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Background: The cell surface glycoprotein, E-Cadherin (CDH1) is a key regulator of adhesive properties in epithelial cells. Germline mutations in CDH1 are well-established as the defects underlying the Hereditary Diffuse Gastric Cancer (HDGC)syndrome: an increased risk of lobular breast cancer (LBC) has been described in HDGC kindreds. However, germline CDH1 mutations have not been described in LBC patients outside of HDGC families. We sought to investigate the frequency of germline CDH1 mutations in LBC patients with early onset disease or family histories of breast cancer without DGC. Methods: Germline DNA was analyzed in 23 women with invasive lobular or mixed ductal and lobular breast cancers who had at least one close relative with breast cancer or had themselves been diagnosed before age 45, had tested negative for a germline BRCA1 or BRCA2 mutation, and reported no personal or family history of diffuse gastric cancer. The full coding sequence of CDH1 including splice junctions was PCR amplified and screened for mutations using DHPLC and sequencing. Results: A novel germline CDH1 truncating mutation in the extracellular portion of the protein (517insA) was identified in one subject who had lobular breast cancer at age 42 and a first degree relative with invasive lobular breast cancer. Conclusions: Germline CDH1 mutations can be associated with invasive lobular breast cancer in the absence of diffuse gastric cancer. The finding, if confirmed, may have implications for management of individuals at risk for this breast cancer subtype, and compels clarification of the cancer risks in the syndrome.

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.

In gastric cancer (GC), epidermal growth factor receptor (EGFR) overexpression associates with poor prognosis. Addition of a chimeric monoclonal antibody against EGFR (cetuximab) to first-line treatment of metastatic colorectal tumours improved outcomes of patients (stratified for KRAS wild-type cancers), whereas GC patients did not benefit from this approach. In GC, however, stratification based on KRAS mutations was not performed, and the 30 % KRAS mutation frequency in microsatellite instable cancers (MSI), which represents ∼4 % of total GC, was disregarded. Further, intratumoural heterogeneity regarding KRAS mutant subpopulations might also contribute to anti-EGFR therapy failure. We assessed the mutational status of the entire KRAS coding sequence in 19 MSI-GC cases by multiplex PCR/sequencing and used peak height ratio determined from electropherograms from KRAS heterozygous mutants and histopathological evaluation to infer tumour heterogeneity in GC. Using 2 multiplex reactions per sample, we found that 26 % (5/19) of MSI-GC cases harboured KRAS mutations (2 G12D, 2 G13D, 1 G12V). No mutations were found outside the codon 12 and 13 hotspots. Our analysis supported the co-existence of KRAS-positive and KRAS-negative tumour populations in 4/5 MSI-GC cases. In conclusion, the method developed stands as a cost-effective and practical way for mutation screening of the entire KRAS coding sequence. KRAS mutations are frequent in our series of MSI cases and are often found in a subpopulation of the tumour and not in the whole tumour. Further studies are needed to access the implications of this heterogeneity in KRAS mutant and wild-type tumour clones in anti-EGFR therapy response.

Summary Familial gastric cancer comprises at least three major syndromes: hereditary diffuse gastric cancer, gastric adenocarcinoma and proximal polyposis of the stomach, and familial intestinal gastric cancer. The risk of development of gastric cancer is high in families affected b-y these syndromes, but only hereditary diffuse gastric cancer is genetically explained (caused by germline alterations of CDH1 , which encodes E-cadherin). Gastric cancer is also associated with a range of several cancer-associated syndromes with known genetic causes, such as Lynch, Li-Fraumeni, Peutz-Jeghers, hereditary breast–ovarian cancer syndromes, familial adenomatous polyposis, and juvenile polyposis. We present contemporary knowledge on the genetics, pathogenesis, and clinical features of familial gastric cancer, and discuss research and technological developments, which together are expected to open avenues for new genetic testing approaches and novel therapeutic strategies.

Contains fulltext : 152968.pdf (Publisher’s version ) (Open Access) Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patient's perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored. 14 p.

