Hereditary Diffuse Gastric Cancer Syndrome Research Articles

CDH1 Genotype Exploration in Women With Hereditary Lobular Breast Cancer Phenotype

Pathogenic or likely pathogenic (P/LP) germline CDH1 variants are associated with risk for diffuse gastric cancer and lobular breast cancer (LBC) in the so-called hereditary diffuse gastric cancer (HDGC) syndrome. However, in some circumstances, LBC can be the first manifestation of this syndrome in the absence of diffuse gastric cancer manifestation. To evaluate the frequency of germline CDH1 variants in women with the hereditary LBC (HLBC) phenotype, somatic CDH1 gene inactivation in germline CDH1 variant carriers' tumor samples, and the association of genetic profiles with clinical-pathological data and survival. This single-center, longitudinal, prospective cohort study was conducted from January 1, 1997, to December 31, 2021, with follow-up until January 31, 2023. Women with LBC seen at the European Institute of Oncology were included. Testing for germline CDH1, BRCA1, and BRCA2 genes was performed. Somatic profiling was assessed for germline CDH1 carriers. Accurate estimates of prevalence of germline CDH1 variants among patients with HLBC and the association of somatic sequence alteration with HLBC syndrome. The Kaplan-Meier method and a multivariable Cox proportional hazards regression model were applied for overall and disease-free survival analysis. Of 5429 cases of primary LBC, familial LBC phenotype accounted for 1867 (34.4%). A total of 394 women with LBC were tested, among whom 15 germline CDH1 variants in 15 unrelated families were identified. Among these variants, 6 (40.0%) were P/LP, with an overall frequency of 1.5% (6 of 394). Of the 6 probands with P/LP CDH1 LBC, 5 (83.3%) had a positive family history of BC and only 1 (16.7%) had sporadic juvenile early-onset LBC. No germline BRCA1 and BRCA2 variants were identified in CDH1 carriers. An inactivating CDH1 mechanism (second hit) was identified in 4 of 6 explored matched tumor samples (66.7%) in P/LP germline carriers. The P/LP CDH1 LBC variant carriers had a significantly lower age at diagnosis compared with the group carrying CDH1 variants of unknown significance or likely benign (42.5 [IQR, 38.3-43.0] vs 51.0 [IQR, 45.0-53.0] years; P = .03). In this cohort study, P/LP germline CDH1 variants were identified in individuals not fulfilling the classic clinical criteria for HDGC screening, suggesting that identification of these variants may provide a novel method to test women with LBC with early age at diagnosis and/or positive family history of BC.

OGBN P16 Endoscopic surveillance allows prediction of burden of early signet ring cell carcinoma in Hereditary Diffuse Gastric Cancer syndrome

Abstract Background Hereditary diffuse gastric cancer (HDGC) syndrome is commonly linked to CDH1 germline pathogenic variants (PV) and carries a high lifetime risk of diffuse gastric cancer (DGC). Definitive treatment remains prophylactic total gastrectomy (PTG). However, endoscopic surveillance can be offered to inform decision-making around surgery, although the optimal time for treatment escalation remains unclear. This study aims to establish whether histopathological assessment of endoscopic biopsies can predict burden of early signet ring cell (SRC) carcinoma on PTG specimens. Methods We performed a retrospective review of prospectively collected data on endoscopic and surgical histopathologic results from CDH1 PV carriers who underwent PTG at Addenbrooke’s Hospital between January 2006 and May 2023. Targeted and systematic Cambridge protocol biopsies were performed. Patients with confirmed DGC (stage 2 or higher) at baseline endoscopy were excluded. Pearson correlation was performed to assess the relationship between number of SRC foci on endoscopy and surgical specimens. Results 46 patients underwent PTG with median of 3 pre-operative surveillance endoscopies over 22 months. Final stage was pT1aN0M0 in 41 patients and pT0N0M0 in 5 patients. The number of SRC foci on PTG specimens ranged from 0 to 273. There was a strong correlation between number of SRC foci on gastrectomy specimens and from targeted and random biopsies when evaluated separately and together for last 2 and all endoscopies. The strongest correlation was seen with total number of SRC foci on random biopsies for last 2 endoscopies (r=0.738, p-value<0.001). Random biopsies outperformed targeted biopsies in prediction of early SRC burden. Conclusions Endoscopic surveillance with systematic targeted and random biopsies by expert endoscopists within a dedicated specialist service provides useful information to estimate the burden of early SRCC. Low number of SRC foci at last two endoscopies indicate scarce gastric neoplastic involvement.

Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy.

Risk-reducing surgery for cancer prevention in solid tumors is a pressing clinical topic because of the increasing availability of germline genetic testing. We examined the short- and long-term outcomes of risk-reducing total gastrectomy (RRTG) and its lesser-known impacts on health-related quality of life (QOL) in individuals with hereditary diffuse gastric cancer syndrome. Individuals who underwent RRTG as part of a single-institution natural history study of hereditary gastric cancers were examined. Clinicopathologic details, acute and chronic operative morbidity, and health-related QOL were assessed. Validated questionnaires were used to determine QOL scores and psycho-social-spiritual measures of healing. One hundred twenty-six individuals underwent RRTG because of a pathogenic or likely pathogenic germline CDH1 variant between October 2017 and December 2021. Most patients (87.3%; 110/126) had pT1aN0 gastric carcinoma with signet ring cell features on final pathology. Acute (<30 days) postoperative major morbidity was low (5.6%; 7/126) and nearly all patients (98.4%) lost weight after total gastrectomy. At 2 years after gastrectomy, 94% (64/68) of patients exhibited at least one chronic complication (ie, bile reflux, dysphagia, and micronutrient deficiency). Occupation change (23.5%), divorce (3%), and alcohol dependence (1.5%) were life-altering consequences attributed to total gastrectomy by some patients. In patients with a median follow-up of 24 months, QOL scores decreased at 1 month after gastrectomy and returned to baseline by 6-12 months. RRTG is associated with life-changing adverse events that should be discussed when counseling patients with CDH1 variants about gastric cancer prevention. The risks of cancer-prevention surgery should not only be judged in the context of likelihood of death due to disease if left untreated, but also based on the real consequences of organ removal.

Confocal endomicroscopy diagnostic criteria for early signet-ring cell carcinoma in hereditary diffuse gastric cancer

BackgroundRecognition of early signet-ring cell carcinoma (SRCC) in patients with hereditary diffuse gastric cancer (HDGC) undergoing endoscopic surveillance is challenging. We hypothesized that probe-based confocal laser endomicroscopy (pCLE) might help diagnose early cancerous lesions in the context of HDGC. The aim of this study was to identify pCLE diagnostic criteria for early SRCC.MethodsPatients with HDGC syndrome were prospectively recruited and pCLE assessment was performed on areas suspicious for early SRCC and control regions during an endoscopic surveillance procedure. Targeted biopsies were taken for gold standard histologic assessment. In Phase I two investigators assessed video sequences off-line to identify pCLE features related to SRCC. In Phase II pCLE diagnostic criteria were evaluated in an independent video set by the investigators blinded to the histologic diagnosis. Sensitivity, specificity, accuracy, and interobserver agreement were calculated.ResultsForty-two video sequences from 16 HDGC patients were included in Phase I. Four pCLE patterns associated to SRCC histologic features were identified: (A) glands with attenuated margins, (B) glands with spiculated or irregular shape, (C) heterogenous granular stroma with sparse glands, (D) enlarged vessels with tortuous shape. In Phase II, 38 video sequences from 15 patients were assessed. Criteria A and B and C had the highest diagnostic accuracy, with a κ for interobserver agreement ranging from 0.153 to 0.565. A panel comprising these 3 criteria with a cut-off of at least one positive criterion had a sensitivity of 80.9% (95%CI:58.1—94.5%) and a specificity of 70.6% (95%CI:44.0—89.7%) for a diagnosis of SRCC.ConclusionsWe have generated and validated off-line pCLE criteria for early SRCC. Future real-time validation of these criteria is required.

