Hepatoid adenocarcinoma of the stomach: a unique subgroup with distinct clinicopathological and molecular features

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Abstract

Objectives

Hepatoid adenocarcinoma of the stomach (HAS) is characterized by histological resemblance to hepatocellular carcinoma and a poor prognosis. The aim of this study is to elucidate the clinicopathological and molecular characteristics of HAS.

Methods

Forty-two patients with HAS who received gastrectomy were enrolled in this study. Based on a panel of 483 cancer-related genes, targeted sequencing of 24 HAS and 22 clinical parameter-matched common gastric cancer (CGC) samples was performed. Prognostic factors for overall survival (OS) and disease-free survival (DFS) were analysed with the Kaplan–Meier method.

Results

The most frequently mutated gene in both HAS and CGC was TP53, with a mutation rate of 30%. Additionally, CEBPA, RPTOR, WISP3, MARK1, and CD3EAP were identified as genes with high-frequency mutations in HAS (10–20%). Copy number gains (CNGs) at 20q11.21-13.12 occurred frequently in HAS, nearly 50% of HAS tumours harboured at least one gene with a CNG at 20q11.21-13.12. This CNG tended to be related to more adverse biobehaviour, including poorer differentiation, greater vascular and nerve invasion, and greater liver metastasis. Pathway enrichment analysis revealed that the HIF-1 signalling pathway and signalling pathways regulating stem cell pluripotency were specifically enriched in HAS. The survival analysis showed that a preoperative serum AFP level ≥ 500 ng/ml was significantly associated with poorer OS ( p = 0.007) and tended to be associated with poorer DFS ( p = 0.05).

Conclusion

CNGs at 20q11.21-13.12 happened frequently in HAS and tended to be related to more adverse biobehaviour. The preoperative serum AFP level was a sensitive prognostic biomarker for DFS and OS.

Electronic supplementary material

The online version of this article (10.1007/s10120-019-00965-5) contains supplementary material, which is available to authorized users.

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Most cited references 36

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Sensitive and accurate detection of copy number variants using read depth of coverage.

Seungtai Yoon, Zhenyu Xuan, Vladimir Makarov … (2009)

Methods for the direct detection of copy number variation (CNV) genome-wide have become effective instruments for identifying genetic risk factors for disease. The application of next-generation sequencing platforms to genetic studies promises to improve sensitivity to detect CNVs as well as inversions, indels, and SNPs. New computational approaches are needed to systematically detect these variants from genome sequence data. Existing sequence-based approaches for CNV detection are primarily based on paired-end read mapping (PEM) as reported previously by Tuzun et al. and Korbel et al. Due to limitations of the PEM approach, some classes of CNVs are difficult to ascertain, including large insertions and variants located within complex genomic regions. To overcome these limitations, we developed a method for CNV detection using read depth of coverage. Event-wise testing (EWT) is a method based on significance testing. In contrast to standard segmentation algorithms that typically operate by performing likelihood evaluation for every point in the genome, EWT works on intervals of data points, rapidly searching for specific classes of events. Overall false-positive rate is controlled by testing the significance of each possible event and adjusting for multiple testing. Deletions and duplications detected in an individual genome by EWT are examined across multiple genomes to identify polymorphism between individuals. We estimated error rates using simulations based on real data, and we applied EWT to the analysis of chromosome 1 from paired-end shotgun sequence data (30x) on five individuals. Our results suggest that analysis of read depth is an effective approach for the detection of CNVs, and it captures structural variants that are refractory to established PEM-based methods.

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An AFP-producing gastric carcinoma with features of hepatic differentiation. A case report.

Y Akishima-Fukasawa, M. Aizawa, H Ishikura … (1985)

A patient with primary gastric adenocarcinoma with extremely high serum alpha-fetoprotein (AFP) levels (12,000 ng/ml) is described. Histologically, foci strongly resembling hepatocellular carcinoma with hyaline globules were noted. Within tumor cells, AFP was identified with both light and electron microscopy, showing the production of AFP by tumor cells themselves. Furthermore, 88% of serum AFP combined with Concanavalin A (ConA), revealing that it was hepatic-type AFP and not germ-cell-type. Localization of alpha-1-antitrypsin within tumor cells was also noted. Ultrastructural study showed that there were two types of structures corresponding to periodic acid-Schiff (PAS)-positive globules, one of which, the proteinaceous material in intracytoplasmic lumina, was found to contain AFP. Among gastric adenocarcinomas with a high serum AFP level (several thousand or more ng/ml of AFP), foci resembling hepatocellular carcinomas have been reported by several investigators. Those gastric carcinomas, together with the current case, may constitute a clinicopathologic entity, hepatoid adenocarcinoma of the stomach.

