Andrea Rajnakova

RUNX3, A Novel Tumor Suppressor, Is Frequently Inactivated in Gastric Cancer by Protein Mislocalization

Loss of RUNX3 expression is suggested to be causally related to gastric cancer as 45% to 60% of gastric cancers do not express RUNX3 mainly due to hypermethylation of the RUNX3 promoter. Here, we examined for other defects in the properties of RUNX3 in gastric cancers that express RUNX3. Ninety-seven gastric cancer tumor specimens and 21 gastric cancer cell lines were examined by immunohistochemistry using novel anti-RUNX3 monoclonal antibodies. In normal gastric mucosa, RUNX3 was expressed most strongly in the nuclei of chief cells as well as in surface epithelial cells. In chief cells, a significant portion of the protein was also found in the cytoplasm. RUNX3 was not detectable in 43 of 97 (44%) cases of gastric cancers tested and a further 38% showed exclusive cytoplasmic localization, whereas only 18% showed nuclear localization. Evidence is presented suggesting that transforming growth factor-β is an inducer of nuclear translocation of RUNX3, and RUNX3 in the cytoplasm of cancer cells is inactive as a tumor suppressor. RUNX3 was found to be inactive in 82% of gastric cancers through either gene silencing or protein mislocalization to the cytoplasm. In addition to the deregulation of mechanisms controlling gene expression, there would also seem to be at least one other mechanism controlling nuclear translocation of RUNX3 that is impaired frequently in gastric cancer.

Experienced versus inexperienced confocal endoscopists in the diagnosis of gastric adenocarcinoma and intestinal metaplasia on confocal images

BACKGROUNDnConfocal laser endomicroscopy (CLE) may be used to diagnose gastric cancer and intestinal metaplasia, but the impact of CLE experience on the accuracy of confocal diagnosis of gastric cancer and intestinal metaplasia is not clear.nnnOBJECTIVEnTo establish the sensitivity, specificity, and intragroup interobserver agreement of CLE image interpretation by 3 experienced (group 1) and 3 inexperienced (group 2) CLE endoscopists for diagnosing gastric intestinal metaplasia (GIM) and adenocarcinoma.nnnDESIGNnBlinded review of CLE images for the diagnosis of gastric cancer or intestinal metaplasia.nnnSETTINGnTertiary care hospital.nnnPATIENTSnCLE images obtained ex vivo from gastrectomy specimens with proven gastric cancer and CLE images obtained in vivo from Chinese subjects older than 50 years of age by using matched biopsy specimens as reference standards.nnnMAIN OUTCOME MEASUREMENTSnSensitivity, specificity, and intragroup interobserver agreement of CLE image interpretation.nnnRESULTSnInterpretation of in vivo images by group 1 was associated with higher sensitivity (95.2% vs 61.9%, P = .039) and higher specificity (93.3% vs 62.2%, P < .001) for GIM than interpretation by group 2. The agreement between interpretation by group 1 and histology for GIM was higher than that for group 2 (κ = 0.864 vs 0.217). The sensitivity (93.3% for group 1 vs 86.7% for group 2, P = 1.000) and specificity (87.7% for group 1 vs 80.7% for group 2, P = .344) of interpretation of ex vivo CLE images for the diagnosis of gastric adenocarcinoma was similar for groups 1 and 2.nnnLIMITATIONSnSingle-center study.nnnCONCLUSIONSnExperience in CLE was associated with greater accuracy in the diagnosis of intestinal metaplasia.

Genomic and Epigenomic Profiling of High-Risk Intestinal Metaplasia Reveals Molecular Determinants of Progression to Gastric Cancer

Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. We performed (epi)genomic profiling of 138 IMs from 148 cancer-free patients, recruited through a 10-year prospective study. Compared with GCs, IMs exhibit low mutational burdens, recurrent mutations in certain tumor suppressors (FBXW7) but not others (TP53, ARID1A), chromosome 8q amplification, and shortened telomeres. Sequencing identified more IM patients with active Helicobacter pylori infection compared with histopathology (11%-27%). Several IMs exhibited hypermethylation at DNA methylation valleys; however, IMs generally lack intragenic hypomethylation signatures of advanced malignancy. IM patients with shortened telomeres and chromosomal alterations were associated with subsequent dysplasia or GC; conversely patients exhibiting normal-like epigenomic patterns were associated with regression.

