation generates a premature stop codon at position 758 giving rise to a truncated E-cadherin protein lacking cytoplasmic region. The specified mutation was detected in the index case and her asymptomatic son who underwent prophylactic gastrectomy. Conclusion The first Iranian family with HDGC which carries a novel CDH1 germline mutation is reported.

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

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. 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. 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. This report underlines that prophylactic gastrectomy remains the only option to eliminate the high risk for gastric cancer in CDH1 mutation carriers.

Pregnancy after prophylactic total gastrectomy

Hereditary diffuse gastric cancer is an autosomal dominant inherited cancer predisposition syndrome characterized by susceptibility to diffuse gastric and lobular breast cancers. Since current screening options for diffuse gastric cancer are ineffective, prophylactic total gastrectomy (PTG) is a recommended option for unaffected germline CDH1 mutation carriers. It is unknown whether pregnancy after surgery is possible or advisable due to potential maternal nutritional deficiencies. In this report we describe the pregnancy outcomes in three CDH1 mutation positive women after PTG and in a CDH1 mutation negative woman after total gastrectomy for early gastric cancer.

CDH-1 germ line mutations in diffuse gastric and infiltrating ductal breast cancer

e22218 Background: Hereditary Diffuse Gastric Cancer (HDGC) syndrome is characterized by the predisposition to gastric cancer of the diffuse type and to breast cancer of the lobular type. The autosomal dominantly inherited germline mutations of the E- cadherin (CDH1) gene are the defects underlying the HDGC syndrome. The median age of onset for diffuse gastric cancer is 38 years. CDH1 mutations are highly penetrant, conferring a cumulative risk of diffuse gastric cancer of 75%. Methods: Genomic DNA was purified from peripheral blood leukocytes following standard chloroform extraction. The complete coding sequences of the CDH1-gene, including splice junctions, were amplified by Polymerase Chain Reaction (PCR) and electrophorized in an ABI Prism 310 Genetic Analyzer. Results: A pathogenic mutation located on exon 7 of the CDH1 gene was identified in a female patient diagnosed with bilateral breast cancer at the age of 36. She underwent bilateral mastectomy for an infiltrating ductal adenocarcinoma of the left breast and in situ lobular of the right breast. At the age of 45 the patient underwent gastrectomy for diffuse type gastric adenocarcinoma. She had a positive family history for breast and gastric cancer from both sides, but without meeting the absolute clinical criteria for hereditary diffuse gastric cancer syndrome. The nonsense mutation found was probably maternally inherited, since the maternal grandmother was diagnosed with breast cancer at the age of 38. Conclusions: The selection process of patients for genetic testing for the HDGC syndrome is not quite clear at the moment, as it is apparent that more types of breast cancer and not only lobular, can be associated with the syndrome. Criteria should be more flexible in respects to the histopathology of the cancer type. This is the first CDH1 mutation identified in a Greek patient. No significant financial relationships to disclose.

Prevalence of CDH1 germline mutations in subjects with early onset or familial lobular breast cancer, a multicenter collaboration

11042 Background: Invasive lobular breast carcinoma (LBC) is part of the hereditary diffuse gastric cancer (HDGC) syndrome, associated with germline mutations in the E-cadherin (CDH1) gene. CDH1 mutations can be identified in 80% of families ascertained by DGC. The risk of DGC in CDH1 mutation carriers is 67% in males, and 83% in females; the estimated risk of LBC in women is 39–50% to age 80. Management of HDGC includes prophylactic gastrectomy. In this study, we estimated the prevalence of germline CDH1mutations among women with LBC who were either diagnosed at young age or had family history of breast cancer (BC). Methods: Germline DNA was collected from 383 women with LBC or mixed, lobular/ductal, BC from breast cancer programs, familial cancer clinics, and population-based cohorts. Germline BRCA1or BRCA2mutations carriers were excluded. Eligible women had (1) LBC before age 45 or (2) LBC at any age with at least two 1st or 2nd degree relatives with BC of any type. Denaturing high pressure liquid chromatography was undertaken, followed by direct sequencing of exons displaying changes. Results: At the time of submission 310 of 383 samples have been fully sequenced. One previously characterized missense mutation and four novel non-synonymous variants (1.6%) were found. Three of these women had LBC before 45 years and no family history of BC; two had BC family history. No gastric cancers were reported in these families. Functional assays to assess the pathogenicity of the variants are in process. Conclusions: These results confirm that CDH1 is responsible for a small proportion of familial and early onset LBC. Given the difficulty of identifying CDH1 mutations from BC history alone and the importance of managing the gastric cancer risk in CDH1carriers, these findings should underscore the need to obtain an accurate abdominal cancer family history from women with LBC. No significant financial relationships to disclose.

Hereditary gastric cancer

Gastric cancer is a heterogeneous and highly prevalent disease, being the fourth most common cancer and the second leading cause of cancer associated death worldwide. Most cases are sporadic and familial clustering is observed in about 10% of the cases. Hereditary gastric cancer accounts for a very low percentage of cases (1-3%) and a single hereditary syndrome - Hereditary Diffuse Gastric Cancer (HDGC) - has been characterised. Among families that fulfil the clinical criteria for HDGC, about 40% carry CDH1 germline mutations, the genetic cause of the others being unknown. The management options for CDH1 asymptomatic germline carriers are intensive endoscopic surveillance and prophylactic gastrectomy. In this chapter we review the pathophysiology and clinicopathological features of HDGC and discuss issues related with genetic testing and management of family members.

E-Cadherin Deficiency Initiates Gastric Signet-Ring Cell Carcinoma in Mice and Man

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.