Hereditary Diffuse Gastric Cancer (HDGC)


Mutated Genes and Abnormal Protein Expression (1)

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CDH1 16q22.1 UVO, CDHE, ECAD, LCAM, Arc-1, CD324 Germline
-CDH1 and Hereditary Diffuse Gastric Cancer

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Jadot V, Segers K, Bours V, et al.
[Hereditary diffuse gastric cancer : case serie of 8 patients from a single family and literature review].
Rev Med Liege. 2019; 74(3):134-138 [PubMed] Related Publications
Hereditary diffuse gastric cancer is a form of gastric cancer associated, in about 40 % of cases, with a germline mutation of the CDH1 gene. The management of patients with a pathogenic mutation of this gene is based on total prophylactic gastrectomy because, until proven otherwise, endoscopic monitoring is insufficient. We report a series of eight patients with pathogenic CDH1 mutation who underwent total prophylactic gastrectomy in our centre.

Drake J, Schreiber KC, Lopez R, et al.
Establishing a center of excellence for hereditary diffuse gastric cancer syndrome.
J Surg Oncol. 2019; 119(6):673-674 [PubMed] Free Access to Full Article Related Publications

Nasri S, Humara B, Anjomshoaa A, et al.
Early Hereditary Diffuse Gastric Cancer (eHDGC) is Characterized by Subtle Genomic Instability and Active DNA Damage Response.
Pathol Oncol Res. 2019; 25(2):711-721 [PubMed] Related Publications
Diffuse gastric cancer (DGC) is one of the two primary types of stomach cancer. Carriers of germline mutations in the gene encoding E-cadherin are predisposed to DGC. The primary aim of the present study was to determine if genomic instability is an early event in DGC and how it may lead to disease progression. Chromosomal aberrations in early intramucosal hereditary diffuse gastric cancer (eHDGC) were assessed using array comparative genomic hybridization (array CGH). Notably, no aneuploidy or other large-scale chromosomal rearrangements were detected. Instead, all aberrations affected small regions (< 4.8 Mb) and were predominantly deletions. Analysis of DNA sequence patterns revealed that essentially all aberrations possessed the characteristics of common fragile sites. These results and the results of subsequent immunohistochemical examinations demonstrated that unlike advanced DGC, eHDGCs is characterized by low levels of genomic instability at fragile sites. Furthermore, they express an active DNA damage response, providing a molecular basis for the observed indolence of eHDGC. This finding is an important step to understanding the pathology underlying natural history of DGC and supports a revision of the current definition of eHDGC as a malignant disease.

Lott PC, Carvajal-Carmona LG
Resolving gastric cancer aetiology: an update in genetic predisposition.
Lancet Gastroenterol Hepatol. 2018; 3(12):874-883 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Every year gastric cancer accounts for nearly 1 million new cases and more than 720 000 deaths worldwide. Prognosis is dismal because most patients are diagnosed with advanced disease; as such, gastric cancer outcomes will benefit from better methods for identification of at-risk individuals that can be targeted for early detection. One approach to targeting high-risk populations is to identify individuals who are genetically predisposed to gastric cancer, as up to 15% of all patients report family history of the disease. On the basis of clinical manifestations, three gastric cancer syndromes have been described, but the diagnosis of some of these syndromes is suboptimal and could benefit from genetic information. Over the past decade, genome-wide association and next-generation sequencing studies have identified several low penetrance variants and high-risk genes, considerably increasing our understanding of inherited gastric cancer predisposition. From these studies, PALB2 has emerged as a new familial gastric cancer gene. Furthermore, genetic analyses in patients with sporadic gastric cancer suggest that more than 10% of all cases have pathogenic mutations, a finding of great importance for cancer aetiology. In this Review, we summarise the role of genetics in gastric cancer aetiology and the implications of genetics findings for the prevention of this malignancy.

