Dataset Information

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

ABSTRACT:

Objective

Prognosis 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.

Design

We 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.

Results

KMT2C 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.

Conclusion

This study discovered novel molecular features prognosticating overall survival in patients with mEGAC and identified potential novel targets in shorter survivors.

SUBMITTER: Hao D

PROVIDER: S-EPMC10643023 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Hao Dapeng D He Siyuan S Harada Kazuto K Pizzi Melissa Pool MP Lu Yang Y Guan Pujun P Chen Lu L Wang Ruiping R Zhang Shaojun S Sewastjanow-Silva Matheus M Abdelhakeem Ahmed A Shanbhag Namita N Bhutani Manoop M Han Guangchun G Lee Jeffrey H JH Zhao Shuangtao S Weston Brian B Blum Murphy Mariela M Waters Rebecca R Estrella Jeannelyn Santiano JS Roy-Chowdhuri Sinchita S Gan Qiong Q Lee Ju-Seog JS Peng Guang G Hanash Samir M SM Calin George Adrian GA Song Xingzhi X Zhang Jianhua J Song Shumei S Wang Linghua L Ajani Jaffer A JA

Gut 20201217 11

<h4>Objective</h4>Prognosis 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.<h4>Design</h4>We profiled 40 untreated mEGACs (20 shorter survivors <13 months and 20 longer survivors >36 months) with whole-exome sequencing (WES) and ...[more]

PMID: 33334899

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Project description:BackgroundThe aim of the present study was to dissect the clinical outcome of GB patients through the integration of molecular, immunophenotypic and MR imaging features.MethodsWe enrolled 57 histologically proven and molecularly tested GB patients (5.3% IDH-1 mutant). Two-Dimensional Free ROI on the Biggest Enhancing Tumoral Diameter (TDFRBETD) acquired by MRI sequences were used to perform a manual evaluation of multiple quantitative variables, among which we selected: SD Fluid Attenuated Inversion Recovery (FLAIR), SD and mean Apparent Diffusion Coefficient (ADC). Characterization of the Tumor Immune Microenvironment (TIME) involved the immunohistochemical analysis of PD-L1, and number and distribution of CD3+, CD4+, CD8+ Tumor Infiltrating Lymphocytes (TILs) and CD163+ Tumor Associated Macrophages (TAMs), focusing on immune-vascular localization. Genetic, MR imaging and TIME descriptors were correlated with overall survival (OS).ResultsMGMT methylation was associated with a significantly prolonged OS (median OS = 20 months), while no impact of p53 and EGFR status was apparent. GB cases with high mean ADC at MRI, indicative of low cellularity and soft consistency, exhibited increased OS (median OS = 24 months). PD-L1 and the overall number of TILs and CD163+TAMs had a marginal impact on patient outcome. Conversely, the density of vascular-associated (V) CD4+ lymphocytes emerged as the most significant prognostic factor (median OS = 23 months in V-CD4high vs. 13 months in V-CD4low, p = 0.015). High V-CD4+TILs also characterized TIME of MGMTmeth GB, while p53mut appeared to condition a desert immune background. When individual genetic (MGMTunmeth), MR imaging (mean ADClow) and TIME (V-CD4+TILslow) negative predictors were combined, median OS was 21 months (95% CI, 0-47.37) in patients displaying 0-1 risk factor and 13 months (95% CI 7.22-19.22) in the presence of 2-3 risk factors (p = 0.010, HR = 3.39, 95% CI 1.26-9.09).ConclusionInterlacing MRI-immune-genetic features may provide highly significant risk-stratification models in GB patients.

Dataset Information

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

Objective

Design

Results

Conclusion

Publications

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

Similar Datasets

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