RHOA mutations and CLDN18-ARHGAP fusions in intestinal-type adenocarcinoma with anastomosing glands of the stomach

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

A subtype of intestinal-type adenocarcinoma of the stomach, characterized by low-grade cytological atypia and anastomosing glands, has been described in several reports under different names. One of the remarkable features of these lesions, herein referred to as intestinal-type adenocarcinoma with anastomosing glands, is the frequent association of poorly differentiated adenocarcinoma components. Here we analyzed 44 intestinal-type adenocarcinomas with anastomosing glands focusing on the molecular abnormalities that are common in diffuse-type gastric cancers. Next-generation sequencing identified RHOA and CDH1 mutations in 22 (50%) and one lesion (2%), respectively. Reverse transcription-PCR detected CLDN18-ARHGAP fusions in three lesions (7%). Immunohistochemically, none of the lesions showed abnormal p53 expression patterns whereas focal and diffuse loss of ARID1A was observed in four and one lesion, respectively. Examination of 37 lesions of dysplasia and 26 usual-type intramucosal adenocarcinomas identified one RHOA mutation in adenocarcinoma and no CLDN18-ARHGAP fusions, indicating that these genetic alterations are highly specific to intestinal-type adenocarcinomas with anastomosing glands among differentiated-type intramucosal neoplasms. The present study showed that intestinal-type adenocarcinoma with anastomosing glands represents a genetically distinct group of tumors with the frequent presence of RHOA mutations and CLDN18-ARHGAP fusions, which are thought to be specific to diffuse-type gastric cancers.

Related collections

Most cited references 16

Record: found
Abstract: found
Article: not found

Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations.

William Jackson, R. Seruca, Mirian Hayashi … (2001)

Germ-line truncating mutations in the E-cadherin (CDH1) gene have been found in families with hereditary diffuse gastric cancer. These families are characterized by a highly penetrant susceptibility to diffuse gastric cancer with an autosomal dominant pattern of inheritance, predominantly in young persons. We describe genetic screening, surgical management, and pathological findings in young persons with truncating mutations in CDH1 from two unrelated families with hereditary diffuse gastric cancer. Mutation-specific predictive genetic testing was performed by polymerase-chain-reaction amplification, followed by restriction-enzyme digestion and DNA sequencing in Family 1 and by heteroduplex analysis in Family 2. A total gastrectomy was performed prophylactically in five carriers of mutations who were between 22 and 40 years old. In each case, the entire mucosa of the stomach was extensively sampled for microscopical analysis. Superficial infiltrates of malignant signet-ring cells were identified in the surgical samples from all five persons who underwent gastrectomy. These early diffuse gastric cancers were multifocal in three of the five cases, and in one person infiltrates of malignant signet-ring cells were present in 65 of the 140 tissue blocks analyzed, representing in aggregate less than 2 percent of the gastric mucosa. We recommend genetic counseling and consideration of prophylactic gastrectomy in young, asymptomatic carriers of germ-line truncating CDH1 mutations who belong to families with highly penetrant hereditary diffuse gastric cancer.

0 comments Cited 58 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Is Open Access

Recurrent Fusion Genes in Gastric Cancer: CLDN18-ARHGAP26 Induces Loss of Epithelial Integrity.

Fei Yao, Jaya P Kausalya, Yee Sia … (2015)

Genome rearrangements, a hallmark of cancer, can result in gene fusions with oncogenic properties. Using DNA paired-end-tag (DNA-PET) whole-genome sequencing, we analyzed 15 gastric cancers (GCs) from Southeast Asians. Rearrangements were enriched in open chromatin and shaped by chromatin structure. We identified seven rearrangement hot spots and 136 gene fusions. In three out of 100 GC cases, we found recurrent fusions between CLDN18, a tight junction gene, and ARHGAP26, a gene encoding a RHOA inhibitor. Epithelial cell lines expressing CLDN18-ARHGAP26 displayed a dramatic loss of epithelial phenotype and long protrusions indicative of epithelial-mesenchymal transition (EMT). Fusion-positive cell lines showed impaired barrier properties, reduced cell-cell and cell-extracellular matrix adhesion, retarded wound healing, and inhibition of RHOA. Gain of invasion was seen in cancer cell lines expressing the fusion. Thus, CLDN18-ARHGAP26 mediates epithelial disintegration, possibly leading to stomach H(+) leakage, and the fusion might contribute to invasiveness once a cell is transformed.

0 comments Cited 56 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Model of the early development of diffuse gastric cancer in E-cadherin mutation carriers and its implications for patient screening.

Caroline A Owen, Thomas C. Smyrk, Fátima Carneiro … (2004)

Hereditary diffuse gastric cancer (HDGC) is a familial cancer syndrome caused, in 30-40% of cases, by germline mutations of the E-cadherin/CDH1 gene. The presence of clinically undetectable early gastric cancers has been previously reported in ten of ten prophylactic gastrectomies from germline E-cadherin mutation carriers. In the present study, detailed maps of the distribution of invasive cancers in nine of these ten stomachs were produced and precursor lesions of HDGC searched for. The nine gastrectomy specimens contained from 1 to 161 foci of early diffuse gastric cancer, occupying 0.005-2.96% of the gastric mucosa. Seven specimens contained focal in situ signet ring carcinoma. Pagetoid spread of signet ring cells was observed beneath the epithelial lining of gastric foveolae/glands. Helicobacter pylori organisms and associated pathology were absent from all cases. Two-dimensional maps of the gastrectomy specimens revealed lesions throughout the gastric mucosa without evidence of antral clustering. The distribution and size of the cancers in the gastrectomy specimens indicate that standard endoscopic screening with random or geographically targeted biopsies is unlikely to provide sufficiently sensitive clinical screening for at-risk individuals. An in situ precursor of signet ring carcinoma was identified and a model for neoplastic progression in the setting of HDGC is proposed. Copyright 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.