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Frequency of CDH1 germline variants and contribution of dietary habits in early age onset gastric cancer patients in Brazil.

ABSTRACT: INTRODUCTION:The contribution of CDH1 germline variants to gastric cancer burden among young adults is unknown in Brazil. We aimed to evaluate the frequency of CDH1 germline variants and the diet/lifestyle habits in early age onset gastric cancer (EOGC, ??55 years old) patients. METHODOLOGY:From 2013 to 2015, a total of 88 unrelated and consecutive patients diagnosed with EOGC were enrolled. All CDH1 exons and intronic boundaries were sequenced, and large genomic rearrangements were screened by MLPA. CDH1 transcription analysis was performed for variants that could potentially induce an effect on splicing. The diet and lifestyle habits of EOGC patients were compared to Brazilian population diet and lifestyle, obtained from governmental databases. RESULTS:Of 88 patients, the mean age at EOGC diagnosis was 39 years and 55% fulfilled the criteria for hereditary diffuse gastric cancer. The majority of the tumors were diffuse (74%) and poorly differentiated (80%). In total, 4 novel missense variants of uncertain significance (VUS) were identified: c.313T>A, c.387G>T, c.1676G>A, and c.1806C>A. The MLPA results revealed no rearrangements and CDH1 transcription analysis for variants of interest were inconclusive. EOGC patients had a higher red (OR:2.6, 95%CI:1.4-4.9) and processed (OR:3.1, 95%CI:1.6-6.0) meat intake and higher fruit consumption (OR:0.4, 95%IC:0.3-0.7) compared to eating habits of the Brazilian population. CONCLUSIONS:No unequivocal pathogenic germline CDH1 variants were identified in Brazilian EOGC patients. Dietary habits may be associated with the EOGC development.

SUBMITTER: Guindalini RSC

PROVIDER: S-EPMC6694034 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Frequency of CDH1 germline variants and contribution of dietary habits in early age onset gastric cancer patients in Brazil.

Guindalini Rodrigo Santa Cruz RSC Cormedi Marina Cândido Visontai MCV Maistro Simone S Pasini Fátima Solange FS Branas Priscila Cristina Abduch Adas PCAA Dos Santos Liliane L de Lima Pereira Gláucia Fernanda GF de Bock Geertruida Hendrika GH Saccaro Daniela Marques DM Katayama Maria Lucia Hirata MLH Faraj Sheila Friedrich SF Safatle-Ribeiro Adriana A Ribeiro Junior Ulysses U Diz Maria Del Pilar Estevez MDPE de Gouvêa Ana Carolina Ribeiro Chaves ACRC Chammas Roger R Folgueira Maria Aparecida Azevedo Koike MAAK

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 20190320 5

<h4>Introduction</h4>The contribution of CDH1 germline variants to gastric cancer burden among young adults is unknown in Brazil. We aimed to evaluate the frequency of CDH1 germline variants and the diet/lifestyle habits in early age onset gastric cancer (EOGC, ≤ 55 years old) patients.<h4>Methodology</h4>From 2013 to 2015, a total of 88 unrelated and consecutive patients diagnosed with EOGC were enrolled. All CDH1 exons and intronic boundaries were sequenced, and large genomic rearrangements we ...[more]

PMID: 30895400

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Project description:ObjectiveTo screen and characterize germline variants for E-cadherin (CDH1) in non-hereditary gastric cancer (GC) patients and in subjects at risk of GC.Methods59 GCs, 59 first degree relatives (FDRs) of GC, 20 autoimmune metaplastic atrophic gastritis (AMAGs) and 52 blood donors (BDs) were analyzed for CDH1 by direct sequencing, structural modelling and bioinformatics. Functional impact on splicing was assessed for intronic mutations. E-cadherin/?-catenin immunohistochemical staining and E-cadherin mRNA quantification using RT-PCR were performed.ResultsIn GCs, 4 missense variants (p.G274S; p.A298T; p.T470I; p.A592T), 1 mutation in the 5'UTR (-71C>G) and 1 mutation in the intronic IVS12 (c.1937-13T>C) region were found. First pathogenic effect of p.A298T mutation was predicted by protein 3D modelling. The novel p.G274S mutation showed a no clear functional significance. Moreover, first, intronic IVS12 (c.1937-13T>C) mutation was demonstrated to lead to an aberrant CDH1 transcript with exon 11 deletion. This mutation was found in 2 GCs and in 1 BD. In FDRs, we identified 4 variants: the polymorphic (p.A592T) and 3 mutations in untranslated regions with unidentified functional role except for the 5'UTR (-54G>C) that had been found to decrease CDH1 transcription. In AMAGs, we detected 2 alterations: 1 missense (p.A592T) and 1 novel variant (IVS1 (c.48+7C>T)) without effect on CDH1 splicing. Several silent and polymorphic substitutions were found in all the groups studied.ConclusionsOverall our study improves upon the current characterization of CDH1 mutations and their functional role in GC and in individuals at risk of GC. Mutations found in untranslated regions and data on splicing effects deserve a particular attention like associated with a reduced E-cadherin amount. The utility of CDH1 screening, in addition to the identification of other risk factors, could be useful for the early detection of GC in subjects at risk (i.e. FDRs and AMAGs), and warrants further study.

