A Multi-Gene Model Effectively Predicts the Overall Prognosis of Stomach Adenocarcinomas With Large Genetic Heterogeneity Using Somatic Mutation Features.

Xianming Liu,Xianxiong Chen,Huayu Kang,Yejun Wang,Aiyue Chen,Qiongfang Fang,Xinjie Hui,Desheng Lu,Yueming Hu

doi:10.3389/fgene.2020.00940

Xianming Liu, Xianxiong Chen + Show 7 more

Open Access

https://doi.org/10.3389/fgene.2020.00940

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Abstract

BackgroundStomach adenocarcinoma (STAD) is one of the most common malignancies worldwide with poor prognosis. It remains unclear whether the prognosis is associated with somatic gene mutations.MethodsIn this research, we collected two independent STAD cohorts with both genetic profiling and clinical follow-up data, systematically investigated the association between the prognosis and somatic mutations, and analyzed the influence of heterogeneity on the prognosis-genetics association.ResultsTypical association was identified between somatic mutations and overall prognosis for individual cohorts. In The Cancer Genome Atlas (TCGA) cohort, a list of 24 genes was also identified that tended to mutate within cases of the poorest prognosis. The association showed apparent heterogeneity between different cohorts, although common signatures could be identified. A machine-learning model was trained with 20 common genes that showed a similar mutation rate difference between prognostic groups in the two cohorts, and it classified the cases in each cohort into two groups with significantly different prognosis. The model outperformed both single-gene models and TNM-based staging system significantly.ConclusionThe study made a systematic analysis on the association between STAD prognosis and somatic mutations, identified signature genes that showed mutation preference in different prognostic groups, and developed an effective multi-gene model that can effectively predict the overall prognosis of STAD in different cohorts.

Highlights

Stomach adenocarcinoma (STAD) represents the global fifth most common malignancy and the third leading cause of cancer mortality, with estimated 1,033,701 newly diagnosed cases and 782,685 deaths in 2018 (Bray et al, 2018)
142 The Cancer Genome Atlas (TCGA) STAD cases remained after filtering the duplicates, the ones missing somatic mutation or clinical information and those treated with targeting therapies
The cases were stratified according to sex and anatomic site, and the somatic mutation profiles were compared among the corresponding strata

Summary

Introduction

Stomach adenocarcinoma (STAD) represents the global fifth most common malignancy and the third leading cause of cancer mortality, with estimated 1,033,701 newly diagnosed cases and 782,685 deaths in 2018 (Bray et al, 2018). Multi-omics studies disclosed a high heterogeneity of STADs in genetics (Cancer Genome Atlas Research Network, 2014; Cristescu et al, 2015; Oh et al, 2018), gene expression (Boussioutas et al, 2003; Tan et al, 2011; Lei et al, 2013), and other molecular levels (Ooi et al, 2016; Ni et al, 2019; Zhang et al, 2019). Stomach adenocarcinoma (STAD) is one of the most common malignancies worldwide with poor prognosis It remains unclear whether the prognosis is associated with somatic gene mutations

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Conclusion