Attitudes toward preimplantation genetic testing and quality of life among individuals with hereditary diffuse gastric cancer syndrome

BackgroundHereditary Diffuse Gastric Cancer (HDGC) syndrome is an autosomal dominant hereditary cancer predisposition associated with germline pathogenic/likely pathogenic variants in the CDH1 gene. Identifying early stage HDGC is difficult, and prophylactic measures can be effective in preventing incidence. Preimplantation Genetic Testing (PGT) can provide information about CDH1 variant status, HDGC risk, and limit familial transmission of CDH1 variants. To date, however, little is known about the attitudes of individuals with CDH1 variants towards PGT.MethodsGiven that little is known about the reproductive attitudes of individuals with HDGC, we recruited participants with CDH1 variants from a familial gastric cancer registry and administered a cross-sectional survey with open- and closed-ended response items. We assessed attitudes regarding PGT and the effect of HDGC on quality of life.ResultsParticipants (n = 21) were predominantly partnered (61.9%), had a personal cancer history (71.4%), and had biological children (71.4%). Interest in learning about PGT was high; 66.7% of participants were interested in PGT and 90.5% approved of healthcare providers discussing PGT with individuals with CDH1 variants. Attitudes regarding personal use were varied. Among all participants, 35% would not, 25% were uncertain, and 40% would use PGT. Personal philosophy and preferences for family and reproduction were key factors related to PGT attitudes. HDGC had moderate effects on participants’ quality of life, including social relationships, health behaviors, and emotional experiences including worry about cancer risk and guilt regarding familial implications.ConclusionPGT was identified by participants as acceptable for use in a variety of contexts and benefits of reproductive counseling involving PGT may extend beyond CDH1 carriers to family members’ reproductive behaviors. Dispositions towards PGT are governed by personal philosophy or belief systems. These findings can help guide providers counseling individuals with CDH1 variants.

CDH1 mutations recurrence and global clustering in genetically tested families with hereditary diffuse gastric cancer syndrome: results from a systematic study.

The global distribution of germline CDH1 mutations in hereditary diffuse gastric cancer families, is highly heterogenous. The aim of this study was to determine if there is any geographic clustering of CDH1 mutations in families with the hereditary diffuse gastric cancer syndrome. Data from 1998 to 2021 were collected systematically according to the PRISMA guidelines. 571 germline CDH1 mutations were recorded worldwide, with 387 (67.8%) of them reported in 108 families. The largest clusters of CDH1 mutations were identified in central Europe, north America, northern Europe, New Zealand (Māori), and south America. A high penetrance risk for GC development was observed for c.1008G > T in New Zealand (Māori), c.1565 + 2insT in northern Europe, c.1901C > T in Portugal, and c.1003C > T in the USA. Our observations are consistent with a specific local clustering of some recurrent CDH1 mutations within specific countries.

Hereditary diffuse gastric cancer syndrome: medical genetic consulting, treatment strategy for family members, prophylactic total gastrectomy, and endoscopic surveillance in CDH1- and CTNNA1-mutation carriers

The purpose of the study was to summarize available data on genetic counseling for people with hereditary diffuse gastric cancer (HDGC) syndrome, treatment strategies for family members with HDGC, prophylactic gastrectomy (PGE), and surveillance of CDH1 and CTNNA1 mutation carriers. Material and methods. A literature search was conducted using Web of Science, Scopus, MedLine, Cochrane Library, and RSCI databases. Results. HDGC syndrome is an inherited genetic syndrome that leads to the increased risk for both diffuse gastric cancer (DGC) and lobular breast cancer (LBC). About 1 to 3% of all gastric cancer cases are HDGCs. A high frequency of CDH1 gene mutation was frst identifed by P. Guilford et al. in 1998 in 3 Maori families from New Zealand. The cumulative risk for HDGC in CDH1 mutation carriers is 42 to 70% for men and 33-56% for women at the age of 80 years. Due to the rarity of the disease, the main publications dealing with this problem are clinical case descriptions. Conclusion. Multicenter clinical trials are required to improve screening and management of HDGC syndrome.

