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Multi-regional sequencing reveals clonal and polyclonal seeding from primary tumor to metastases in advanced gastric cancer

  • Original Article—Liver, Pancreas, and Biliary Tract
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Abstract

Background

Tumor metastases to lymph nodes and distant organs are associated with worse prognosis in gastric cancer. However, little is known about the genetic profiles, subclonal architecture, and evolutional processes across primary tumors and metastases.

Methods

We analyzed the genetic alterations of 106 multiregional samples including primary tumors, lymph node metastases, and visceral metastases from 10 patients with advanced gastric cancer. Histologically different portions were obtained by laser-capture microdissection. We reconstructed the subclonal architectures and inferred the primary to lymph or visceral metastatic seeding patterns.

Results

The different histological portions in primary tumors had common mutations, suggesting common ancestral tumor origins transformed into distinct histological types. In almost all cases, TP53 mutations were identified as clonal mutations across primary tumors and metastases. Subclonal reconstruction and phylogenetic analysis showed primary tumors were classified into monoclonal or polyclonal tumors. All monoclonal primary tumors disseminated as metastases with the same tumor composition (100%, 26/26 samples). In contrast, polyclonal primary tumors mainly spread as metastases by way of polyclonal seeding (84%: 37/44 samples).

Conclusions

Clonal mutations were maintained at both the primary and metastatic sites and genetic divergence of these was low. These findings shed light on the genetic basis of primary tumor dissemination and metastatic processes in advanced gastric cancer.

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Acknowledgements

We thank all medical and ancillary staff of the hospital and the patients for consenting to participate. We thank H. Nikki March, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Funding

This study was supported by Grant-in-Aid for Genome Research Project from Yamanashi Prefecture, The Japan Society for the Promotion of Science (JSPS) KAKENHI Early-Career Scientists, Research Grant for Young Scholars, The YASUDA Medical Foundation and The Uehara Memorial Foundation.

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Authors and Affiliations

  1. Genome Analysis Center, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan

    Yosuke Hirotsu, Kenji Amemiya & Hitoshi Mochizuki

  2. Department of Surgery, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan

    Masao Hada

  3. Department of Pathology, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan

    Toshio Oyama

  4. Department of Gastroenterology, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan

    Hitoshi Mochizuki & Masao Omata

  5. The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8654, Japan

    Masao Omata

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  1. Yosuke Hirotsu
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Correspondence to Yosuke Hirotsu.

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Hirotsu, Y., Hada, M., Amemiya, K. et al. Multi-regional sequencing reveals clonal and polyclonal seeding from primary tumor to metastases in advanced gastric cancer. J Gastroenterol 55, 553–564 (2020). https://doi.org/10.1007/s00535-019-01659-6

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  • DOI: https://doi.org/10.1007/s00535-019-01659-6

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