Abstract
Simple SummaryIn this study, we present a simple but comprehensive molecular analysis of gastric carcinoma. The two major existing classification schemes show some discrepancies and are highly technically demanding, which makes them hardly feasible in daily diagnostic routines. Our workflow is based on simple and commercially available technology and provides a potential consensus approach by integrating the two major classification schemes. Furthermore, our approach allows the molecular subtypes to be assigned to different prognostic groups. We are convinced that our approach may help to better understand the molecular mechanisms of this worldwide health burden and that it could pave the way for new therapeutic targets.Gastric adenocarcinoma (GAC) is a heterogeneous disease and at least two major studies have recently provided a molecular classification for this tumor: The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ARCG). Both classifications quote four molecular subtypes, but these subtypes only partially overlap. In addition, the classifications are based on complex and cost-intensive technologies, which are hardly feasible for everyday practice. Therefore, simplified approaches using immunohistochemistry (IHC), in situ hybridization (ISH) as well as commercially available next generation sequencing (NGS) have been considered for routine use. In the present study, we screened 115 GAC by IHC for p53, MutL Homolog 1 (MLH1) and E-cadherin and performed ISH for Epstein–Barr virus (EBV). In addition, sequencing by NGS for TP53 and tumor associated genes was performed. With this approach, we were able to define five subtypes of GAC: (1) Microsatellite Instable (MSI), (2) EBV-associated, (3) Epithelial Mesenchymal Transition (EMT)-like, (4) p53 aberrant tumors surrogating for chromosomal instability and (5) p53 proficient tumors surrogating for genomics stable cancers. Furthermore, by considering lymph node metastasis in the p53 aberrant GAC, a better prognostic stratification was achieved which finally allowed us to separate the GAC highly significant in a group with poor and good-to-intermediate prognosis, respectively. Our data show that molecular classification of GAC can be achieved by using commercially available assays including IHC, ISH and NGS. Furthermore, we present an integrative workflow, which has the potential to overcome the uncertainty resulting from discrepancies from existing classification schemes.
Highlights
Gastric cancer is the fifth most common cancer worldwide and the third most common cause of cancer-related death, with over one million new cases annually and more than three-quarters of patients succumbing to the disease [1]
We present a combined approach using in situ hybridization (ISH), IHC and commercially available molecular tests to classify gastric cancers are adenocarcinomas (GAC) based on the The Cancer Genome Atlas (TCGA) and ACGR classification including the lymph node status and propose a simplified but integrated molecular classification of GAC, including prognostic subgroups
GAC were more common in males (64.3%) and most of the tumors were located in the antrum (47.0%)
Summary
Gastric cancer is the fifth most common cancer worldwide and the third most common cause of cancer-related death, with over one million new cases annually and more than three-quarters of patients succumbing to the disease [1]. The prognosis remains poor, despite implementation of standardized surgical procedures, reduced postoperative mortality and increased use of multimodal treatment, reaching a 5-year overall survival rate of 20–25% and a median survival of approximately 24 months [2,3,4,5,6]. Over 95% of gastric cancers are adenocarcinomas (GAC) [7,8]. GAC is classified histologically most widely by the Lauren classification, introduced in 1965 [9] and recently updated by further clarifying the histological features [10]. The WHO proposed a further histological classification, based on various morphological patterns but without prognostic impact [7]
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