\u201cI have always lived with the disease in the family\u201d: family adaptation to hereditary cancer-risk

BackgroundHereditary cancer syndromes have been conceptualized as a family level process. The present study explores the complexity and challenges of family adaptation to the hereditary cancer syndrome, in the context of genetic counseling and long-term cancer risk management and follow-up surveillance.MethodsWe performed semi-structured interviews with 13 participants with one of the following hereditary cancer syndromes: Lynch Syndrome, Hereditary Diffuse Gastric Cancer Syndrome, Hereditary Breast and Ovarian Cancer Syndrome, or Familial Adenomatous Polyposis. The interview was developed through a participatory approach with the involvement of healthcare professionals and individuals with first-hand experience of living with the hereditary cancer syndromes.ResultsThe family is the main source of information and emotional support to deal with hereditary cancer syndromes. Multiple individual adaptation processes and communal coping networks interact, influencing the emotional and health-related behavior of family members. This is affected and affects the family’s communication and its’ members reactions to disclosure, with consequent changes in relationships.ConclusionsThe systemic interdependent dynamics of family adaptation calls for family-centered care of genetic cancer syndromes.

E-Cadherin-Deficient Cells Are Sensitive to the Multikinase Inhibitor Dasatinib.

Simple SummaryInactivating mutations in the CDH1 gene, encoding the cell adhesion protein E-cadherin, cause hereditary diffuse gastric cancer syndrome (HDGC), as well as being a hallmark of sporadic diffuse gastric cancers and lobular breast cancers. We have previously identified AKT3 as a potential vulnerability in gastric cancers lacking CDH1 expression. This study aimed to test whether drugs which inhibit the AKT3-associated gene, discoidin domain receptor tyrosine kinase 2 (DDR2) specifically targeted cells deficient in E-cadherin. We demonstrated that cells and organoids lacking E-cadherin exhibited heightened sensitivity to dasatinib, a drug that targets multiple kinases including DDR2 and SRC.The CDH1 gene, encoding the cell adhesion protein E-cadherin, is one of the most frequently mutated genes in gastric cancer and inactivating germline CDH1 mutations are responsible for the cancer syndrome hereditary diffuse gastric cancer (HDGC). CDH1-deficient gastric cancers exhibit high AKT serine/threonine kinase 3 (AKT3) expression, but specific drugs against this AKT isoform are not available. We therefore used two publicly available datasets to identify AKT3-associated genes which could be used to indirectly target AKT3. Reactome analysis identified an enrichment of extracellular matrix remodelling genes in AKT3-high gastric cancers. Of the 51 genes that were significantly correlated with AKT3 (but not AKT1), discoidin domain receptor tyrosine kinase 2 (DDR2) showed the strongest positive association. Treatment of isogenic human cells and mouse gastric and mammary organoids with dasatinib, a small molecule inhibitor of multiple kinases including SRC, BCR-ABL and DDR2, preferentially slowed the growth and induced apoptosis of E-cadherin-deficient cells. Dasatinib treatment also preferentially slowed the growth of gastric and mammary organoids harbouring both Cdh1 and Tp53 mutations. In organoid models, dasatinib treatment was associated with decreased phosphorylation of total AKT, with a stronger effect seen in Cdh1-deficient organoids. Treatment with combinations of dasatinib and an inhibitor of AKT, MK2206, enhanced the effect of dasatinib in breast MCF10A cells. In conclusion, targeting the DDR2-SRC-AKT3 axis with dasatinib represents a promising approach for the chemoprevention and chemotherapy of gastric and breast cancers lacking E-cadherin.

Diffuse gastric adenocarcinoma during pregnancy and genetic counseling.

