Integrated genomic profiling and modelling for risk stratification in patients with advanced oesophagogastric adenocarcinoma

Abstract

ObjectivePrognosis of patients with advanced oesophagogastric adenocarcinoma (mEGAC) is poor and molecular determinants of shorter or longer overall survivors are lacking. Our objective was to identify molecular features and develop a prognostic model by profiling the genomic features of patients with mEGAC with widely varying outcomes.DesignWe profiled 40 untreated mEGACs (20 shorter survivors <13 months and 20 longer survivors >36 months) with whole-exome sequencing (WES) and RNA sequencing and performed an integrated analysis of exome, transcriptome, immune profile and pathological phenotypes to identify the molecular determinants, developing an integrated model for prognosis and comparison with The Cancer Genome Atlas (TCGA) cohorts.ResultsKMT2C alterations were exclusively observed in shorter survivors together with high level of intratumour heterogeneity and complex clonal architectures, whereas the APOBEC mutational signatures were significantly enriched in longer survivors. Notably, the loss of heterozygosity in chromosome 4 (Chr4) was associated with shorter survival and ‘cold’ immune phenotype characterised by decreased B, CD8, natural killer cells and interferon-gamma responses. Unsupervised transcriptomic clustering revealed a shorter survivor subtype with distinct expression features (eg, upregulated druggable targets JAK2, MAP3K13 and MECOM). An integrated model was then built based on clinical variables and the identified molecular determinants, which significantly segregated shorter and longer survivors. All the above features and the integrated model have been validated independently in multiple TCGA cohorts.ConclusionThis study discovered novel molecular features prognosticating overall survival in patients with mEGAC and identified potential novel targets in shorter survivors.

Therapeutic prevention of COVID-19 in elderly: a case–control study

“…Recent studies have demonstrated a higher risk of mortality for COVID-19 patients taking PPIs [ 19 ]. The hypothesis explaining a greater severity under PPI would be that PPIs facilitate bacterial superinfections, due to a decrease in gastric acidity [ 21 ].…”

“…Therefore, it seems important to keep patients on PPIs, including those taking them for no obvious reason, awaiting further studies in this area. However, PPIs have no curative interest in our study, and they increase the risk of death if the treatment is left during the disease according to a retrospective Korean study [ 19 ]. On the curative side, metformin and antipsychotics seem to have beneficial effects on patient survival.…”

Multi-omics consensus ensemble refines the classification of muscle-invasive bladder cancer with stratified prognosis, tumour microenvironment and distinct sensitivity to frontline therapies

“…Recently, Hao et al . suggested that chromosome 4 (Chr4) loss could induce an unfavourable “cold” tumour immune microenvironment [41]. We then decided to investigate whether such an association between CNA and immunophenotype existed in the MIBC-TCGA cohort.…”

Rapidly Evolving Treatment Landscape for Metastatic Esophagogastric Carcinoma: Review of Recent Data

“…In this regard, a recent exome, transcriptome, immune profile analysis identified multiple independent prognostic factors in EGC discriminating longer from shorter survivors. 95 96 This agent is currently being evaluated in two phase 3 trials (NCT03504397, NCT03653507).…”

“…A shorter survivor subtype was found to be associated with aggressive phenotypes and distinct expression features (eg, upregulated druggable targets JAK2, MAP3K13 and MECOM), whereas a long survivor Chr4 and high APOBEC mutation signature with potentially greater benefit from immunotherapy 95. In addition, recent data provides compelling evidence for targeting Claudin18.2 (CLDN18.2), a gastric-specific tight junction protein exposed during tumorigenesis that may be enriched in HER2-negative…”