Molecular Landscape and Clinical Implication of CCNE1-amplified Esophagogastric Cancer

Abstract

Cyclin E overexpression as a result of CCNE1 amplification is a critical driver of genomic instability in gastric cancer, but its clinical implication is largely unknown. Thus, we integrated genomic, transcriptomic, and immune profiling analysis of 7,083 esophagogastric tumors and investigated the impact of CCNE1 amplification on molecular features and treatment outcomes. We identified CCNE1 amplification in 6.2% of esophageal adenocarcinoma samples, 7.0% of esophagogastric junction carcinoma, 4.2% of gastric adenocarcinoma samples, and 0.8% of esophageal squamous cell carcinoma. Metastatic sites such as lymph node and liver showed an increased frequency of CCNE1 amplification relative to primary tumors. Consistent with a chromosomal instability phenotype, CCNE1 amplification was associated with decreased CDH1 mutation and increased TP53 mutation and ERBB2 amplification. We observed no differences in immune biomarkers such as PD-L1 expression and tumor mutational burden comparing CCNE1-amplified and nonamplified tumors, although CCNE1 amplification was associated with changes in immune populations such as decreased B cells and increased M1 macrophages from transcriptional analysis. Real-world survival analysis demonstrated that patients with CCNE1-amplified gastric cancer had worse survival after trastuzumab for HER2-positive tumors, but better survival after immunotherapy. These data suggest that CCNE1-amplified gastric cancer has a distinct molecular and immune profile with important therapeutic implications, and therefore further investigation of CCNE1 amplification as a predictive biomarker is warranted.

Significance: Advanced gastric cancer has a relatively dismal outcome with a 5-year overall survival of less than 10%. Furthermore, while comprehensive molecular analyses have established molecular subtypes within gastric cancers, biomarkers of clinical relevance in this cancer type are lacking. Overall, this study demonstrates that CCNE1 amplification is associated with a distinct molecular profile in gastric cancer and may impact response to therapy, including targeted therapy and/or immunotherapy.

FIGURE 1

Incidence of CCNE1 amplification in EGC by real-world analysis. NGS, including targeted and WES, was performed on 7,083 patients including 751 patients with ESCC, 2,276 patients with EA, 1,449 patients with EJC, and 2,607 patients with gastric adenocarcinoma (A). CN distribution of CCNE1 is reported by total numbers for EAC, ESCC, gastric adenocarcinoma, and EJC. CCNE1 amplification is defined as a CN ≥ 6 which is denoted by the black line. Percent CCNE1 amplification across cancer types (B). CCNE1 amplification by site, either primary tumor or metastasis, is shown for EAC, gastric adenocarcinoma, and EJC (C).

FIGURE 2

Frequently occurring molecular coalterations in CCNE1-amplified EGC. Frequency of comutated genes among all CCNE1-amplified and nonamplified EG adenocarcinoma by WES and NGS (A). CNAs co-occurring with CCNE1 amplification (B). LOH with CCNE1 amplification (C). HER2 overexpression or ERBB2 amplification in CCNE1-amplified EG adenocarcinoma by CISH assays, IHC, or NGS (D). Statistical significance is displayed as the following: *, q < 0.05; **, q < 0.01; ***, q < 0.001; ****, q < 0.0001.

FIGURE 3

Immune microenvironment and biomarker analysis of CCNE1-amplified EGC. Breakdown of immune biomarkers of CCNE1-amplified versus nonamplified EG adenocarcinoma by MMR/MSI-H status, PD-L1 (22C3) expression, and TMB high status (A). Characterization of percentage infiltration of specified immune cell populations in CCNE1-amplified versus nonamplified EGC from WTS by RNA deconvolution analysis (B). Expression of immune-related genes in CCNE1-amplified versus nonamplified from RNA sequencing (C). Immune-related gene signatures including IFNG and T cell–inflamed signatures (D). Statistical significance is displayed as the following: *, q < 0.05; **, q < 0.01; ***, q < 0.001; ****, q < 0.0001.

FIGURE 4

rwOS in patients with CCNE1-amplified gastric adenocarcinoma. OS (calculated from tissue collection to last day of contact) of CCNE1-amplified versus nonamplified gastric adenocarcinoma (A). Comparison of survival of CCNE1-amplified versus nonamplified gastric adenocarcinoma treated with oxaliplatin (calculated from start of treatment to last day of contact; B). Comparison of survival of CCNE1-amplified versus nonamplified gastric adenocarcinoma treated with trastuzumab (C). Comparison of survival of CCNE1-amplified versus nonamplified HER2-positive gastric adenocarcinoma (by IHC) treated with trastuzumab (D). Comparison of survival of CCNE1-amplified versus nonamplified HER2-positive gastric adenocarcinoma (by ERBB2 CNA analysis) treated with trastuzumab (E). Comparison of survival of CCNE1-amplified versus nonamplified gastric adenocarcinoma treated with immunotherapy with a PD1 or PD-L1 inhibitor (F).