Obermair F, Rammer M, Burghofer J, et al.
Cleft lip/palate and hereditary diffuse gastric cancer: report of a family harboring a CDH1 c.687 + 1G > A germline mutation and review of the literature.
Fam Cancer. 2019; 18(2):253-260 [PubMed] Related Publications
Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominantly inherited cancer syndrome associated with a high risk for diffuse gastric and lobular breast cancer, caused by heterozygous CDH1 germline mutations. Of note, also cleft lip/palate (CLP) has been described in few HDGC families. Here we report on an extensive pedigree presenting with HDGC, CLP and a CDH1 splice site mutation (c.687 + 1G > A) and review the literature for families with CDH1 mutations, HDGC and CLP. Transcript analysis showed that the c.687 + 1G > A mutation leads to loss of the last 42 bp of exon 5 and is consequently predicted to cause loss of 14 amino acids in the first extracellular cadherin repeat (EC) domain. Five mutation carriers developed diffuse gastric cancer and four individuals presented with CLP. Wild type CDH1 expression levels did not differ between CDH1 mutation carriers with CLP compared to those without CLP. Beside this extensive pedigree, we outline another previously unreported HDGC/CLP family with a CDH1 (c.1711 + 1G > C) germline mutation in this study. Review of the literature revealed a significant enrichment of CDH1 mutations within the EC domains in CLP/HDGC families (Fisher's exact test, p = 0.007) in comparison to CDH1 mutations associated with HDGC only. Report of further CLP/HDGC associated mutations is necessary to confirm this observation. This study highlights that CLP represents an important phenotypic feature of CDH1 germline mutation carriers and emphasizes the inclusion of CLP in the HDGC testing criteria. The underlying causes for the appearance of variable phenotypes in CDH1 mutation carriers could include genetic variation, epigenetic changes and environmental factors and should be investigated in future studies.

Moslim MA, Heald B, Tu C, et al.
Early genetic counseling and detection of CDH1 mutation in asymptomatic carriers improves survival in hereditary diffuse gastric cancer.
Surgery. 2018; 164(4):754-759 [PubMed] Related Publications
BACKGROUND: Hereditary diffuse gastric cancer is associated with E-cadherin (CDH1) germline mutations. The implications of CDH1 mutations detected with multigene panels in those without family history of HDGC are uncertain.
METHODS: A registry of patients who underwent genetic counseling for CDH1 mutation was queried for the period 2011-2017.
RESULTS: Twenty-one patients with CDH1 mutation were identified. The most common indication for CDH1 genetic screening was family history of hereditary diffuse gastric cancer (known risk) in 10 patients (48%); 11 patients (52%), however, were diagnosed by multigene cancer panels (unknown risk). Nine of the 21 patients underwent total gastrectomy, and 5 others had metastatic gastric cancer at presentation. In the gastrectomy group, 5 of the 9 patients (56%) were known to have gastric cancer based on preoperative screening endoscopy, but final pathologic examinations indicated diffuse gastric cancer in 8 of the 9 patients. The 11 patients with unknown risk for CDH1 mutation tended to be older (median 41 vs 24 years) and more likely to have metastatic disease and to die of the disease (43% vs 29%) compared with patients with family history of hereditary diffuse gastric cancer.
CONCLUSION: CDH1 mutation-associated hereditary diffuse gastric cancer is a biologically aggressive variant of gastric cancer that appears to behave similarly in patients detected only by multigene panels. The detection of CDH1 mutation at a minimum warrants genetic counseling and preferably total gastrectomy.

Ansari S, Gantuya B, Tuan VP, Yamaoka Y
Diffuse Gastric Cancer: A Summary of Analogous Contributing Factors for Its Molecular Pathogenicity.
Int J Mol Sci. 2018; 19(8) [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Gastric cancer is the third leading cause of cancer-related deaths and ranks as the fifth most common cancer worldwide. Incidence and mortality differ depending on the geographical region and gastric cancer ranks first in East Asian countries. Although genetic factors, gastric environment, and

Polom K, Marrelli D, Voglino C, et al.
Familial aggregation of gastric cancer with microsatellite instability.
Acta Chir Belg. 2018; 118(5):287-293 [PubMed] Related Publications
BACKGROUND: Microsatellite instability (MSI) is currently a new molecular subtype of gastric cancer (GC). About 90% of GC cases appear sporadically. MSI seems to be responsible for both sporadic and familial GC. The aim of this study was to analyze the frequency of MSI in GC with familial history of GC.
METHODS: The MSI analysis was conducted using five quasi-monomorphic mononucleotide repeats: BAT-26, BAT-25, NR-24, NR-21 and NR-27. From our database, we analyzed 457 patients in terms of cancer history across family members, particularly focusing on GC.
RESULTS: MSI status in patients without familial history of GC was present in 22.1% of the cases, whereas in the patients with familial history of GC it was present in 28% of the cases (p = 0.220). For 1st or 2nd degree family members with GC, MSI was observed in 27.6% and in 30.8%, respectively (p = 0.812). MSI was observed in hereditary gastric cancer (HGC) in 33.3% and in familial gastric cancer (FGC) in 30%. No difference in survival rates was observed between the analyzed groups.
CONCLUSIONS: In our publication, we could not find any link between familial background and the MSI status in GC patients. More detailed molecular and genetic analysis of subgroups of these patients is required.

