4.7 Article

Integrative analysis reveals a clinicogenomic landscape associated with liver metastasis and poor prognosis in hepatoid adenocarcinoma of the stomach

Journal

INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
Volume 18, Issue 14, Pages 5554-5574

Publisher

IVYSPRING INT PUBL
DOI: 10.7150/ijbs.71449

Keywords

hepatoid adenocarcinoma of the stomach; liver metastasis; prognosis; whole-exome sequencing; clinicogenomic landscape

Funding

  1. Zhejiang Science and Technology Planning Project [2021C03119]
  2. Key Research and Development Program of Science and Technology Department of Zhejiang Province [2018C03022]
  3. National Natural Science Foundation of China [81803107]
  4. Natural Science Foundation of Zhejiang Province [LQ20H160043]
  5. Project of the Regional Diagnosis and Treatment Centre of the Health Planning Committee [JBZX-201903]

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This study revealed the poor prognosis and high risk of liver metastasis in patients with hepatoid adenocarcinoma of the stomach (HAS). By comparing genomic data, the researchers identified a genomic landscape associated with unfavorable clinical features in HAS and potential therapeutic targets. These findings lay the foundations for precise diagnosis and therapy for this rare but lethal disease.
Hepatoid adenocarcinoma of the stomach (HAS) is a rare subtype of gastric cancer (GC) that histologically resembles hepatocellular carcinoma (HCC). Despite its low incidence, HAS had a poor 5-year survival rate. Currently, the linkages between clinicopathological and genomic features of HAS and its therapeutic targets remain largely unknown. Herein, we enrolled 90 HAS patients and 270 stage-matched non-HAS patients from our institution for comparing clinicopathological features. We found that HAS had worse overall survival and were more prone to develop liver metastasis than non-HAS in our cohort, which was validated via meta-analysis. By comparing whole-exome sequencing data of HAS (n=30), non-HAS (n=63), and HCC (n=355, The Cancer Genome Atlas), we identified a genomic landscape associated with unfavorable clinical features in HAS, which contained frequent somatic mutations and widespread copy number variations. Notably, signaling pathways regulating pluripotency of stem cells affected by frequent genomic alterations might contribute to liver metastasis and poor prognosis in HAS patients. Furthermore, HAS developed abundant multiclonal architecture associated with liver metastasis. Encouragingly, target analysis suggested that HAS patients might potentially benefit from anti-ERBB2 or anti-PD-1 therapy. Taken together, this study systematically demonstrated a high risk of liver metastasis and poor prognosis in HAS, provided a clinicogenomic landscape underlying these unfavorable clinical features, and identified potential therapeutic targets, laying the foundations for developing precise diagnosis and therapy in this rare but lethal disease.

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