Merkel cell carcinoma; VP1; polyomavirus; replication; trichoblastoma; Pathology and Forensic Medicine; Histology; General Medicine
Abstract :
[en] [en] AIMS: Merkel cell carcinoma (MCC) is frequently caused by the Merkel cell polyomavirus (MCPyV). Characteristic for these virus-positive (VP) MCC is MCPyV integration into the host genome and truncation of the viral oncogene Large T antigen (LT), with full-length LT expression considered as incompatible with MCC growth. Genetic analysis of a VP-MCC/trichoblastoma combined tumour demonstrated that virus-driven MCC can arise from an epithelial cell. Here we describe two further cases of VP-MCC combined with an adnexal tumour, i.e. one trichoblastoma and one poroma.
METHODS AND RESULTS: Whole-genome sequencing of MCC/trichoblastoma again provided evidence of a trichoblastoma-derived MCC. Although an MCC-typical LT-truncating mutation was detected, we could not determine an integration site and we additionally detected a wildtype sequence encoding full-length LT. Similarly, Sanger sequencing of the combined MCC/poroma revealed coding sequences for both truncated and full-length LT. Moreover, in situ RNA hybridization demonstrated expression of a late region mRNA encoding the viral capsid protein VP1 in both combined as well as in a few cases of pure MCC.
CONCLUSION: The data presented here suggest the presence of wildtype MCPyV genomes and VP1 transcription in a subset of MCC.
Disciplines :
Oncology
Author, co-author :
Kervarrec, Thibault ; Department of Pathology, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France ; "Biologie des Infections à Polyomavirus" Team, UMR INRAE ISP 1282, Université de Tours, Tours, France
Appenzeller, Silke; Comprehensive Cancer Center Mainfranken, University Hospital of Würzburg, Würzburg, Germany
Tallet, Anne; Platform of Somatic Tumor Molecular Genetics, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France
Jullie, Marie-Laure; Department of Pathology, Hôpital Haut-Lévêque, CHU de Bordeaux, CARADERM Network, Pessac, France
Sohier, Pierre; Faculté de Médecine, Université Paris Cité, Paris, France ; Department of Pathology, Hôpital Cochin, AP-HP.Centre-Université Paris Cité, Paris, France
Guillonneau, Francois; 3P5 Proteomics, Hôpital Cochin, AP-HP, Centre-Université Paris Cité, Paris, France
Berthon, Patricia; "Biologie des Infections à Polyomavirus" Team, UMR INRAE ISP 1282, Université de Tours, Tours, France
Le Corre, Yannick; Dermatology Department, LUNAM Université, CHU Angers, Angers, France
Hainaut-Wierzbicka, Ewa; Dermatology Department, Université de Poitiers, CHU de Poitiers, Poitiers, France
Blom, Astrid; Department of General and Oncologic Dermatology, CARADERM Network Ambroise-Paré hospital, APHP & Research Unit EA 4340, University of Versailles-Saint-Quentin-en-Yvelines, Paris-Saclay University, Boulogne-Billancourt, France
Beneton, Nathalie; Dermatology Department, CHR Le Mans, Le Mans, France
Bens, Guido; Dermatology Department, CHR d'Orléans, Orléans, France ; Dermatology Department, CH de Blois, Blois, France
Nardin, Charline; Dermatology Department, Inserm 1098, Université de Franche Comté, CHU Besançon, Besançon, France
Aubin, Francois; Dermatology Department, Inserm 1098, Université de Franche Comté, CHU Besançon, Besançon, France
Dinulescu, Monica; Dermatology Department, CHR Rennes, Rennes, France ; Institut Dermatologique du Grand Ouest (IDGO), Rennes, France
Visée, Sebastien; Department of Pathology, Centre Hospitalier d'Angoulème, Angoulème, France
Herfs, Michael ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Touzé, Antoine; "Biologie des Infections à Polyomavirus" Team, UMR INRAE ISP 1282, Université de Tours, Tours, France
Guyétant, Serge; Department of Pathology, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France ; "Biologie des Infections à Polyomavirus" Team, UMR INRAE ISP 1282, Université de Tours, Tours, France
Samimi, Mahtab; "Biologie des Infections à Polyomavirus" Team, UMR INRAE ISP 1282, Université de Tours, Tours, France ; Departement of Dermatology, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France
Houben, Roland; Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany
Schrama, David; Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany
Interdisziplinäres Zentrum für Klinische Forschung Würzburg (IZKF B‐343), German Research Foundation (SCHR 1178/3‐1) and Ligue Nationale Contre le Cancer, Comités 16, 18, 28, HUGO Grant.
Harms PW, Harms KL, Moore PS et al. The biology and treatment of Merkel cell carcinoma: current understanding and research priorities. Nat. Rev. Clin. Oncol. 2018; 15; 763–776.
Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008; 319; 1096–1100.
Houben R, Celikdemir B, Kervarrec T, Schrama D. Merkel cell polyomavirus: infection, genome, transcripts and its role in development of Merkel cell carcinoma. Cancer 2023; 15; 444.
Shuda M, Feng H, Kwun HJ et al. T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. Proc. Natl. Acad. Sci. U.S.A. 2008; 105; 16272–16277.