Hereditary Diffuse Gastric Cancer is an autosomal dominant inherited gastric cancer syndrome caused by germline alterations in CDH1 (E-cadherin) and CTNNA1 (alpha-E-catenin) genes. Germline CDH1 alterations encompass small frameshifts, splice-site, nonsense, and missense mutations, as well as large rearrangements. Most CDH1 truncating mutations are pathogenic, and several missense CDH1 mutations have a deleterious effect on E-cadherin function. CDH1 testing should be performed in probands. Screening of at-risk individuals is indicated from the age of consent following counselling with a multidisciplinary team. In mutation-positive individuals prophylactic gastrectomy is recommended. Endoscopic surveillance is an option for those refusing/postponing gastrectomy, those with mutations of undetermined significance, and in CDH1-negative families. Ongoing research focus on the search of genetic causes other than CDH1 or CTNNA1 germline defects; assessment of the pathogenicity and penetrance of CDH1 missense mutations and identification of somatic mechanisms behind the progression from early (indolent) lesions to invasive (lethal) carcinomas.

Hereditary diffuse gastric cancer (HDGC) syndrome, although rare, is highly penetrant at an early age, and is severe and incurable because of ineffective screening tools and therapy. Approximately 45% of HDGC families carry germline CDH1/E-cadherin alterations, 20% of which are nonsense leading to premature protein truncation. Prophylactic gastrectomy is the only recommended approach for all asymptomatic CDH1 mutation carriers. Suppressor-tRNAs can replace premature stop codons (PTCs) with a cognate amino acid, inducing readthrough and generating full-length proteins. The use of suppressor-tRNAs in HDGC patients could therefore constitute a less invasive therapeutic option for nonsense mutation carriers, delaying the development of gastric cancer. Our analysis revealed that 23/108 (21.3%) of E-cadherin-mutant families carried nonsense mutations that could be potentially corrected by eight suppressor-tRNAs, and arginine was the most frequently affected amino acid. Using site-directed mutagenesis, we developed an arginine suppressor-tRNA vector to correct one HDGC nonsense mutation. E-cadherin- deficient cell lines were transfected with plasmids carrying simultaneously the suppressor-tRNA and wild-type or mutant CDH1 mini-genes. RT-PCR, western blot, immunofluorescence, flow cytometry and proximity ligation assay (PLA) were used to establish the model, and monitor mRNA and protein expression and function recovery from CDH1 vectors. Cells expressing a CDH1 mini-gene, carrying a nonsense mutation and the suppressor-tRNA, recovered full-length E-cadherin expression and its correct localization and incorporation into the adhesion complex. This is the first demonstration of functional recovery of a mutated causative gene in hereditary cancer by cognate amino acid replacement with suppressor-tRNAs. Of the HDGC families, 21.3% are candidates for correction with suppressor-tRNAs to potentially delay cancer onset.

Submitted by Cristina Afonso (cac@lisboa.ucp.pt) on 2015-04-08T10:31:57Z No. of bitstreams: 1 Tese - O valor dos Comentários à Convenção Modelo da OCDE à luz dos protocolos e outros acordos c.pdf: 1466460 bytes, checksum: 1b5ceccd82398d02d7479b3a08b0e652 (MD5) Approved for entry into archive by Cristina Afonso (cac@lisboa.ucp.pt) on 2015-04-08T10:32:06Z (GMT) No. of bitstreams: 1 Tese - O valor dos Comentários à Convenção Modelo da OCDE à luz dos protocolos e outros acordos c.pdf: 1466460 bytes, checksum: 1b5ceccd82398d02d7479b3a08b0e652 (MD5) Made available in DSpace on 2015-04-08T10:32:06Z (GMT). No. of bitstreams: 1 Tese - O valor dos Comentários à Convenção Modelo da OCDE à luz dos protocolos e outros acordos c.pdf: 1466460 bytes, checksum: 1b5ceccd82398d02d7479b3a08b0e652 (MD5) Previous issue date: 2014-09-05

The only gastric cancer (GC) syndrome with a proven inherited defect is designated as hereditary diffuse gastric cancer (HDGC) and is caused by germline E-cadherin/CDH1 alterations. Other E-cadherin-associated hereditary disorders have been identified, encompassing HDGC families with or without cleft-lip/palate involvement, isolated early-onset diffuse GCs, and lobular breast cancer families without GC. To date, 141 probands harboring more than 100 different germline CDH1 alterations, mainly point mutations and large deletions, have been described in these different settings. A third of all HDGC families described so far carry recurrent CDH1 alterations. Full screening of CDH1 is recommended in patients fulfilling the HDGC criteria and total prophylactic gastrectomy is the only reliable intervention for carriers of pathogenic alterations. In this chapter, we discuss CDH1-associated syndromes, frequency and type of CDH1 germline alterations, clinical criteria, and guidelines for genetic counseling, molecular pathology, and available animal/cell line models of the disease.

