Comprehensive histopathological analysis of gastric cancer in European and Latin America populations reveals differences in PDL1, HER2, p53 and MUC6 expression

Abstract

Introduction: Gastric cancer (GC) burden is currently evolving with regional differences associated with complex behavioural, environmental, and genetic risk factors. The LEGACy study is a Horizon 2020-funded multi-institutional research project conducted prospectively to provide comprehensive data on the tumour biological characteristics of gastroesophageal cancer from European and LATAM countries.

Material and methods: Treatment-naïve advanced gastroesophageal adenocarcinoma patients were prospectively recruited in seven European and LATAM countries. Formalin-fixed paraffin-embedded primary tumour endoscopic biopsy samples were collected and submitted for central morphological and immunohistochemical characterization and TP53 molecular assessment and Helicobacter pylori infection.

Results: A total of 259 patients were included in the study: 137 (53%) from LATAM and 122 (47%) from Europe. Significant biological differences were detected between European and LATAM patients. Low representation of chromosomal instability (CIN) and HER2 positive cases were found in LATAM. MUC6 and PD-L1 were more frequently overexpressed in European cases, showing a significant correlation across the entire study population, with this association being especially pronounced in MMRdeficient cases. Both TP53 mutation by next-generation sequencing and p53 immunohistochemical aberrant pattern were linked with features associated with chromosomal instability. No regional differences were observed in H. pylori prevalence or abundance, indicating that the afore mentioned variations cannot be attributed to this factor.

Conclusion: Our findings underscore a need for region-specific approaches in gastroesophageal cancer diagnosis and treatment. MUC6 emerges as a putative immune regulator that needs further investigation. Research tailored to the unique biological profiles in different global regions is crucial to effectively address the observed disparities.

Keywords: Helicobacter pylori; Biomarkers; Europe; Gastric cancer; LATAM.

Fig. 1

A–I Immunohistochemical patterns of p53 and Ki67 expression. A tubular low-grade adenocarcinoma (HE, 20X, A) shows strong p53 immunostaining in all tumor cells (aberrant pattern, H-score = 300) (p53, 20X, B) and high proliferative activity (Ki67, 20X, C). An undifferentiated carcinoma (HE, 20X, D) exhibits a complete absence of p53 immunostaining in all tumor cells (aberrant pattern, H-score = 0) (p53, 20X, E) and high proliferative activity (Ki67, 20X, F). A poorly cohesive adenocarcinoma with signet ring cell morphology (HE, 20X, G) presents heterogeneous p53 expression in some tumor cells (normal pattern, H-score = 185) (p53, 20X, H) and proliferative activity below the median (Ki67, 20X, I). J–K: Distribution of cases according with TP53 mutational status (inner ring) and p53 immunohistochemical pattern (external ring) in Latin America (J) and Europe (K). L, M Correlation between histological Lauren’s classification (inner ring), WHO classification (middle ring) and the molecular surrogate immunohistochemical classification (external ring) in Latin America (L) and Europe (M)

Fig. 2

A–D A high-grade tubular adenocarcinoma (HE, 10X, A) shows loss of MLH1 and PMS2 nuclear expression in all tumor cells (MLH1, 20X, B). There is intense immunostaining of MUC6 in most neoplastic cells (MUC6, 20X, C) and diffuse expression of PD-L1 in the inflammatory component with a CPS score of 75 (PD-L1, 20X, D). E–G Correlation between the percentage of tumor cells expressing MUC6 and PD-L1 CPS categories: CPS ≥ 1 (E), CPS ≥ 5 (F), and CPS ≥ 10 (G). H Variation in MUC6 expression in tumor cells based on MMRp status. I Differences in PD-L1 CPS scores stratified by MUC6 expression levels (high: > 50% of tumor cells; low: ≤ 50% of tumor cells)