Development and Validation of an Easy-to-Implement, Practical Algorithm for the Identification of Molecular Subtypes of Gastric Cancer: Prognostic and Therapeutic Implications

Abstract

Background. Gastric cancer (GC) is a heterogeneous disease, and substantial efforts have been made to develop a molecular biology-based classification system for GC. Analysis of the genomic signature is not always feasible, and thus, we aimed to (i) develop and validate a practical immunohistochemistry (IHC)-and polymerase chain reaction (PCR)-based molecular classification of GC and (ii) to assess HER2 status according to this classification. Materials and Methods. A total of 894 consecutive patients with GC from two individual cohorts (training, n = 507; validation, n = 387) were classified using Epstein-Barr virus (EBV) in situ hybridization, microsatellite instability (MSI) testing, and IHC for E-cadherin and p53. Results. We were able to classify patients into five groups in the training cohort: group 1 (MSI + ), group 2 (EBV − , MSI − , non-epithelial-mesenchymal transition [non-EMT]-like, p53 − ), group 3 (EBV + ), group 4 (EBV − , MSI − , non-EMT-like, p53 + ), and group 5 (EBV − , MSI − , EMT-like). In the training cohort, each group showed different overall survival (OS) after gastrectomy (p < .001); group 1 had the best prognosis, and group 5 showed the worst survival outcome. The significant impact of the classification system on OS was also verified in the validation cohort (p = .004). HER2 positivity was observed in 6.5% of total population, and most of HER2-positive cases (93.1%) were included in groups 2 and 4. Conclusion. We developed and validated a modified IHCand PCR-based molecular classification system in GC, which showed significant impact on survival, irrespective of stage or other clinical variables. We also found close association between HER2 status and non-EMT phenotype in our classification system. The Oncologist 2019;24:e1321-e1330 Implications for Practice: Molecular classification of gastric cancer suggested by previous studies mostly relies on extensive genomic data analysis, which is not always available in daily practice. The authors developed a simplified immunohistochemistry-and polymerase chain reaction-based molecular classification of gastric cancer and proved the prognostic significance of this classification, as well as the close association between HER2 status and certain groups of the classification, in the largest consecutive cohort of gastric cancer. Results of this study suggest that this scheme is a cost-effective, easy-to-implement, and feasible way of classifying gastric cancer in daily clinical practice, also serving as a practical tool for aiding therapeutic decisions and predicting prognosis.

Prediction of <i>TP53</i> mutations by p53 immunohistochemistry and their prognostic significance in gastric cancer

“…These results suggest that p53 IHC can be used as a surrogate marker in predicting TP53 mutations, especially for strong expression, to predict nonsynonymous mutations. There have been recent attempts to use IHC for molecular classifications, and their clinicopathological significance has been increasingly important in GC [8,10]. Our results will be helpful for these new molecular classifications although negative expression should be cautiously interpreted.…”

“…However, one of the limitations of those two studies was that the methodology used requires high-end and high-cost technologies such as next-generation gene sequencing. Different groups have attempted to develop a more practical imple-Prediction of TP53 mutations by p53 immunohistochemistry and their prognostic significance in gastric cancer mentation of the molecular classification of GC in clinical settings based on the biomarkers of TCGA and ACRG studies [8][9][10].…”

Are Immunohistochemical Markers Useful in Phenotypic Gastric Cancer Classification?

“…The TCGA study found a high percentage of CDH1 gene mutations in the group of genomically stable GCs [8]. In addition, it has been shown that altered E-cadherin IHC is often not related to molecular CDH1 alterations [16,17], but is associated with a diffuse-type histology [33,34]. In fact, we found that cases with aberrant E-cad- herin were all diffuse-type GCs (Table 2).…”

“…Some studies interpret this heterogeneous staining pattern as normal E-cadherin expression [10], but others as aberrant [35]. To better define this category of GCs, a recent study even suggested considering mesenchymal-like morphologic features as histological criteria, in addition to altered E-cadherin expression [16].…”

“…Studies on immunophenotypic classification are still ongoing, because ever since the first study by Setia et al [10], they have highlighted some critical issues concerning the correct immunohistochemical definition of the subtypes, especially for p53 and E-cadherin assessments [14][15][16][17].…”