We present the case of a 38-year-old woman who, in the context of a 22-week gestation, was diagnosed with diffuse gastric adenocarcinoma. The age of the patient and the way in which the cancer presented itself, make genetic counseling mandatory to rule out hereditary diffuse gastric carcinoma syndrome. This rare entity, of autosomal dominant inheritance and closely linked to mutations in the CDH1 (in most cases) and CTNNA1 genes, is associated with a greater predisposition to develop malignant neoplasms of the breast and stomach. Genetic sequencing ruled out hereditary diffuse gastric cancer syndrome. Unfortunately, 24 months after the cesarean section, our patient dies.

Frequency of CDH1 Germline Mutations in Non-Gastric Cancers.

Simple SummaryDiffuse gastric cancer is the hallmark of the hereditary diffuse gastric cancer syndrome related with the E-cadherin germline mutations. Other cancers (non-gastric) are described in association with the CDH1 gene germline alterations. In this study, we aimed to assess the overall frequency of CDH1 mutations in non-gastric tumors reported in literature so far.Hereditary Diffuse Gastric Cancer (HDGC) is a complex inherited syndrome caused by CDH1 germline mutations. DGC is the hallmark cancer of this genetic predisposition, but several other cancers are associated with these CDH1 mutations. In this review, we revised all studies reporting CDH1 mutations in non-GC patients. The selected studies included: (a) families aggregating with GC and other cancers, both, and (b) families presenting only non-gastric tumors association. Among non-gastric tumors, our results show that CDH1 mutations are most frequently identified in breast cancer. The frequency of missense mutations is higher in the non-GC group, as the age at diagnosis in this group. Moreover, the predominant CDH1 mutation affects the extracellular domain. Our data suggest that CDH1 genetic testing should be considered also in other cancers, especially breast tumors.

Genetic and Epigenetic Alterations of CDH1 Regulatory Regions in Hereditary and Sporadic Gastric Cancer.

E-cadherin is a key player in gastric cancer (GC) and germline alterations of CDH1, its encoding gene, are responsible for Hereditary Diffuse Gastric Cancer (HDGC) syndrome. This study aimed at elucidating the role of genetic variants and DNA methylation of CDH1 promoter and enhancers in the regulation of gene expression. For this purpose, we analyzed genetic variants of the CDH1 gene through Next-Generation Sequencing (NGS) in a series of GC cell lines (NCI-N87, KATO-III, SNU-1, SNU-5, GK2, AKG, KKP) and the corresponding CDH1 expression levels. By bisulfite genomic sequencing, we analyzed the methylation status of CDH1 regulatory regions in 8 GC cell lines, in a series of 13 sporadic GC tissues and in a group of 20 HDGC CDH1-negative patients and 6 healthy controls. The NGS analysis on CDH1 coding and regulatory regions detected genetic alterations in 3 out of 5 GC cell lines lacking functional E-cadherin. CDH1 regulatory regions showed different methylation patterns in patients and controls, GC cell lines and GC tissues, expressing different E-cadherin levels. Our results showed that alterations in terms of genetic variants and DNA methylation patterns of both promoter and enhancers are associated with CDH1 expression levels and have a role in its regulation.

CDH1 germline mutations in families with hereditary lobular breast cancer.

Pathogenic CDH1 germline mutations are associated with lobular breast cancer in the so-called hereditary lobular breast cancer (HLBC) syndrome, without apparent correlation with the classic hereditary diffuse gastric cancer (HDGC). Recent international guidelines recommend CDH1 screening also in absence of diffuse gastric cancer (DGC) history. Genomic characteristics underlying gastric and breast tumorigenesis in this varied population of patients is still unclear. In this review we revised all CDH1 germline mutations described in literature associated with lobular breast cancer (LBC). We distinguish two subgroups of CDH1 mutant carriers: (a) 'mixed' HDGC syndrome, showing both DGC plus LBC and (b) HLBC, in which DGC is absent and the LBC phenotype is predominant. A higher frequency of CDH1 mutations was identified in the HLBC syndrome with an early age at LBC diagnosis; it is possible that LBCs with CDH1 germline mutations are an independent inherited syndrome. This evidence allows us to gain biological insight into the pathophysiological mechanisms responsible for the different phenotypes of the disease and potentially tailor the prophylactic and screening procedures.