Endoscopic tri-modal imaging improves detection of gastric intestinal metaplasia among a high-risk patient population in Singapore

BackgroundDetection of pre-neoplastic gastric mucosal changes and early gastric cancer (EGC) by white-light endoscopy (WLE) is often difficult. In this study we investigated whether combined autofluorescence imaging (AFI) and narrow band imaging (NBI) can improve detection of pre-neoplastic lesions and early gastric cancer in high-risk patients.Patients and MethodsChinese patients who were 50-years-old or above with dyspepsia were examined by both high-resolution WLE and combined AFI followed by NBI (AFI–NBI), consecutively in a prospective randomized cross-over setting, by two experienced endoscopists. The primary outcome was diagnostic ability of the two methods for patients with pre-neoplastic lesions such as intestinal metaplasia (IM) and mucosal atrophy.ResultsSixty-five patients were recruited. One patient with large advanced gastric cancer was found and excluded from the analysis. Among the remaining 64 patients, 38 (59xa0%) had IM; of these, 26 (68xa0%) were correctly identified by AFI–NBI (sensitivity 68xa0%, specificity 23xa0%) and only 13 (34xa0%) by WLE (sensitivity 34xa0%, specificity 65xa0%). AFI–NBI detected more patients with IM than did WLE (pxa0=xa00.011). Thirty-one patients (48xa0%) had mucosal atrophy. Ten patients (32xa0%) were identified by AFI–NBI (sensitivity 32xa0%, specificity 79xa0%) and four patients (13xa0%) by WLE (sensitivity 13xa0%, specificity 88xa0%) (pxa0=xa00.100). No dysplasia or EGC was found.ConclusionAFI–NBI identified significantly more patients with IM than did WLE. Our result warrants further studies to define the role of combined AFI–NBI endoscopy for detection of precancerous conditions.

Mo1993 Identification of Individuals at High Risk of Gastric Cancer for Targeted Endoscopic Screening

Identification of Individuals at High Risk of Gastric Cancer for Targeted Endoscopic Screening Zhu Feng, Li Lin Lim, Calvin J. Koh, David E. Ong, Lee Guan Lim, Khek-Yu Ho, Chia Chung-King, Christopher J. Khor, Choon Jin Ooi, Kwong Ming Fock, Jimmy B. So, Wee Chian Lim, Khoon-Lin Ling, Tiing Leong Ang, Andrew S. Wong, Jaideepraj Rao, Andrea Rajnakova, Ming Teh, Manuel Salto-Tellez, Supriya Srivastava, Yik Ying Teo, Khay Guan Yeoh

Recurrent lower gastrointestinal bleeding secondary to cytomegalovirus‐associated colonic ulcer in a non human immunodeficiency virus infected patient: timely diagnosis and treatment averted surgery

Mr C, a 68-year-old Chinese male with diabetes mellitus, previous stroke and ischaemic cardiomyopathy on clopidogrel, presented with haematochezia. Colonoscopy showed a sigmoid ulcer, which was treated endoscopically. Histology of the biopsy from the ulcer revealed non-specific changes. However, he presented with recurrent bleeding from this non-healing sigmoid ulcer. A review of the histologic specimen revealed CMV intranuclear inclusion bodies. He was treated with intravenous ganciclovir, with no further hematochezia.

RUNX3, a novel tumor suppressor, is frequently inactivated in gastric cancer by protein mislocalization (vol 65, pg 7743, 2005)

Loss of RUNX3 expression is suggested to be causally related to gastric cancer as 45% to 60% of gastric cancers do not express RUNX3 mainly due to hypermethylation of the RUNX3 promoter. Here, we examined for other defects in the properties of RUNX3 in gastric cancers that express RUNX3. Ninety-seven gastric cancer tumor specimens and 21 gastric cancer cell lines were examined by immunohistochemistry using novel anti-RUNX3 monoclonal antibodies. In normal gastric mucosa, RUNX3 was expressed most strongly in the nuclei of chief cells as well as in surface epithelial cells. In chief cells, a significant portion of the protein was also found in the cytoplasm. RUNX3 was not detectable in 43 of 97 (44%) cases of gastric cancers tested and a further 38% showed exclusive cytoplasmic localization, whereas only 18% showed nuclear localization. Evidence is presented suggesting that transforming growth factor-beta is an inducer of nuclear translocation of RUNX3, and RUNX3 in the cytoplasm of cancer cells is inactive as a tumor suppressor. RUNX3 was found to be inactive in 82% of gastric cancers through either gene silencing or protein mislocalization to the cytoplasm. In addition to the deregulation of mechanisms controlling gene expression, there would also seem to be at least one other mechanism controlling nuclear translocation of RUNX3 that is impaired frequently in gastric cancer.