Project description:BACKGROUND & AIMS:Early-onset gastric cancer, which develops in patients younger than most gastric cancers, is usually detected at advanced stages, has diffuse histologic features, and occurs more frequently in women. We investigated somatic genomic alterations associated with the unique characteristics of sporadic diffuse gastric cancers (DGCs) from younger patients. METHODS:We conducted whole exome and RNA sequence analyses of 80 resected DGC samples from patients 45 years old or younger in Korea. Patients with pathogenic germline mutations in CDH1, TP53, and ATM were excluded from the onset of this analysis, given our focus on somatic alterations. We used MutSig2CV to evaluate the significance of mutated genes. We recruited 29 additional early-onset Korean DGC samples and performed SNP6.0 array and targeted sequencing analyses of these 109 early-onset DGC samples (54.1% female, median age, 38 years). We compared the SNP6.0 array and targeted sequencing data of the 109 early-onset DGC samples with those from diffuse-type stomach tumor samples collected from 115 patients in Korea who were 46 years or older (late onset) at the time of diagnosis (controls; 29.6% female, median age, 67 years). We compared patient survival times among tumors from different subgroups and with different somatic mutations. We performed gene silencing of RHOA or CDH1 in DGC cells with small interfering RNAs for cell-based assays. RESULTS:We identified somatic mutations in the following genes in a significant number of early-onset DGCs: the cadherin 1 gene (CDH1), TP53, ARID1A, KRAS, PIK3CA, ERBB3, TGFBR1, FBXW7, RHOA, and MAP2K1. None of 109 early-onset DGC cases had pathogenic germline CDH1 mutations. A higher proportion of early-onset DGCs had mutations in CDH1 (42.2%) or TGFBR1 (7.3%) compared with control DGCs (17.4% and 0.9%, respectively) (P < .001 and P = .014 for CDH1 and TGFBR1, respectively). In contrast, a smaller proportion of early-onset DGCs contained mutations in RHOA (9.2%) than control DGCs (19.1%) (P = .033). Late-onset DGCs in The Cancer Genome Atlas also contained less frequent mutations in CDH1 and TGFBR1 and more frequent RHOA mutations, compared with early-onset DGCs. Early-onset DGCs from women contained significantly more mutations in CDH1 or TGFBR1 than early-onset DGCs from men. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times in patients with early-onset DGCs (hazard ratio, 3.4; 95% confidence interval, 1.5-7.7). RHOA activity was reduced by an R5W substitution-the RHOA mutation most frequently detected in early-onset DGCs. Silencing of CDH1, but not RHOA, increased migratory activity of DGC cells. CONCLUSIONS:In an integrative genomic analysis, we found higher proportions of early-onset DGCs to contain somatic mutations in CDH1 or TGFBR1 compared with late-onset DGCs. However, a smaller proportion of early-onset DGCs contained somatic mutations in RHOA than late-onset DGCs. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times of patients, which might account for the aggressive clinical course of early-onset gastric cancer. Female predominance in early-onset gastric cancer may be related to relatively high rates of somatic CDH1 and TGFBR1 mutations in this population.

Dataset Information

Frequency of CDH1 germline variants and contribution of dietary habits in early age onset gastric cancer patients in Brazil.

Publications

Frequency of CDH1 germline variants and contribution of dietary habits in early age onset gastric cancer patients in Brazil.

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