Evaluation of confocal laser endomicroscopy for detection of occult gastric carcinoma in CDH1 variant carriers.

Hereditary diffuse gastric cancer syndrome, attributed to inactivating germline CDH1 variants, is associated with an elevated lifetime risk of gastric cancer. We sought to evaluate cancer detection using probe-based confocal laser endomicroscopy (pCLE) during endoscopic surveillance. A prospective, single-institution study was conducted in asymptomatic adults with pathogenic or likely pathogenic (P/LP) CDH1 variants. Subjects received endoscopic gastric surveillance using pCLE in conjunction with the Cambridge method (CM). Abnormalities visualized by pCLE were biopsied, followed by non-targeted mucosal biopsies according to the CM. Primary endpoint was to determine pCLE sensitivity for detection of occult SRC carcinoma compared to CM. Thirty-six patients with P/LP CDH1 variants underwent endoscopy using pCLE and CM. Majority were female (75%) with median age 47 years. Targeted biopsies of focal abnormalities on WLE were negative for carcinoma. Overall, 19.4% (7/36) patients had SRC detected on ≥1 biopsy. Non-targeted CM biopsies revealed SRC in 11.1% (4/36), whereas pCLE revealed SRC in 16.7% (6/36). Fifteen patients underwent total gastrectomy; all 15 explants contained occult carcinoma. In those 15 patients, the false-negative SRC detection rates for pCLE and CM were 67% and 87%, respectively. Confocal endomicroscopy alone has low sensitivity for occult cancer detection in CDH1 variant carriers, although it appeared no worse than the current recommended method and required fewer biopsies per patient. A more reliable endoscopic surveillance is needed as a viable alternative to surgery in this high-risk population (ClinicalTrials.gov, Number: NCT03648879).

Resolving pathogenicity classification for the CDH1 c.[715G>A] (p.Gly239Arg) Variant.

Hereditary Diffuse Gastric Cancer (HDGC) syndrome is associated with CDH1 germline likely pathogenic/pathogenic variants. Carriers of CDH1 germline likely pathogenic/pathogenic variants are predisposed to diffuse gastric cancer and lobular breast cancer. This study aims to classify the CDH1 c.[715G>A] missense variant identified in a diffuse gastric cancer prone family by performing splicing studies. RT-PCR and subsequent cloning experiments were performed to investigate whether this variant completely disrupts normal splicing. This variant preferentially abolishes normal splicing through activation of a cryptic 3' acceptor splice site within exon 6 of CDH1, presumably leading to a premature protein truncation within first extracellular domain repeat of E-cadherin protein. Our results contributed to evidence necessary to resolve pathogenicity classification of this variant, indicating that this variant is to be classified as pathogenic.

Significance of E-cadherin Gene Mutations in Patients With Hereditary Diffuse Gastric Cancer Syndrome: A Systematic Review.

Gastric cancer is the third-most fatal cancer in the world. Though over the years, we saw patients mostly with intestinal type accounting for the highest mortality rate, the recent rise of the diffuse form with germline E-cadherin (CDH1) mutations has added a whole new level of interest to study in detail about the association between CDH1 and diffuse gastric cancer (DGC). This introduced a set guideline formulated by Internal Gastric Cancer Linkage Consortium (IGCLC) for patients with family history of diffuse gastric cancer and invasive lobular breast cancer (ILBC). The analysis of this link was also important to set proper management protocol for patients who were CDH1 mutation carriers which now involves genetic counselling, endoscopic surveillance and screening and prophylactic total gastrectomy (PTG). The study was conducted in accordance to the ‘PRISMA guidelines for reporting systematic review and meta-analysis’. Peer-reviewed studies were included from the PubMed database and relevant articles were selected to be included in the study. Appropriate inclusion/exclusion criteria with free full text English articles were applied while selecting the articles. A total of 10 studies on review with different study populations showed that of the 42 patients who were diagnosed with diffuse gastric cancer, 88% of them showed a positive germline E-cadherin gene mutation and 100% of the CDH1 mutation carriers showed microscopic changes of signet ring cell adenocarcinoma of the stomach. The beneficial effects of PTG with better survival rates and low mortality rates has outweighed other treatment modalities. Laparoscopic approach has proved to be more useful and a safer approach for gastrectomy surgeries with better post-operative management. The need for prophylactic mastectomy is also increased in the recent times and thus this requires a new set of guidelines for ILBC patients with hereditary diffuse gastric cancer (HDGC) syndrome.