Figueiredo J, Melo S, Gamet K, et al.
E-cadherin signal sequence disruption: a novel mechanism underlying hereditary cancer.
Mol Cancer. 2018; 17(1):112 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
The aim of this study was to uncover the pathogenic relevance and the underlying molecular mechanism of a novel CDH1 variant found in a Hereditary Diffuse Gastric Cancer family (p.L13_L15del), which affects the signal peptide of E-cadherin without changing the remaining predicted sequence. We verified that p.L13_L15del cells yield low levels of E-cadherin, decreased cell adhesion and enhanced cell invasion. Further, we demonstrated that the disruption of the highly conserved hydrophobic core of the signal peptide hampers the binding of cellular components crucial for E-cadherin translation and translocation into the endoplasmic reticulum, constituting a new molecular basis for the loss of a tumour suppressor gene causative of hereditary cancer.

Gjyshi O, Vashi P, Seewald L, et al.
Therapeutic and prophylactic gastrectomy in a family with hereditary diffuse gastric cancer secondary to a CDH1 mutation: a case series.
World J Surg Oncol. 2018; 16(1):143 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
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.

Pena-Couso L, Perea J, Melo S, et al.
Clinical and functional characterization of the CDH1 germline variant c.1679C>G in three unrelated families with hereditary diffuse gastric cancer.
Eur J Hum Genet. 2018; 26(9):1348-1353 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Germline changes in the CDH1 tumor suppressor gene predispose to diffuse gastric cancer and lobular breast cancer. In carriers of deleterious germline CDH1 variants, prophylactic gastrectomy is recommended. In case of germline missense variants, it is mandatory to assess the functional impact on E-cadherin, the protein encoded by CDH1, and to predict their clinical significance. Herein, we have identified a recurrent germline missense variant, c.1679C>G, segregating with gastric cancer in three unrelated Spanish families. Through genetic, transcriptional, in silico and in vitro studies, we demonstrate the deleterious effect of the c.1679C>G variant and its association with hereditary diffuse gastric cancer, providing relevant data to relatives and allowing an accurate genetic counseling.

Fewings E, Larionov A, Redman J, et al.
Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing study.
Lancet Gastroenterol Hepatol. 2018; 3(7):489-498 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Germline pathogenic variants in the E-cadherin gene (CDH1) are strongly associated with the development of hereditary diffuse gastric cancer. There is a paucity of data to guide risk assessment and management of families with hereditary diffuse gastric cancer that do not carry a CDH1 pathogenic variant, making it difficult to make informed decisions about surveillance and risk-reducing surgery. We aimed to identify new candidate genes associated with predisposition to hereditary diffuse gastric cancer in affected families without pathogenic CDH1 variants.
METHODS: We did whole-exome sequencing on DNA extracted from the blood of 39 individuals (28 individuals diagnosed with hereditary diffuse gastric cancer and 11 unaffected first-degree relatives) in 22 families without pathogenic CDH1 variants. Genes with loss-of-function variants were prioritised using gene-interaction analysis to identify clusters of genes that could be involved in predisposition to hereditary diffuse gastric cancer.
FINDINGS: Protein-affecting germline variants were identified in probands from six families with hereditary diffuse gastric cancer; variants were found in genes known to predispose to cancer and in lesser-studied DNA repair genes. A frameshift deletion in PALB2 was found in one member of a family with a history of gastric and breast cancer. Two different MSH2 variants were identified in two unrelated affected individuals, including one frameshift insertion and one previously described start-codon loss. One family had a unique combination of variants in the DNA repair genes ATR and NBN. Two variants in the DNA repair gene RECQL5 were identified in two unrelated families: one missense variant and a splice-acceptor variant.
INTERPRETATION: The results of this study suggest a role for the known cancer predisposition gene PALB2 in families with hereditary diffuse gastric cancer and no detected pathogenic CDH1 variants. We also identified new candidate genes associated with disease risk in these families.
FUNDING: UK Medical Research Council (Sackler programme), European Research Council under the European Union's Seventh Framework Programme (2007-13), National Institute for Health Research Cambridge Biomedical Research Centre, Experimental Cancer Medicine Centres, and Cancer Research UK.

