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Molecular profiling of signet-ring-cell carcinoma (SRCC) from the stomach and colon reveals potential new therapeutic targets

Oncogene volume 41, pages 3455–3460 (2022)Cite this article

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Abstract

Signet ring cell carcinoma (SRCC) is rare: about 10% of gastric cancer (GC) and 1% of colorectal cancer (CRC). SRCC is associated with poor prognosis, however the underlying molecular characteristics are unknown. SRCCs were analyzed using NGS, immunohistochemistry, and in situ hybridization. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. A total of 8500 CRC and 1100 GC were screened. Seventy-six SRCC were identified from the CRC cohort (<1%) and 98 from the GC cohort (9%). The most frequently mutated genes in CRC-SRCC were TP53 (47%), ARID1A (26%), APC (25%); in GC-SRCC were TP53 (42%), ARID1A (27%), CDH1 (11%). When compared to non-SRCC histology (N = 3522), CRC-SRCC (N = 37) more frequently had mutations in BRCA1 (11% vs 1%, P < 0.001) and less frequently mutations in APC (19% vs 78%, P < 0.001), KRAS (22% vs 51%, P = 0.001) and TP53 (47% vs 73%, P = 0.001). Among the GC cohort, SRCC (N = 54) had a higher frequency of mutations in CDH1, BAP1, and ERBB2, compared to non-SRCC (N = 540). Our data suggest that SRCCs harbor a similar molecular profile, regardless of the tumor location. Tailored therapy may become available for these patients.

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Fig. 1: Patient demographics.
Fig. 2
Fig. 3: Signet ring cell histology vs non-SRCC from colorectal primary sites.
Fig. 4
Fig. 5: Signet ring cell histology vs non-SRCC from gastric primary sites.
Fig. 6: Comparison of signet ring cell carcinomas between gastric and colorectal primaries.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was partly supported by National Cancer Institute (grant number P30CA014089), Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Gene Gregg Pancreas Research Fund, San Pedro Peninsula Cancer Guild, Daniel Butler Research Fund, Victoria and Philip Wilson Research Fund, Fong research project and Ming Hsieh research fund. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute of the National Institutes of Health.

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Authors and Affiliations

  1. Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Alberto Puccini, Martin D. Berger, Francesca Battaglin, Ryuma Tokunaga, Madiha Naseem, Wu Zhang & Heinz-Josef Lenz

  2. University of Genoa, Ospedale Policlinico San Martino—IRCCS, Genova, Italy

    Alberto Puccini & Fabio Catalano

  3. Caris Life Sciences, Phoenix, AZ, USA

    Kelsey Poorman & W. Michael Korn

  4. Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Innsbruck Medical University, Innsbruck, Austria

    Andreas Seeber

  5. West Virginia University Cancer Institute, Morgantown, WV, USA

    Richard M. Goldberg

  6. Levine Cancer Institute, Charlotte, NC, USA

    Mohamed E. Salem

  7. Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

    Anthony F. Shields & Philip A. Philip

  8. Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA

    John L. Marshall

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Contributions

Conception of the work; acquisition, analysis, and interpretation of data: AP, KP, HJL. Revision and approval of the submitted version: All authors

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Correspondence to Heinz-Josef Lenz.

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Competing interests

KP and WMK are employed by Caris Life Sciences. JLM and AS are consultants for Caris Life Sciences. AFS and RMG received research and travel support from Caris Life Sciences. MES and H-JL received travel support from Caris Life Sciences. AP, FC, FB, MDB, RT, MN, WZ, and PAP declare that there are no competing interests.

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All human subjects’ data were de-identified prior to analysis. Thus, this research was determined to be exempt from the requirement for informed consent per the Western Institutional Review Board (WIRB).

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Puccini, A., Poorman, K., Catalano, F. et al. Molecular profiling of signet-ring-cell carcinoma (SRCC) from the stomach and colon reveals potential new therapeutic targets. Oncogene 41, 3455–3460 (2022). https://doi.org/10.1038/s41388-022-02350-6

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