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Early Hereditary Diffuse Gastric Cancer (eHDGC) is Characterized by Subtle Genomic Instability and Active DNA Damage Response

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Pathology & Oncology Research

Abstract

Diffuse gastric cancer (DGC) is one of the two primary types of stomach cancer. Carriers of germline mutations in the gene encoding E-cadherin are predisposed to DGC. The primary aim of the present study was to determine if genomic instability is an early event in DGC and how it may lead to disease progression. Chromosomal aberrations in early intramucosal hereditary diffuse gastric cancer (eHDGC) were assessed using array comparative genomic hybridization (array CGH). Notably, no aneuploidy or other large-scale chromosomal rearrangements were detected. Instead, all aberrations affected small regions (< 4.8 Mb) and were predominantly deletions. Analysis of DNA sequence patterns revealed that essentially all aberrations possessed the characteristics of common fragile sites. These results and the results of subsequent immunohistochemical examinations demonstrated that unlike advanced DGC, eHDGCs is characterized by low levels of genomic instability at fragile sites. Furthermore, they express an active DNA damage response, providing a molecular basis for the observed indolence of eHDGC. This finding is an important step to understanding the pathology underlying natural history of DGC and supports a revision of the current definition of eHDGC as a malignant disease.

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Acknowledgements

This research was supported by HS and JC Anderson Charitable Trust and the Health Research Council of New Zealand.

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Authors and Affiliations

  1. Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, P.O. Box: 56, Dunedin, 9054, New Zealand

    Soroush Nasri, Bostjan Humara & Ahmad Anjomshoaa

  2. Milad Center for Medical Genetics, P.O. Box: 48156-59176, Sari, Iran

    Soroush Nasri, Nourodin Moradi & Naghmeh Gholipour

  3. Department of Medical Genetics, Faculty of Medicine, Kerman University of Medical Sciences, P.O. Box: 6619-14155, Kerman, Iran

    Ahmad Anjomshoaa

  4. Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology, Shahrak-e Pajoohesh, km 15, Tehran - Karaj Highway, P.O. Box: 14965-161, Tehran, Iran

    Naghmeh Gholipour

  5. Department of Marine biology, Faculty of Marine Science and Technology, Hormozgan University, P.O. Box: 3995, Bandar Abbas, Iran

    Sakineh Mashjoor

  6. Division of Biomedical Science and Biochemistry, Research School of Biology, ANU College of Medicine, Biology and Environment, Australian National University, P.O. Box: 2601, Canberra, Australia

    Peng Zhang

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  1. Soroush Nasri
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Correspondence to Naghmeh Gholipour.

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Nasri, S., Humara, B., Anjomshoaa, A. et al. Early Hereditary Diffuse Gastric Cancer (eHDGC) is Characterized by Subtle Genomic Instability and Active DNA Damage Response. Pathol. Oncol. Res. 25, 711–721 (2019). https://doi.org/10.1007/s12253-018-0547-9

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  • DOI: https://doi.org/10.1007/s12253-018-0547-9

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