Hakkaart C, Ellison-Loschmann L, Day R, et al.
Germline CDH1 mutations are a significant contributor to the high frequency of early-onset diffuse gastric cancer cases in New Zealand Māori.
Fam Cancer. 2019; 18(1):83-90 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
New Zealand Māori have a considerably higher incidence of gastric cancer compared to non-Māori, and are one of the few populations worldwide with a higher prevalence of diffuse-type disease. Pathogenic germline CDH1 mutations are causative of hereditary diffuse gastric cancer, a cancer predisposition syndrome primarily characterised by an extreme lifetime risk of developing diffuse gastric cancer. Pathogenic CDH1 mutations are well described in Māori families in New Zealand. However, the contribution of these mutations to the high incidence of gastric cancer is unknown. We have used next-generation sequencing, Sanger sequencing, and Multiplex Ligation-dependent Probe Amplification to examine germline CDH1 in an unselected series of 94 Māori gastric cancer patients and 200 healthy matched controls. Overall, 18% of all cases, 34% of cases diagnosed with diffuse-type gastric cancer, and 67% of cases diagnosed aged less than 45 years carried pathogenic CDH1 mutations. After adjusting for the effect of screening known HDGC families, we estimate that 6% of all advanced gastric cancers and 13% of all advanced diffuse-type gastric cancers would carry germline CDH1 mutations. Our results demonstrate that germline CDH1 mutations are a significant contributor to the high frequency of diffuse gastric cancer in New Zealand Māori.

Melo S, Figueiredo J, Fernandes MS, et al.
Predicting the Functional Impact of CDH1 Missense Mutations in Hereditary Diffuse Gastric Cancer.
Int J Mol Sci. 2017; 18(12) [PubMed] Article available free on PMC after 01/12/2019 Related Publications
The role of E-cadherin in Hereditary Diffuse Gastric Cancer (HDGC) is unequivocal. Germline alterations in its encoding gene (

Caggiari L, Miolo G, Canzonieri V, et al.
A new mutation of the CDH1 gene in a patient with an aggressive signet-ring cell carcinoma of the stomach.
Cancer Biol Ther. 2018; 19(4):254-259 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Germline mutations in CDH1, the gene coding for the E-cadherin adhesion protein, are known to cause hereditary diffuse gastric cancer. We identified a new truncating germline mutation (p.Asp538Thrfs*19) in exon 11 of the CDH1 gene in a 41-year-old male with a diffuse gastric cancer. Although he had no parental history of gastric cancer, the co-segregation study in the family detected the same mutation in his healthy 31-year-old brother. The mutation affects one of the extracellular repeat (CAD repeats) domains which is essential for the homophilic binding specificity that directs "E-cadherin" to bind with itself each others. In this case, immunohistochemical analysis showed no expression of E-cadherin in the tumor sample and was a useful prescreening tool to genetic testing. This finding was associated with a poor response to trastuzumab-based treatment.

Betés M, Alonso-Sierra M, Valentí V, Patiño A
A multidisciplinary approach allows identification of a new pathogenic CDH1 germline missense mutation in a hereditary diffuse gastric cancer family.
Dig Liver Dis. 2017; 49(7):825-826 [PubMed] Related Publications

DA Silva Oliveira KC, Bona AB, DA Silva FJ, et al.
Expression of hsa-miR-9 and
Anticancer Res. 2017; 37(5):2401-2406 [PubMed] Related Publications
BACKGROUND/AIM: Approximately, 15-50% of families affected by hereditary diffuse gastric cancer (HDGC) exhibit CDH1 germline mutations. CDH1 gene encodes E-cadherin, protein essential to the cell-cell contact of gastric epithelium. Studies have shown that hsa-miR-9 participates in this protein downregulation. Moreover, MYC is responsible for the transcription of hsa-miR-9-3. In the present study, hsa-miR-9 expression and MYC copy number variation were investigated to elucidate the hsa-miR-9 role in HDGC.
PATIENTS AND METHODS: Tumor samples were obtained from nine individuals with HDGC history belonging to four Brazilian families. Then, relative quantification of hsa-miR-9 expression and MYC gene copy number variation analysis were performed by real-time PCR.
RESULTS: In all the samples, an overexpression of hsa-miR-9 and an increased MYC copy number (≥3 copies) were observed.
CONCLUSION: hsa-miR-9 acts as an oncomiR in HDGC. In addition, we suggest that hsa-miR-9 acts as second event in individuals with HDGC carrying CDH1 gene germinline mutations.