Germline mutations in the CDH1 gene remained for more than 10 years the single molecular defect in hereditary diffuse gastric cancer families screened worldwide. The remaining families which completed the International Gastric Cancer Linkage Consortium criteria kept genetically unexplained, raising great concern from a clinical management standpoint.

Hereditary Diffuse Gastric Cancer is the only gastric cancer syndrome with a proven inherited defect. So far, a single gene has been found altered in this context – CDH1 – the E-cadherin encoding gene. Other E-cadherin-associated hereditary or inheritable disorders have been identified, encompassing Hereditary Diffuse Gastric Cancer families with or without cleft-lip/palate involvement, lobular breast cancer families, and early onset diffuse gastric cancers.

The only gastric cancer (GC) syndrome with a proven inherited defect is designated as hereditary diffuse gastric cancer (HDGC) and is caused by germline E-cadherin/CDH1 alterations. Other E-cadherin-associated hereditary disorders have been identified, encompassing HDGC families with or without cleft-lip/palate involvement, isolated early-onset diffuse GCs, and lobular breast cancer families without GC. To date, 141 probands harboring more than 100 different germline CDH1 alterations, mainly point mutations and large deletions, have been described in these different settings. A third of all HDGC families described so far carry recurrent CDH1 alterations. Full screening of CDH1 is recommended in patients fulfilling the HDGC criteria and total prophylactic gastrectomy is the only reliable intervention for carriers of pathogenic alterations. In this chapter, we discuss CDH1-associated syndromes, frequency and type of CDH1 germline alterations, clinical criteria, and guidelines for genetic counseling, molecular pathology, and available animal/cell line models of the disease.

E-cadherin and P-cadherin are major contributors to cell-cell adhesion in epithelial tissues, playing pivotal roles in important morphogenetic and differentiation processes during development, and in maintaining integrity and homeostasis in adult tissues. It is now generally accepted that alterations in these two molecules are observed during tumour progression of most carcinomas. Genetic or epigenetic alterations in E- and P-cadherin-encoding genes (CDH1 and CDH3, respectively), or alterations in their proteins expression, often result in tissue disorder, cellular de-differentiation, increased invasiveness of tumour cells and ultimately in metastasis. In this review, we will discuss the major properties of E- and P-cadherin molecules, its regulation in normal tissue, and their alterations and role in cancer, with a specific focus on gastric and breast cancer models.

Submitted by Cristina Afonso (cac@lisboa.ucp.pt) on 2014-07-21T14:48:12Z No. of bitstreams: 1 Tese.pdf: 495838 bytes, checksum: 3a6880d4bc24c60d2216e651394eee14 (MD5) Approved for entry into archive by Cristina Afonso (cac@lisboa.ucp.pt) on 2014-07-21T14:48:20Z (GMT) No. of bitstreams: 1 Tese.pdf: 495838 bytes, checksum: 3a6880d4bc24c60d2216e651394eee14 (MD5) Made available in DSpace on 2014-07-21T14:48:20Z (GMT). No. of bitstreams: 1 Tese.pdf: 495838 bytes, checksum: 3a6880d4bc24c60d2216e651394eee14 (MD5) Previous issue date: 2012-05

