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

Corso, Giovanni; Pedrazzani, Corrado; Pinheiro, Hugo; Fernandes, Eduardo; Marrelli, Daniele; Rinnovati, Andrea; Pascale, Valeria; Seruca, Raquel; Oliveira, Carla; Roviello, Franco

doi:10.1016/j.ejca.2010.10.011

Cited by 67 publications

(61 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After observing the occurrence of germline Ecadherin mutations (CDH1) in hereditary diffuse GAC, and the earlier onset of these tumors, groups start investigating this mutation in EOGAC. Kim et al found only 2/25 EOGAC-patients to carry CDH1-mutaions patients (<50 years-old) [63], and Corso et al, 2011 [65] obtained similar data (2/21) for diffuse GACs. After reviewing the literature these authors found 7.2% of EOGAC carrying CDH1 mutations, but only 2.3% of EOGAC appear to have mutations that are highly likely to be pathogenic, and those were found in patients diagnosed before the age of 35 [66].…”

Section: Genetic and Genomics Aspectssupporting

confidence: 55%

Genomics and epidemiology for gastric adenocarcinomas

2017

Appl Cancer Res

View full text Add to dashboard Cite

Whereas the pathological aspects of Gastric Adenocarcinomas (GACs) have been well defined, the actual knowledge of its genesis and evolution remains to be translated to better diagnosis and to more effective therapeutics. As a consequence, the current treatment modalities are not yet able to modify the natural history of the disease, which still presents high mortality-rates worldwide. In this review we highlight the current status of relevant epidemiologic, therapeutic and genomics aspects of GACs and point to some of the current knowledge gaps that, if fully addressed, could contribute to a more effective treatment and better management of the patients that suffer from this often-lethal disease.

show abstract

Section: Genetic and Genomics Aspectssupporting

confidence: 55%

Genomics and epidemiology for gastric adenocarcinomas

2017

Appl Cancer Res

View full text Add to dashboard Cite

show abstract

“…E-cad genetic testing should be proposed also in cases of sporadic DGC with age at onset of B35 years (Fig. 1) [50].…”

Section: Resultsmentioning

confidence: 99%

Familial gastric cancer: update for practice management

2010

Self Cite

View full text Add to dashboard Cite

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

show abstract

“…3,4 Notably, germline CDH1 mutations may also be rarely found in families with LBC, lacking mutations in breast cancer-associated genes, 5 and in patients without prior descriptions of cancer familial aggregation, but presenting early onset of DGC (EODGC). 6 Approximately 80% of germline CDH1 mutations are truncating, 7-9 20% of which are nonsense. 10 Missense mutations, present in B20% of HDGC families, may be highly deleterious.…”

Section: Introductionmentioning

confidence: 99%

Rescue of wild-type E-cadherin expression from nonsense-mutated cancer cells by a suppressor-tRNA

et al. 2014

Self Cite

View full text Add to dashboard Cite

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/Ecadherin 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.

show abstract

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

Cited by 67 publications

References 56 publications

Genomics and epidemiology for gastric adenocarcinomas

Genomics and epidemiology for gastric adenocarcinomas

Familial gastric cancer: update for practice management

Rescue of wild-type E-cadherin expression from nonsense-mutated cancer cells by a suppressor-tRNA

Contact Info

Product

Resources

About