Abstract
Alpha-fetoprotein producing gastric carcinoma (AFPGC) is a rare and aggressive subtype of gastric cancer. However, little is known about the genomic features of this disease. We perform whole-exome sequencing analysis of AFPGC, and identify 34 significantly mutated genes. Somatic copy number alterations analysis reveals several significant focal amplifications (e.g. 19q12, 17q12) and focal deletions (e.g. 1p36.11, 9p21.3), and some of these negatively affect the patient prognosis. Comparative analyses reveal that AFPGC has distinct genomic features from gastric cancer of The Cancer Genome Atlas as well as four molecular subtypes. Several frequently altered genes with potential as therapeutic targets are identified in AFPGC. Further analysis reveals that AFPGC with amplification of CCNE1 at 19q12 and/or ERBB2 at 17q12 show poorer survival and more aggressive. Subsequently, based on our established patient-derived xenograft models for AFPGC, translational research is performed and the therapeutic value of targeting CCNE1 and ERBB2 is validated. In this work, we provide an understanding of genomic characteristics of AFPGC and propose a platform to explore and validate the genome-guided personalized treatment for this disease.
Highlights
Alpha-fetoprotein producing gastric carcinoma (AFPGC) is a rare and aggressive subtype of gastric cancer
We provided an understanding of the clinicopathological and molecular features of AFPGC and focused on targetable genomic alterations
We validated that AFPGC had a higher liver metastasis rate and poorer prognosis
Summary
Integrated Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of somatic mutations and SCNA data revealed core signaling pathway alterations in AFPGC, including RTK/RAS/PI(3)K, p53/cell cycle, and JAK/ STAT (Fig. 3 and Supplementary Data 8). The results revealed that the patients with a positive status of ERBB2 or CCNE1 had worse survival outcomes when compared to those with a negative status in AFPGC (HR = 2.07, P = 0.009, Fig. 4e; HR = 2.64, P < 0.001, Fig. 4g) Such phenomenon was not found in the TCGA-CIN cohort, which harbors the most frequent ERBB2 and CCNE1 amplification in TCGA subtypes (Fig. 4f, h). Patients with a positive status of CCNE1 demonstrated higher ratio of lymphovascular invasion (P = 0.012) and liver metastasis (P = 0.003) These findings indicated that amplification in ERBB2 or CCNE1 might contribute to tumor progression in AFPGC. The expressions of p-ERK, p-AKT, CDK2, and p-Rb were greatly decreased in the combined trastuzumab and AZD5438 treatment group as compared to other groups
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