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Investigation of the RB1-SOX2 axis constitutes a tool for viral status determination and diagnosis in Merkel cell carcinoma

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Abstract

MCC (Merkel cell carcinoma) is an aggressive neuroendocrine cutaneous neoplasm. Integration of the Merkel cell polyomavirus (MCPyV) is observed in about 80% of the cases, while the remaining 20% are related to UV exposure. Both MCPyV-positive and -negative MCCs—albeit by different mechanisms—are associated with RB1 inactivation leading to overexpression of SOX2, a major contributor to MCC biology. Moreover, although controversial, loss of RB1 expression seems to be restricted to MCPyV-negative cases.

The aim of the present study was to assess the performances of RB1 loss and SOX2 expression detected by immunohistochemistry to determine MCPyV status and to diagnose MCC, respectively.

Overall, 196 MCC tumors, 233 non-neuroendocrine skin neoplasms and 70 extra-cutaneous neuroendocrine carcinomas (NEC) were included. SOX2 and RB1 expressions were assessed by immunohistochemistry in a tissue micro-array. Diagnostic performances were determined using the likelihood ratio (LHR).

RB1 expression loss was evidenced in 27% of the MCC cases, 12% of non-neuroendocrine skin tumors and 63% of extra-cutaneous NEC. Importantly, among MCC cases, RB1 loss was detected in all MCPyV(-) MCCs, while MCPyV( +) cases were consistently RB1-positive (p < 0.001). SOX2 diffuse expression was observed in 92% of the MCC cases and almost never observed in non-neuroendocrine skin epithelial neoplasms (2%, p < 0.0001, LHR +  = 59). Furthermore, SOX2 diffuse staining was more frequently observed in MCCs than in extra-cutaneous NECs (30%, p < 0.001, LHR +  = 3.1).

These results confirm RB1 as a robust predictor of MCC viral status and further suggest SOX2 to be a relevant diagnostic marker of MCC.

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Funding

La ligue contre le cancer, HUGO Grant (Hôpitaux Universitaires du Grand Ouest).

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Authors and Affiliations

  1. Department of Pathology, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France

    Soumanth Thanguturi, Elodie Miquelestorena-Standley, Catherine Coco, Marie-Christine Machet, Gaëlle Fromont, Serge Guyétant & Thibault Kervarrec

  2. Platform of Somatic Tumor Molecular Genetics, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France

    Anne Tallet & Christine Collin

  3. Dermatology Department, LUNAM Université, CHU Angers, Angers, France

    Yannick Le Corre

  4. Dermatology Department, Université de Poitiers, CHU de Poitiers, 2 rue de la Milétrie, Poitiers, France

    Ewa Hainaut-Wierzbicka

  5. Department of General and Oncologic Dermatology, APHP & Research unit EA 4340, CARADERM network Ambroise-Paré hospital, Paris-Saclay University, university of Versailles-Saint-Quentin-en-Yvelines, Boulogne-Billancourt, France

    Astrid Blom & Philippe Saiag

  6. Dermatology Department, CHR Le Mans, 194 avenue Rubillard, Le Mans Cedex 09, France

    Nathalie Beneton

  7. Dermatology Department, CHR d’Orléans, 14 avenue de l’hôpital, Orléans, France

    Guido Bens & Julia Zaragoza

  8. Dermatology Department, Université de Franche Comté, CHU Besançon, 2 boulevard Fleming, EA3181, IFR133, Besançon, France

    Charlee Nardin & François Aubin

  9. Dermatology Department, CHR Rennes, Cedex,;InstitutDermatologique du Grand Ouest (IDGO), 2 rue Henri le Guilloux, Rennes , France

    Monica Dinulescu

  10. Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany

    Roland Houben & David Schrama

  11. Department of Pathology, Université de Bordeaux, Centre Hospitalier Universitaire de Bordeaux, Tours, France

    Marie-Laure Jullie

  12. Department of Pathology, APHM, Timone University Hospital, Marseille, France

    Nicolas Macagno

  13. Biologie des infections à polyomavirus” team, UMR INRA ISP 1282, Université de Tours, Tours, France

    Pauline Gaboriaud, Patricia Berthon, Antoine Touzé, Serge Guyétant, Mahtab Samimi & Thibault Kervarrec

  14. Department of Dermatology, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France

    Mahtab Samimi

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  1. Soumanth Thanguturi
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  2. Anne Tallet
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Contributions

ST, ATa, SG, SM, TK made substantial contributions to the conception, design of the work; contributed to the acquisition, analysis, interpretation of data; and drafted the work.

EM, CaC, YL, EH, AB, PS, NB, GB, JZ, CN, FA, MD, MM, RH, DS, ChC, GF MLJ, NM, PG, PB and ATo made substantial contributions to the acquisition, analysis and revised the work critically for important intellectual content.

All authors approved the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Thibault Kervarrec.

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Ethical approval

The local Ethics Committee in Human Research of Tours (France) approved the study (no. ID RCB2009-A01056-51)

Conflict of Interest:

The authors declare no conflict of interest.

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Serge Guyétant, Mahtab Samimi and Thibault Kervarrec contributed equally to this work.

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Thanguturi, S., Tallet, A., Miquelestorena-Standley, E. et al. Investigation of the RB1-SOX2 axis constitutes a tool for viral status determination and diagnosis in Merkel cell carcinoma. Virchows Arch 480, 1239–1254 (2022). https://doi.org/10.1007/s00428-022-03315-6

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  • DOI: https://doi.org/10.1007/s00428-022-03315-6

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