Abstract 2523: Loss of expression of wild-type transcript of CDH1 gene is associated with overexpression of microRNA-20 in diffuse-type of gastric cancer

Abstract Background: Gastric cancer (GC) is the third cause of cancer death in the world. In Latin America, GC is one of the leading causes of death, particularly in Chile. E-cadherin has been classified as a tumor suppressor gene that participates in cell adhesion. Reduction or loss of E-cadherin expression could promote tumor progression particularly in the sporadic diffuse subtype of GC (SDGC). In addition, inactivation germline mutations of CDH1 (E-cadherin gene) have been linked to the hereditary diffuse gastric cancer (HDGC) syndrome. Methods: We evaluated the expression of E-cadherin by Immunohistochemistry (IHC) in SDGC (n=27) and HDGC (n=22) cohorts. We also analyzed, by Sanger sequencing the full coding region of CDH1 in both cohorts. To identified miRNA-CDH1 interactions, an in silico analysis by mirWalk 2.0 software (5 or more algorithms) was performed. To validated in silico findings, 10 paired tumor and normal matched fresh gastric tissues were analyzed by miQ-PCR (miRNA) and qRT-PCR assay (CDH1 transcript) were performed. Results: The expression analysis of E-cadherin showed loss of expression in 13/27 (48%) SDGC and in 19/22 (90%) HDGC cases, respectively. The decrease of E-cadherin expression was significantly higher in the hereditary cohort (p=0.002, χ2: 9.12, 95%CI:13.0-63.3). Exome sequence analysis of the full coding region of CDH1 identified 3 and 9 mutations in SDGC and HDGC, respectively. Correlation between loss of protein expression by IHC and mutations was not found. Next, we explore the role of miRNA, as an alternative mechanism of the loss of E-cadherin protein expression. In silico analysis identified 417 miRNAs candidates with predicted binding sites. Among these candidates, all members of the polycistronic cluster miR-17/92 have seed regions against the 3'-UTR of the CDH1 transcript. Levels of expression of all 6 members of the polycistronic cluster were validated against CDH1 expression in paired normal and tumor fresh tissues of SDGC. A strong inverse correlation between the overexpression of miR-20a and downregulation of CDH1 transcript was found exclusively in tumor tissue (p= 0.0267) but not in normal counterparts. These results were validated in the STAD-TCGA cohort. Conclusions: Our results might explain the loss of expression of CDH1 in GC due to overexpression miR-20, a member of the polycistronic cluster miR-17/92. Future experimental validation of the predicted seed region will be necessary to confirm these findings. Grant support: CONICYT-FONDAP-15130011, Fondecyt-1191928 Citation Format: Natalia Landeros, Maria A. Alarcon, Graciela Molina, Pablo Santoro, Keila Torres, Wilda Olivares, Ignacio Wichmann, Franz Villarroel-Espindola, Iva Polakovicova, Enrique Norero, Alejandro H. Corvalan. Loss of expression of wild-type transcript of CDH1 gene is associated with overexpression of microRNA-20 in diffuse-type of gastric cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2523.

Surveillance Endoscopy in the Management of Hereditary Diffuse Gastric Cancer Syndrome

Hereditary diffuse gastric cancer (HDGC) syndrome results from a germline CDH1 mutation, and microscopic foci of signet-ring carcinoma cells (SRCC) are present in nearly all gastrectomy specimens.1 The lifetime risk of invasive gastric cancer (GC) has been thought to be 70%,2 but recent data have suggested a lower risk of 37%.3 Prophylactic total gastrectomy is considered the standard of care, but many patients choose surveillance endoscopy instead. We sought to define the outcomes in CDH1-positive individuals who pursued endoscopic surveillance.