Chen I, Mathews-Greiner L, Li D, et al.
Transcriptomic profiling and quantitative high-throughput (qHTS) drug screening of CDH1 deficient hereditary diffuse gastric cancer (HDGC) cells identify treatment leads for familial gastric cancer.
J Transl Med. 2017; 15(1):92 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Patients with hereditary diffuse gastric cancer (HDGC), a cancer predisposition syndrome associated with germline mutations of the CDH1 (E-cadherin) gene, have few effective treatment options. Despite marked differences in natural history, histopathology, and genetic profile to patients afflicted by sporadic gastric cancer, patients with HDGC receive, in large, identical systemic regimens. The lack of a robust preclinical in vitro system suitable for effective drug screening has been one of the obstacles to date which has hampered therapeutic advances in this rare disease.
METHODS: In order to identify therapeutic leads selective for the HDGC subtype of gastric cancer, we compared gene expression profiles and drug phenotype derived from an oncology library of 1912 compounds between gastric cancer cells established from a patient with metastatic HDGC harboring a c.1380delA CDH1 germline variant and sporadic gastric cancer cells.
RESULTS: Unsupervised hierarchical cluster analysis shows select gene expression alterations in c.1380delA CDH1 SB.mhdgc-1 cells compared to a panel of sporadic gastric cancer cell lines with enrichment of ERK1-ERK2 (extracellular signal regulated kinase) and IP3 (inositol trisphosphate)/DAG (diacylglycerol) signaling as the top networks in c.1380delA SB.mhdgc-1 cells. Intracellular phosphatidylinositol intermediaries were increased upon direct measure in c.1380delA CDH1 SB.mhdgc-1 cells. Differential high-throughput drug screening of c.1380delA CDH1 SB.mhdgc-1 versus sporadic gastric cancer cells identified several compound classes with enriched activity in c.1380 CDH1 SB.mhdgc-1 cells including mTOR (Mammalian Target Of Rapamycin), MEK (Mitogen-Activated Protein Kinase), c-Src kinase, FAK (Focal Adhesion Kinase), PKC (Protein Kinase C), or TOPO2 (Topoisomerase II) inhibitors. Upon additional drug response testing, dual PI3K (Phosphatidylinositol 3-Kinase)/mTOR and topoisomerase 2A inhibitors displayed up to >100-fold increased activity in hereditary c.1380delA CDH1 gastric cancer cells inducing apoptosis most effectively in cells with deficient CDH1 function.
CONCLUSION: Integrated pharmacological and transcriptomic profiling of hereditary diffuse gastric cancer cells with a loss-of-function c.1380delA CDH1 mutation implies various pharmacological vulnerabilities selective to CDH1-deficient familial gastric cancer cells and suggests novel treatment leads for future preclinical and clinical treatment studies of familial gastric cancer.

Hallowell N, Badger S, Richardson S, et al.
High-risk individuals' perceptions of reproductive genetic testing for CDH1 mutations.
Fam Cancer. 2017; 16(4):531-535 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Reproductive genetic testing- PreNatal Diagnosis (PND) and Preimplantation Genetic Diagnosis (PGD)-for CDH1 mutations associated with Hereditary Diffuse Gastric Cancer (HDGC)is available in the UK. This qualitative interview study examined high-risk individuals' (n = 35) views of CDH1 reproductive genetic testing. Interviewees generally regarded reproductive genetic testing as an acceptable form of HDGC risk management. However, some were concerned that their genetic risks required them to plan reproduction and anticipated difficulties communicating this to reproductive partners. Individuals had a preference for PGD over PND because it avoided the need for a termination of pregnancy. However, those who had not yet had children expressed concerns about having to undergo IVF procedures and worries about their effectiveness and the need for embryo selection in PGD. It is suggested that high-risk individuals are provided with access to reproductive genetic counselling.