Aim Mitogen-activated protein kinase ( MAPK ) cascade and phosphatidylinositol 3-kinase ( PI3K ) survival pathways are frequently activated in the progression of gastrointestinal malignancies. In this study, we aimed to determine the frequency of gene mutations in members of these pathways – Epithelial Growth Factor Receptor ( EGFR ) , KRAS, BRAF, PIK3CA and MLK3 in a series of 63 gastric carcinomas with high levels of microsatellite instability (MSI). Methods Gene mutation analysis was performed by PCR amplification followed by direct sequencing. In selected tumour cases, EGFR expression was evaluated by immunohistochemistry. Association studies between molecular data and clinicopathologic characteristics were performed. Results Mutations in EGFR (3′-untranslated region [UTR] polyA repeat), KRAS , PIK3CA and MLK3 genes occurred in 30 (47.6%), 11 (17.5%), 9 (14.3%) and 2 (3.2%) of the MSI gastric cancer (GC) cases, respectively. No BRAF or EGFR hotspot mutations were identified. Overall, mutations in at least one of these genes were found in 55.6% (35/63) of gastric carcinomas. From those mutant cases 40.0% (14/35) of them had concomitant gene mutations, always involving EGFR polyA deletions. Interestingly, we observed significant associations between oncogenic mutations and female gender ( p =0.046) old age of diagnosis ( p =0.001) and intestinal subtype ( p =0.043). Conclusion Our results show that MSI gastric carcinoma frequently shows activation of EGFR - MAPK and PI3K pathways. Within all alterations found, deletions of the A13 repeats of EGFR were common, suggesting this molecular event as an important biomarker for stratification of GC patients for treatment with EGFR inhibitors.

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.

FUNDAMENTOS: Insuficiência cardíaca (IC) é uma doença comum com alta taxa de mortalidade. Anemia e insuficiência renal (IR) são frequentemente encontradas em portadores de IC associadas com maior gravidade da doença cardíaca e pior prognóstico. OBJETIVO: Avaliar a prevalência de anemia e insuficiência renal, bem como a associação entre esses dois quadros, em portadores de IC não hospitalizados. MÉTODOS: Foram observados pacientes acompanhandos na clínica de IC de um hospital universitário de julho de 2003 a novembro de 2006. Anemia foi definida como níveis de hemoglobina abaixo de 13 mg/dl para homens e de 12 mg/dl para mulheres. A função renal foi avaliada por meio da taxa de filtração glomerular (TFG), calculada pela fórmula simplificada do estudo MDRD (Modification of Diet in Renal Disease). RESULTADOS: Dos trezentos e quarenta e cinco pacientes incluídos neste estudo, 26,4% (n = 91) tinham anemia e 29,6% tinham insuficiência renal moderada a grave (TFG < 60 ml/min). A associação entre anemia e maior prevalência de insuficiência renal foi estatisticamente significante (41,8% vs. 25,2%; p = 0,005). Os pacientes em classe funcional III e IV apresentaram maior incidência de anemia (39,0% vs. 19,4%; p

Germline CDH1 point or small frameshift mutations can be identified in 30-50% of hereditary diffuse gastric cancer (HDGC) families. We hypothesized that CDH1 genomic rearrangements would be found in HDGC and identified 160 families with either two gastric cancers in first-degree relatives and with at least one diffuse gastric cancer (DGC) diagnosed before age 50, or three or more DGC in close relatives diagnosed at any age. Sixty-seven carried germline CDH1 point or small frameshift mutations. We screened germline DNA from the 93 mutation negative probands for large genomic rearrangements by Multiplex Ligation-Dependent Probe Amplification. Potential deletions were validated by RT-PCR and breakpoints cloned using a combination of oligo-CGH-arrays and long-range-PCR. In-silico analysis of the CDH1 locus was used to determine a potential mechanism for these rearrangements. Six of 93 (6.5%) previously described mutation negative HDGC probands, from low GC incidence populations (UK and North America), carried genomic deletions (UK and North America). Two families carried an identical deletion spanning 193 593 bp, encompassing the full CDH3 sequence and CDH1 exons 1 and 2. Other deletions affecting exons 1, 2, 15 and/or 16 were identified. The statistically significant over-representation of Alus around breakpoints indicates it as a likely mechanism for these deletions. When all mutations and deletions are considered, the overall frequency of CDH1 alterations in HDGC is approximately 46% (73/160). CDH1 large deletions occur in 4% of HDGC families by mechanisms involving mainly non-allelic homologous recombination in Alu repeat sequences. As the finding of pathogenic CDH1 mutations is useful for management of HDGC families, screening for deletions should be offered to at-risk families.

