Molecular subtyping of gastroesophageal dysplasia heterogeneity according to TCGA/ACRG classes

Abstract

Gastric adenocarcinoma has recently been classified into several subtypes on the basis of molecular profiling, which has been successfully reproduced by immunohistochemistry (IHC) and in situ hybridization (ISH). A series of 73 gastroesophageal dysplastic lesions (37 gastric dysplasia and 36 Barrett dysplasia; 44 low-grade dysplasia and 29 high-grade dysplasia) was investigated for mismatch repair proteins, E-cadherin, p53, and EBER status, to reproduce The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) molecular clustering. Overall, the dysplastic lesions were classified as follows: according to TCGA classification, EBV, 0/73 (0%), MSI, 6/73 (8.2%), GS, 4/73 (5.5%), CIN, 63/73 (86.3%); according to ACRG molecular subtyping, MSI, 6/73 (8.2%), MSS/EMT, 4/73 (5.5%), MSS/TP53−, 33/73 (45.2%), MSS/TP53+, 30/73 (41.1%). A positive association was found between MSS/TP53− and Barrett dysplasia (p = 0.0004), between MSS/TP53+ and LG dysplasia (p = 0.001) and between MSS/TP53+ and gastric dysplasia (p = 0.0018). Gastroesophageal dysplastic lesions proved to be heterogenous in terms of TCGA/ACRG classes, but with a different distribution from that of cancers, with no EBV-positive cases, an increasing presence of mismatch repair deficiency from low grade to high grade lesions, and a prevalence of p53 aberrations in Barrett dysplasia. The present study further demonstrated that gastroesophageal dysplastic lesions may be characterized by alterations in predictive/prognostic biomarkers, and this should be considered in routine diagnostic.

p53 as Exemplar Next-generation Immunohistochemical Marker: A Molecularly Informed, Pattern-based Approach, Methodological Considerations, and Pan-cancer Diagnostic Applications

“…There is little contemporary literature to address this application in the stomach. I found a recent study that used IHC and in situ hybridization [mismatch repair (MMR), p53, e-cadherin, and Epstein-Barr virus–encoded RNA] as correlates to TCGA molecular subtypes in gastric dysplasia; the authors reported mutant-pattern p53 (ie, completely absent or diffuse and strong) in 12.5% of 24 low-grade and 46.2% of 13 high-grade gastric dysplasia cases 60 . Given this result, it is certainly possible that mutant-pattern p53 is much less common in the stomach than in BE.…”

“…I found a recent study that used IHC and in situ hybridization [mismatch repair (MMR), p53, e-cadherin, and Epstein-Barr virus-encoded RNA] as correlates to TCGA molecular subtypes in gastric dysplasia; the authors reported mutant-pattern p53 (ie, completely absent or diffuse and strong) in 12.5% of 24 low-grade and 46.2% of 13 high-grade gastric dysplasia cases. 60 Given this result, it is certainly possible that mutant-pattern p53 is much less common in the stomach than in BE. I will note that I used to perform p53 IHC in foci of epithelial atypia in autoimmune metaplastic atrophic gastritis characterized by nuclear enlargement but uniform chromatin; I found all of these to be wild-type pattern and I suspect this represents "megaloblastic change.…”