Sahasrabudhe R, Lott P, Bohorquez M, et al.
Germline Mutations in PALB2, BRCA1, and RAD51C, Which Regulate DNA Recombination Repair, in Patients With Gastric Cancer.
Gastroenterology. 2017; 152(5):983-986.e6 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Up to 10% of cases of gastric cancer are familial, but so far, only mutations in CDH1 have been associated with gastric cancer risk. To identify genetic variants that affect risk for gastric cancer, we collected blood samples from 28 patients with hereditary diffuse gastric cancer (HDGC) not associated with mutations in CDH1 and performed whole-exome sequence analysis. We then analyzed sequences of candidate genes in 333 independent HDGC and non-HDGC cases. We identified 11 cases with mutations in PALB2, BRCA1, or RAD51C genes, which regulate homologous DNA recombination. We found these mutations in 2 of 31 patients with HDGC (6.5%) and 9 of 331 patients with sporadic gastric cancer (2.8%). Most of these mutations had been previously associated with other types of tumors and partially co-segregated with gastric cancer in our study. Tumors that developed in patients with these mutations had a mutation signature associated with somatic homologous recombination deficiency. Our findings indicate that defects in homologous recombination increase risk for gastric cancer.

Petrovchich I, Ford JM
Genetic predisposition to gastric cancer.
Semin Oncol. 2016; 43(5):554-559 [PubMed] Related Publications
Gastric cancer ranks as the third leading cause of cancer mortality worldwide and confers a 5-year survival of 20%. While most gastric cancers are sporadic, ~1%-3% can be attributed to inherited cancer predisposition syndromes. Germline E-cadherin/CDH1 mutations have been identified in families with an autosomal dominant inherited predisposition to diffuse gastric cancer. The cumulative risk of gastric cancer for CDH1 mutation carriers by age 80 years is reportedly 70% for men and 56% for women. Female mutation carriers also have an estimated 42% risk for developing lobular breast cancer by age 80 years. However, most individuals meeting clinical criteria for hereditary diffuse gastric cancer syndrome (HDGC) do not have a germline CDH1 mutation, and germline CDH1 mutation carriers do not all exhibit similar clinical outcomes in terms of age of diagnosis or cancer types. E-cadherin (CDH1) as the one known causative gene for HDGC accounts for only 40% of cases, leaving 60% with an unknown genetic diagnosis. In addition to HDGC, we will review other genetic syndromes with elevated gastric cancer risk, as well as newly implicated alterations in other genes (CTNNA1, DOT1L, FBXO24, PRSS1, MAP3K6, MSR1, and INSR) that may affect gastric cancer susceptibility and age-specific penetrance.

Hallowell N, Lawton J, Badger S, et al.
The Psychosocial Impact of Undergoing Prophylactic Total Gastrectomy (PTG) to Manage the Risk of Hereditary Diffuse Gastric Cancer (HDGC).
J Genet Couns. 2017; 26(4):752-762 [PubMed] Related Publications
Individuals identified as at high risk of developing Hereditary Diffuse Gastric Cancer (HDGC) are advised to undergo prophylactic surgery - have their stomach removed - in their early twenties. Research with (older) cancer patients who undergo gastrectomy for curative reasons suggests that gastric resection has a number of physical and psychosocial sequelae. Because it is difficult to extrapolate the findings of studies of older cancer patients to younger healthy patients who are considering prophylactic total gastrectomy (PTG), the aim of this qualitative interview study was to determine the psychosocial implications of undergoing prophylactic surgery to manage genetic risk. Fourteen men and 13 women from the UK's Familial Gastric Cancer study who had undergone PTG were invited to participate in qualitative interviews. Most reported that undergoing surgery and convalescence was easier than anticipated. There was evidence that age affected experiences of PTG, with younger patients tending to report faster recovery times and more transient aftereffects. All saw the benefits of risk reduction as outweighing the costs of surgery. Surgery was described as having a range of physical impacts (disrupted appetite, weight loss, fatigue, GI symptoms) that had related psychological, social and economic implications. Those considering PTG need to be aware that its impact on quality of life is difficult to predict and negative sequelae may be ongoing for some individuals.