p.249-254 Submitted by Texeira Ana (atanateixeira@gmail.com) on 2012-06-21T12:48:41Z No. of bitstreams: 1 Reis, Francisco José Farias Borges dos.pdf: 486859 bytes, checksum: 9ba08b4e18dac6831ae35a77f0f87268 (MD5) Made available in DSpace on 2012-06-21T12:48:41Z (GMT). No. of bitstreams: 1 Reis, Francisco José Farias Borges dos.pdf: 486859 bytes, checksum: 9ba08b4e18dac6831ae35a77f0f87268 (MD5) Previous issue date: 2009 Background: Heart Failure (HF) is a common disease with a high rate of mortality. Anemia and renal failure (RF) are often found in patients with HF associated with higher severity of the heart disease and a worse prognosis. Objective: To evaluate the prevalence of anemia and RF, as well as the association between these two conditions, in non-hospitalized patients with HF. Methods: Patients treated at the HF Outpatient Clinic of a university hospital were followed from July 2003 to November 2006. Anemia was defined as hemoglobin levels < 13 mg/dl for men and 12 mg/dl for women. Renal function was assessed by the glomerular filtration rate (GFR), calculated by the simplified formula of the MDRD (Modification of Diet in Renal Disease) study. Results: Of the 345 patients included in this study, 26.4% (n = 91) had anemia and 29.6% had moderate to severe renal failure (GFR < 60 ml/min). The association between anemia and a higher prevalence of renal failure was statistically significant (41.8% vs. 25.2%; p = 0.005). The patients at functional class III and IV presented a higher incidence of anemia (39.0% vs. 19.4%; p

Importance. Hereditary gastric cancer (HGC) is a rare, autosomal dominant susceptibility syndrome characterized either by early onset diffuse gastric cancer and lobular breast cancer or aggregates of intestinal gastric cancer. The genetic etiology of Objectives. 1) Determine whether pathogenic germline mutations in genes related to upper gastrointestinal disorders (UGI) are causative in HGC and 2) show that a targeted multiplexed next generation sequencing approach is effective and efficient for detecting such mutations. Methods & Participants. 115 probands from families who met clinical criteria for HDGC (n=108) or FIGC (n=7) were included. HDGC participants have all previously tested negative for CDH1 variants. A custom panel of 55 genes previously associated with heritable UGI disorders was designed through literature research and collaborative efforts. The germline DNA of probands from each family was sequenced for all targeted regions using the MiSeq platform. Candidate variants were selected based on likelihood of pathogenicity (protein truncating, rare/novel pathogenic missense variants) then validated via Sanger sequencing. Tumour materials from mutation-carriers were analyzed for loss of heterozygosity via immunohistochemistry and/or second hit analysis. When available, germline DNA of additional family members was collected for segregation analysis. Results. We have identified clearly pathogenic mutations in unrelated HGC families, including two protein truncating mutations each in CTNNA1 and BRCA2 genes and two rare, pathogenic missense mutations each in SDHB and STK11 genes. Additional protein truncating mutations were identified in moderately penetrant genes ATM (4 families), MSR1 (2 families), and PALB2 (1 family). Overall, 13% of families included in this study were found to have pathogenic (8) or likely pathogenic (7) mutations in genes included on our custom panel. Tumour material was available from probands with truncating CTNNA1 variants, revealing distinct loss of protein expression using immunohistochmistry. This further supports the likelihood of pathogenicity. Conclusion & Relevance. Using a targeted next generation sequencing approach that significantly reduced sequencing cost while simultaneously improving turn-around time, we show that HGC families can carry pathogenic mutations outside the CDH1-locus, including genes commonly associated with other UGI syndromes. The genetic basis of the remaining families likely lies in yet to be discovered susceptibility genes or, in the case of HDGC, additional abnormalities at the CDH1-locus. Citation Format: Samantha Hansford, Hector LiChang, Pardeep Kaurah, Michelle Woo, Karey Shumansky, David F. Schaeffer, Giovanni Corso, George Zogopoulos, Steven Gallinger, Hugo Pinheiro, Franco Roviello, Carla Oliveira, David Huntsman. Genetic basis of hereditary gastric cancer: Beyond the CDH1 locus. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1282. doi:10.1158/1538-7445.AM2014-1282

E-cadherin plays a major role in cell–cell adhesion and inactivating germline mutations in its encoding gene predispose to hereditary diffuse gastric cancer. Evidence indicates that aside from its recognized role in early tumourigenesis, E-cadherin is also pivotal for tumour progression, including invasion and metastization. Herein, we discuss E-cadherin alterations found in a cancer context, associated cellular effects and signalling pathways, and we raise new key questions that will impact in the management of GC patients and families.

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