Identification of c.1531C>T Pathogenic Variant in the CDH1 Gene as a Novel Germline Mutation of Hereditary Diffuse Gastric Cancer.

Germline pathogenic variants in the CDH1 gene are a well-established cause of hereditary diffuse gastric cancer (HDGC) syndrome. The aim of this study was to characterize CDH1 mutations associated with HDGC from Chile, a country with one of the highest incidence and mortality rates in the world for gastric cancer (GC). Here, we prospectively include probands with family history/early onset of diffuse-type of GC. The whole coding sequence of the CDH1 gene was sequenced from genomic DNA in all patients, and a multidisciplinary team managed each family member with a pathogenic sequence variant. Thirty-six cases were included (median age 44 years/male 50%). Twenty-seven (75%) patients had diffuse-type GC at ≤50 years of age and 19 (53%) had first or second-degree family members with a history of HDGC. Two cases (5.5%) carried a non-synonymous germline sequence variant in the CDH1 gene: (a) The c.88C>A missense variant was found in a family with three diffuse-type GC cases; and (b) c.1531C>T a nonsense pathogenic variant was identified in a 22-year-old proband with no previous family history of HDGC. Of note, six family members carry the same nonsense pathogenic variant. Prophylactic gastrectomy in the proband’s sister revealed stage I signet-ring cell carcinoma. The finding of 1531C>T pathogenic variant in the CDH1 in proband with no previous family history of HDGC warrants further study to uncover familial clustering of disease in CDH1 negative patients. This finding may be particularly relevant in high incidence countries, such as the case in this report.

826P - Identification of a spectrum of germline mutations for hereditary diffuse gastric cancer in the Russian population by next-generation sequencing

BackgroundGastric cancer is the fifth most common malignancy in the world and the third leading cause of cancer death. Approximately 1–3% of gastric cancers are hereditary. Mutations of CDH1,the gene encoding E-cadherin, are the most common germline mutations detected in gastric cancer and cause hereditary diffuse gastric cancer (HDGC) syndrome. However, there has been no research previously conducted to identify candidate genes for predisposition to hereditary gastric cancer in the Russian population. The purpose of our research was to fill this gap. MethodsFor this study, we collected specimens of the venous blood of 40 patients (age up to 50 years) diagnosed with diffuse gastric cancer, and 80 gastric cancer tumor samples. To define the mutation in these patients we have used NGS with two panels -an Ion AmpliSeq Cancer Hot spot Panel v2, widely used for the analysis of «hot spots» in cancer related genes, and an in-house panel developed for sequencing the genes involved in gastric carcinogenesis (BMPR1A, SMAD4, CDH1, TP53, STK11, PTEN). All found mutations were verified in DNA obtained from peripheral blood lymphocytes, using polymerase chain reaction followed by Sanger sequencing. ResultsIn total, with two panels, we have identified 16 genetic germline variants with exceptionally low general population frequencies (no higher than 0.00004 according to the gnomAD database), and 4 genetic variants that have never been reported previously. We detected 6 deleterious mutations in CDH1 gene. All found mutations were missense mutations (A2512G:p.S838G, c.G1234A:p.V412I,.G2635A:p.G879S, c.C8G:p.P3R, c.C670T:p.R224C). Among these 6 mutations, one (c.A907c:pT303P) was newly discovered in this study. Other deleterious germline variants were found in APC,CDKN2B, STK11, MET, SMO and two in RB1 genes. The mean age at diagnosis of gastric cancer patients with mutation was 46,1. ConclusionsIdentifying mutation carriers in families is extremely important. The identification of germline CDH1 mutations offers the opportunity for potentially lifesaving prophylactic gastrectomy, which is the standard of care for these individuals. Legal entity responsible for the studyThe authors. FundingRussian Foundation for Basic Research (project No. 18-015-00333), Russian Foundation for Basic Research (project No. 18-29-09020). DisclosureAll authors have declared no conflicts of interest.