Strong VE, Gholami S, Shah MA, et al.
Total Gastrectomy for Hereditary Diffuse Gastric Cancer at a Single Center: Postsurgical Outcomes in 41 Patients.
Ann Surg. 2017; 266(6):1006-1012 [PubMed] Related Publications
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.

van der Post RS, Gullo I, Oliveira C, et al.
Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future.
Adv Exp Med Biol. 2016; 908:371-91 [PubMed] Related Publications
Familial clustering is seen in 10 % of gastric cancer cases and approximately 1-3 % of gastric cancer arises in the setting of hereditary diffuse gastric cancer (HDGC). In families with HDGC, gastric cancer presents at young age. HDGC is predominantly caused by germline mutations in CDH1 and in a minority by mutations in other genes, including CTNNA1. Early stage HDGC is characterized by a few, up to dozens of intramucosal foci of signet ring cell carcinoma and its precursor lesions. These include in situ signet ring cell carcinoma and pagetoid spread of signet ring cells. Advanced HDGC presents as poorly cohesive/diffuse type carcinoma, normally with very few typical signet ring cells, and has a poor prognosis. Currently, it is unknown which factors drive the progression towards aggressive disease, but it is clear that most intramucosal lesions will not have such progression.Immunohistochemical profile of early and advanced HDGC is often characterized by abnormal E-cadherin immunoexpression, including absent or reduced membranous expression, as well as "dotted" or cytoplasmic expression. However, membranous expression of E-cadherin does not exclude HDGC. Intramucosal HDGC (pT1a) presents with an "indolent" phenotype, characterized by typical signet ring cells without immunoexpression of Ki-67 and p53, while advanced carcinomas (pT > 1) display an "aggressive" phenotype with pleomorphic cells, that are immunoreactive for Ki-67 and p53. These features show that the IHC profile is different between intramucosal and more advanced HDGC, providing evidence of phenotypic heterogeneity, and may help to define predictive biomarkers of progression from indolent to aggressive, widely invasive carcinomas.

Rogers M
Cate's Story: Hereditary Diffuse Gastric Cancer.
Clin J Oncol Nurs. 2016; 20(4):443-5 [PubMed] Related Publications
Gastric cancer is a major cause of cancer-related mortality worldwide and is thought to be responsible for about 10% of cancer-related deaths across the globe. A small proportion of all gastric cancers arise because of a known hereditary syndrome, the most common of which is hereditary diffuse gastric cancer (HDGC). This is an autosomal dominant genetic disease characterized by an increased risk of developing diffuse gastric cancer at a young age. The gene responsible for HDGC is CDH1, also known as E-cadherin, a germline mutation conferring an 80% risk of developing gastric cancer during the lifetime of the carrier. Females with germline CDH1 mutations face an additional risk of developing lobular breast cancer, with a reported cumulative risk of 60% by the age of 80 years.

Hata K, Yamamoto Y, Kiyomatsu T, et al.
Hereditary gastrointestinal cancer.
Surg Today. 2016; 46(10):1115-22 [PubMed] Related Publications
Gastrointestinal (GI) cancer, including gastric and colorectal cancer, is a major cause of death worldwide. A substantial proportion of patients with GI cancer have a familial history, and several causative genes have been identified. Gene carriers with these hereditary GI syndromes often harbor several kinds of cancer at an early age, and genetic testing and specific surveillance may save their lives through early detection. Gastroenterologists and GI surgeons should be familiar with these syndromes, even though they are not always associated with a high penetrance of GI cancer. In this review, we provide an overview and discuss the diagnosis, genetic testing, and management of four major hereditary GI cancers: familial adenomatous polyposis, Lynch syndrome, hereditary diffuse gastric cancer, and Li-Fraumeni syndrome.

Huang DS, Tao HQ, He XJ, et al.
Prevalence of deleterious ATM germline mutations in gastric cancer patients.
Oncotarget. 2015; 6(38):40953-8 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Besides CDH1, few hereditary gastric cancer predisposition genes have been previously reported. In this study, we discovered two germline ATM mutations (p.Y1203fs and p.N1223S) in a Chinese family with a history of gastric cancer by screening 83 cancer susceptibility genes. Using a published exome sequencing dataset, we found deleterious germline mutations of ATM in 2.7% of 335 gastric cancer patients of different ethnic origins. The frequency of deleterious ATM mutations in gastric cancer patients is significantly higher than that in general population (p=0.0000435), suggesting an association of ATM mutations with gastric cancer predisposition. We also observed biallelic inactivation of ATM in tumors of two gastric cancer patients. Further evaluation of ATM mutations in hereditary gastric cancer will facilitate genetic testing and risk assessment.

