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Microbiome-derived cobalamin and succinyl-CoA as biomarkers for improved screening of anal cancer

Nature Medicine volume 29, pages 1738–1749 (2023)Cite this article

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An Author Correction to this article was published on 16 August 2023

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Abstract

Human papillomavirus can cause preinvasive, high-grade squamous intraepithelial lesions (HSILs) as precursors to cancer in the anogenital area, and the microbiome is suggested to be a contributing factor. Men who have sex with men (MSM) living with human immunodeficiency virus (HIV) have a high risk of anal cancer, but current screening strategies for HSIL detection lack specificity. Here, we investigated the anal microbiome to improve HSIL screening. We enrolled participants living with HIV, divided into a discovery (n = 167) and validation cohort (n = 46), and who were predominantly (93.9%) cisgender MSM undergoing HSIL screening with high-resolution anoscopy and anal biopsies. We identified no microbiome composition signatures associated with HSILs, but elevated levels of microbiome-encoded proteins producing succinyl coenzyme A and cobalamin were significantly associated with HSILs in both cohorts. Measurement of these candidate biomarkers alone in anal cytobrushes outperformed anal cytology as a diagnostic indicator for HSILs, increasing the sensitivity from 91.2% to 96.6%, the specificity from 34.1% to 81.8%, and reclassifying 82% of false-positive results as true negatives. We propose that these two microbiome-derived biomarkers may improve the current strategy of anal cancer screening.

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Fig. 1: Distribution of most abundant taxonomic groups among patients.
Fig. 2: Differences in microbial protein abundances among patient groups.
Fig. 3: Identification of two HSIL-associated metabolites produced by the anal microbiome through proteomic analysis.
Fig. 4: Succinyl CoA and cobalamin concentrations in anal samples are increased in patients with HSIL.
Fig. 5: Comparative diagnostic performance of succinyl CoA and cobalamin versus anal cytology for detecting anal HSIL.

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Data availability

The data used for these analyses are available as supporting material at https://github.com/sajanraju/SCRAtCH-Codes. All of the sequences are publicly available in the European Nucleotide Archive database under accession number PRJEB58898. The mass spectrometry proteomics data have been deposited with the ProteomeXchange Consortium via the PRIDE partner repository70 with the dataset identifier PXD037268.

Code availability

The code used for these analyses is available as supporting material at https://github.com/sajanraju/SCRAtCH-Codes.

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Acknowledgements

This work was supported by the ERANET TRANSCAN-2 program, JTC 2016 (SCRAtCH project, grant agreement no. 643638), funded by Instituto de Salud Carlos III (project AC17/00019), AECC (grant TRNSC17002SER), Lombardy Foundation for Biomedical Research, Italy (SCRAtCH project, grant agreement no. 643638); Federal Ministry of Education and Research, Germany (SCRAtCH project, grant agreement no. 643638); and the Research Council of Norway and Norwegian Cancer Society, Norway (SCRAtCH project, grant agreement no. 643638). The work was also supported by grants PI18/00154, ICI20/00058 and PI21/00141, funded by Instituto de Salud Carlos III and cofounded by the European Union, and grants PID2020-112758RB-I00 and PDC2021-121534-I00 funded by the Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación (AEI) (https://doi.org/10.13039/501100011033) and the European Union (‘NextGenerationEU’). The authors thank all of the study participants and their families and the staff involved in this study for their commitment to clinical research.

Author information

Author notes

  1. These authors contributed equally: Marius Trøseid, Jana Seifert, Manuel Ferrer.

Authors and Affiliations

  1. Department of Infectious Diseases, Hospital Universitario Ramón y Cajal, Facultad de Medicina, Universidad de Alcalá, IRYCIS, Madrid, Spain

    Sergio Serrano-Villar, Elena Moreno, Jose A. Perez Molina & Santiago Moreno

  2. CIBERINFEC, Instituto de Salud Carlos III, Madrid, Spain

    Sergio Serrano-Villar, Elena Moreno, Elena Sendagorta, Jose A. Perez Molina, Rosa del Campo & Santiago Moreno

  3. Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, Presidio Ospedaliero San Paolo, University of Milan, Milan, Italy

    Camilla Tincati

  4. Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway

    Sajan C. Raju, Johannes R. Hov & Marius Trøseid

  5. Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    Sajan C. Raju, Johannes R. Hov & Marius Trøseid

  6. Institute of Animal Science, University of Hohenheim, Stuttgart, Germany

    Johan S. Sáenz, Alina Kurz & Jana Seifert

  7. Centre for Environmental Biotechnology, Bangor University, Bangor, UK

    Rafael Bargiela

  8. Department of Infectious Diseases, IIS-FJD, Hospital Universitario Fundación Jiménez Diaz, Madrid, Spain

    Alfonso Cabello-Ubeda

  9. Department of Dermatology, Hospital Universitario La Paz-IdiPaz, Madrid, Spain

    Elena Sendagorta

  10. Department of Pathology, IRYCIS, Hospital Universitario Ramón y Cajal, Madrid, Spain

    Amparo de Benito

  11. Norwegian PSC Research Center and Section of Gastroenterology and Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway

    Johannes R. Hov

  12. Instituto de Catalisis y Petroleoquimica (ICP), CSIC, Madrid, Spain

    Laura Fernandez-Lopez & Manuel Ferrer

  13. Biostatistics Unit, IRYCIS, Hospital Universitario Ramón y Cajal, CIBERESP, Universidad de Alcalá, Madrid, Spain

    Alfonso Muriel

  14. Department of Microbiology, IRYCIS, Hospital Universitario Ramón y Cajal, Madrid, Spain

    Rosa del Campo

  15. Section for Clinical Immunology and Infectious Diseases, Oslo University Hospital, Oslo, Norway

    Marius Trøseid

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  1. Sergio Serrano-Villar
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Contributions

S.S.-V. conceptualized the study; S.S.-V., C.T., A.C.-U., E.S., S.M. and J.A.P.M. carried out recruitment and clinical follow-up; J.S.S., E.M., A.B., J.S. and M.F. handled the clinical specimens; L.F.-L. and M.F. carried out sample processing and metabolite analysis; M.F. supervised the 16S sequencing analysis; A.K., J.S.S. and J.S. carried out the proteomic analyses; E.M. performed the bacterial culture experiments; R.C. supervised the bacterial culture experiments; S.C.R., J.S.S. and R.B. performed the bioinformatic analysis; S.S.-V., M.T., J.R.H., and M.F. supervised the 16S RNA gene bioinformatic analysis; S.S.-V. carried out the statistical analysis; A.M. supervised the statistical analysis; S.S.-V. wrote the first version of the manuscript. All of the authors reviewed and approved the final manuscript.

Corresponding author

Correspondence to Sergio Serrano-Villar.

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Competing interests

S.S-V. and M.F. have filed a pending patent (Ref. EP22383112.4) as inventors related to the use of succinyl-CoA and cobalamin for HSIL detection. All other authors have no competing interests.

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Nature Medicine thanks Adam Burgener and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Alison Farrell, in collaboration with the Nature Medicine team.

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Serrano-Villar, S., Tincati, C., Raju, S.C. et al. Microbiome-derived cobalamin and succinyl-CoA as biomarkers for improved screening of anal cancer. Nat Med 29, 1738–1749 (2023). https://doi.org/10.1038/s41591-023-02407-3

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