RB1-deficient squamous cell carcinoma: the proposed source of combined Merkel cell carcinoma

Ryan C. DeCoste, Noreen M. Walsh, Daniel Gaston, Thai Yen Ly, Sylvia Pasternak, Sam Cutler, Mat Nightingale, Michael D. Carter

Producción científica: Contribución a una revistaArtículorevisión exhaustiva

14 Citas (Scopus)

Resumen

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine (NE) carcinoma arising from integration of Merkel cell polyomavirus (MCPyV) DNA into a host cell or from ultraviolet light-induced genetic damage (proportions vary geographically). Tumors in the latter group include those with “pure” NE phenotype and those “combined” with other elements, most often squamous cell carcinoma (SCC). We performed comprehensive genomic profiling (CGP) of MCPyV+ and MCPyV− (pure and combined) tumors, to better understand their mutational profiles and shed light on their pathogenesis. Supplemental immunohistochemistry for Rb expression was also undertaken. After eliminating low quality samples, 37 tumors were successfully analyzed (14 MCPyV+, 8 pure MCPyV− and 15 combined MCPyV−). The SCC and NE components were sequenced separately in 5 combined tumors. Tumor mutational burden was lower in MCPyV+ tumors (mean 1.66 vs. 29.9/Mb, P < 0.0001). MCPyV− tumors featured frequent mutations in TP53 (95.6%), RB1 (87%), and NOTCH family genes (95.6%). No recurrently mutated genes were identified in MCPyV+ tumors. Mutational overlap in the NE and SCC components of combined tumors was substantial (‘similarity index’ >24% in 4/5 cases). Loss of Rb expression correlated with RB1 mutational (P < 0.0001) and MCPyV− status (P < 0.0001) in MCCs and it was observed more frequently in the SCC component of combined MCC than in a control group of conventional cutaneous SCC (P = 0.0002). Our results (i) support existing evidence that MCPyV+ and MCPyV− MCCs are pathogenetically distinct entities (ii) concur with earlier studies linking the NE and SCC components of combined MCCs via shared genetic profiles and (iii) lend credence to the proposal that an Rb-deficient subset of SCC’s is the source of phenotypically divergent combined MCCs.

Idioma originalEnglish
PublicaciónModern Pathology
DOI
EstadoAccepted/In press - 2022

Nota bibliográfica

Funding Information:
Financial support was provided by the Nova Scotia Health Authority Research Fund and the Department of Pathology and Laboratory Medicine Fund for Molecular Pathology housed at the QEII Foundation, Halifax, Nova Scotia, Canada.

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.

ASJC Scopus Subject Areas

  • Pathology and Forensic Medicine

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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