Setia N, Clark JW, Duda DG, et al.
Familial Gastric Cancers.
Oncologist. 2015; 20(12):1365-77 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Although the majority of gastric carcinomas are sporadic, approximately 10% show familial aggregation, and a hereditary cause is determined in 1%-3% cases. Of these, hereditary diffuse gastric cancer is the most recognized predisposition syndrome. Although rare, the less commonly known syndromes also confer a markedly increased risk for development of gastric cancer. Identification and characterization of these syndromes require a multidisciplinary effort involving oncologists, surgeons, genetic counselors, biologists, and pathologists. This article reviews the molecular genetics, clinical and pathologic features, surveillance guidelines, and preventive measures of common and less common hereditary gastric cancer predisposition syndromes.

Colvin H, Yamamoto K, Wada N, Mori M
Hereditary Gastric Cancer Syndromes.
Surg Oncol Clin N Am. 2015; 24(4):765-77 [PubMed] Related Publications
Hereditary gastric cancer syndromes are a rare but distinct cause of gastric cancers. The genetic mutations underlying most affected families are unknown. Mutations of CDH1 occur in some patients affected by hereditary diffuse gastric cancer, and is the only practical marker for guiding management. Carriers of CDH1 mutations are at risk for a highly penetrant, aggressive and early-onset diffuse-type gastric cancer, and these individuals are usually offered prophylactic total gastrectomy. Further research is required to identify other genetic mutations responsible for these syndromes to improve our understanding of the underlying disease mechanisms and optimize the clinical management of affected individuals.

Hansford S, Kaurah P, Li-Chang H, et al.
Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond.
JAMA Oncol. 2015; 1(1):23-32 [PubMed] Related Publications
IMPORTANCE: E-cadherin (CDH1) is a cancer predisposition gene mutated in families meeting clinically defined hereditary diffuse gastric cancer (HDGC). Reliable estimates of cancer risk and spectrum in germline mutation carriers are essential for management. For families without CDH1 mutations, genetic-based risk stratification has not been possible, resulting in limited clinical options.
OBJECTIVES: To derive accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and determine if germline mutations in other genes are associated with HDGC.
DESIGN, SETTING, AND PARTICIPANTS: Testing for CDH1 germline mutations was performed on 183 index cases meeting clinical criteria for HDGC. Penetrance was derived from 75 mutation-positive families from within this and other cohorts, comprising 3858 probands (353 with gastric cancer and 89 with breast cancer). Germline DNA from 144 HDGC probands lacking CDH1 mutations was screened using multiplexed targeted sequencing for 55 cancer-associated genes.
MAIN OUTCOMES AND MEASURES: Accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and the relative contribution of other cancer predisposition genes in familial gastric cancers.
RESULTS: Thirty-one distinct pathogenic CDH1 mutations (14 novel) were identified in 34 of 183 index cases (19%). By the age of 80 years, the cumulative incidence of gastric cancer was 70% (95% CI, 59%-80%) for males and 56% (95% CI, 44%-69%) for females, and the risk of breast cancer for females was 42% (95% CI, 23%-68%). In CDH1 mutation-negative index cases, candidate mutations were identified in 16 of 144 probands (11%), including mutations within genes of high and moderate penetrance: CTNNA1, BRCA2, STK11, SDHB, PRSS1, ATM, MSR1, and PALB2.
CONCLUSIONS AND RELEVANCE: This is the largest reported series of CDH1 mutation carriers, providing more precise estimates of age-associated risks of gastric and breast cancer that will improve counseling of unaffected carriers. In HDGC families lacking CDH1 mutations, testing of CTNNA1 and other tumor suppressor genes should be considered. Clinically defined HDGC families can harbor mutations in genes (ie, BRCA2) with different clinical ramifications from CDH1. Therefore, we propose that HDGC syndrome may be best defined by mutations in CDH1 and closely related genes, rather than through clinical criteria that capture families with heterogeneous susceptibility profiles.

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