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SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice.

Yupo Ma, Jun Qu, Jennifer D. Krause … (2006)

SALL4, a human homolog to Drosophila spalt, is a novel zinc finger transcriptional factor essential for development. We cloned SALL4 and its isoforms (SALL4A and SALL4B). Through immunohistochemistry and real-time reverse-transcription-polymerase chain reaction (RT-PCR), we demonstrated that SALL4 was constitutively expressed in human primary acute myeloid leukemia (AML, n = 81), and directly tested the leukemogenic potential of constitutive expression of SALL4 in a murine model. SALL4B transgenic mice developed myelodysplastic syndrome (MDS)-like features and subsequently AML that was transplantable. Increased apoptosis associated with dysmyelopoiesis was evident in transgenic mouse marrow and colony-formation (CFU) assays. Both isoforms could bind to beta-catenin and synergistically enhanced the Wnt/beta-catenin signaling pathway. Our data suggest that the constitutive expression of SALL4 causes MDS/AML, most likely through the Wnt/beta-catenin pathway. Our murine model provides a useful platform to study human MDS/AML transformation, as well as the Wnt/beta-catenin pathway's role in the pathogenesis of leukemia stem cells.

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Author and article information

Contributors

Lin Shen:

ORCID: http://orcid.org/0000-0002-8798-4756

+86-10-88196561 , linshenpku@163.com

Xiaotian Zhang: +86-10-88196561 , zhangxiaotianmed@163.com

Journal

Journal ID (nlm-ta): Gastric Cancer

Journal ID (iso-abbrev): Gastric Cancer

Title: Gastric Cancer

Publisher: Springer Singapore (Singapore )

ISSN (Print): 1436-3291

ISSN (Electronic): 1436-3305

Publication date (Electronic): 15 April 2019

Publication date PMC-release: 15 April 2019

Publication date (Print): 2019

Volume: 22

Issue: 6

Pages: 1183-1192

Affiliations

[1 ]GRID grid.412474.0, ISNI 0000 0001 0027 0586, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), , Peking University Cancer Hospital and Institute, ; Fucheng Road 52, Haidian District, Beijing, 100142 China

[2 ]GRID grid.412474.0, ISNI 0000 0001 0027 0586, Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), , Peking University Cancer Hospital and Institute, ; Beijing, 100142 China

Author information

Lin Shen http://orcid.org/0000-0002-8798-4756

Article

Publisher ID: 965

DOI: 10.1007/s10120-019-00965-5

PMC ID: 6811386

PubMed ID: 30989433

SO-VID: 839361de-71bc-4026-8fc6-ced38866086d

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 3 January 2019

Date accepted : 6 April 2019

Funding

Funded by: National Key Research and Development Program of China

Award ID: 2017YFC1308900

Award Recipient : Lin Shen

Funded by: Beijing Natural Science Foundation

Award ID: 7161002

Award Recipient : Lin Shen

Funded by: Capital’s Funds for Health Improvement and Research

Award ID: 2016-1-1021

Award Recipient : Xiaotian Zhang

Custom metadata

issue-copyright-statement © The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2019

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hepatoid adenocarcinoma of the stomach (has),copy number gain (cng),chromosome 20

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hepatoid adenocarcinoma of the stomach (has), copy number gain (cng), chromosome 20

Hepatoid adenocarcinoma of the stomach: a unique subgroup with distinct clinicopathological and molecular features

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Karger: Oncology

Most cited references 36

Sensitive and accurate detection of copy number variants using read depth of coverage.

An AFP-producing gastric carcinoma with features of hepatic differentiation. A case report.

SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice.

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