Touzé A, Le Bidre E, Laude H et al. High levels of antibodies against merkel cell polyomavirus identify a subset of patients with merkel cell carcinoma with better clinical outcome. J. Clin. Oncol. 2011; 29; 1612–1619.
Cheng J, Rozenblatt-Rosen O, Paulson KG, Nghiem P, DeCaprio JA. Merkel cell polyomavirus large T antigen has growth-promoting and inhibitory activities. J. Virol. 2013; 87; 6118–6126.
Liu W, Yang R, Payne AS et al. Identifying the target cells and mechanisms of Merkel cell polyomavirus infection. Cell Host Microbe 2016; 19; 775–787.
Becker JC, Zur HA. Cells of origin in skin cancer. J. Invest. Dermatol. 2014; 134; 2491–2493.
Kervarrec T, Samimi M, Guyétant S et al. Histogenesis of Merkel cell carcinoma: a comprehensive review. Front. Oncol. 2019b; 9; 451.
Sunshine JC, Jahchan NS, Sage J, Choi J. Are there multiple cells of origin of Merkel cell carcinoma? Oncogene 2018; 37; 1409–1416.
Verhaegen ME, Harms PW, Van Goor JJ et al. Direct cellular reprogramming enables development of viral T antigen-driven Merkel cell carcinoma in mice. J. Clin. Invest. 2022; 132; e152069.
Walsh NM. Primary neuroendocrine (Merkel cell) carcinoma of the skin: morphologic diversity and implications thereof. Hum. Pathol. 2001; 32; 680–689.
Harms PW, Verhaegen ME, Hu K et al. Genomic evidence suggests that cutaneous neuroendocrine carcinomas can arise from squamous dysplastic precursors. Mod. Pathol. 2022; 35(4):506–514.
Kervarrec T, Appenzeller S, Samimi M et al. Merkel cell polyomavirus-negative-Merkel cell carcinoma originating from in situ squamous cell carcinoma: a keratinocytic tumor with neuroendocrine differentiation. J. Invest. Dermatol. 2022; 142(3 Pt A):516–527.
Martin B, Poblet E, Rios JJ et al. Merkel cell carcinoma with divergent differentiation: histopathological and immunohistochemical study of 15 cases with PCR analysis for Merkel cell polyomavirus. Histopathology 2013; 62; 711–722.
Kervarrec T, Aljundi M, Appenzeller S et al. Polyomavirus-positive Merkel cell carcinoma derived from a trichoblastoma suggests an epithelial origin of this Merkel cell carcinoma. J. Invest. Dermatol. 2020; 140(5):976–985.
Kervarrec T, Tallet A, Miquelestorena-Standley E et al. Diagnostic accuracy of a panel of immunohistochemical and molecular markers to distinguish Merkel cell carcinoma from other neuroendocrine carcinomas. Mod. Pathol. 2019; 32(4):499–510.
Harms KL, Healy MA, Nghiem P et al. Analysis of prognostic factors from 9387 Merkel cell carcinoma cases forms the basis for the new 8th edition AJCC staging system. Ann. Surg. Oncol. 2016; 23; 3564–3571.
Kervarrec T, Samimi M, Gaboriaud P et al. Detection of the Merkel cell polyomavirus in the neuroendocrine component of combined Merkel cell carcinoma. Virchows Arch. Int. J. Pathol 2018; 472(5):825–837.
Jiang H, Lei R, Ding S-W, Zhu S. Skewer: a fast and accurate adapter trimmer for next-generation sequencing paired-end reads. BMC Bioinf. 2014; 15; 182.
Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet. J. 2011; 17; 10.
Li H, Durbin R. Fast and accurate short read alignment with burrows-wheeler transform. Bioinformatics 2009; 25; 1754–1760.
Li H, Handsaker B, Wysoker A et al. The sequence alignment/map format and SAMtools. Bioinformatics 2009; 25; 2078–2079.
McKenna A, Hanna M, Banks E et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010; 20; 1297–1303.
Cibulskis K, Lawrence MS, Carter SL et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat. Biotechnol. 2013; 31; 213–219.
Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010; 38; e164.
Goncearenco A, Rager SL, Li M, Sang Q-X, Rogozin IB, Panchenko AR. Exploring background mutational processes to decipher cancer genetic heterogeneity. Nucleic Acids Res. 2017; 45(W1); W514–W522.
Liang Y, Qiu K, Liao B et al. Seeksv: an accurate tool for somatic structural variation and virus integration detection. Bioinformatics 2017; 33; 184–191.
Collina G, Bagni A, Fano RA. Combined neuroendocrine carcinoma of the skin (Merkel cell tumor) and trichilemmal cyst. Am. J. Dermatopathol. 1997; 19; 545–548.
Ivan D, Bengana C, Lazar AJ, Diwan AH, Prieto VG. Merkel cell tumor in a trichilemmal cyst: collision or association? Am. J. Dermatopathol. 2007; 29; 180–183.
Molina-Ruiz AM, Bernárdez C, Requena L, Rütten A. Merkel cell carcinoma arising within a poroma: report of two cases. J. Cutan. Pathol. 2015; 42; 353–360.
Ogawa T, Donizy P, Wu C-L, Cornejo KM, Ryś J, Hoang MP. Morphologic diversity of Merkel cell carcinoma. Am. J. Dermatopathol. 2020; 42; 629–640.
Requena L, Jaqueti G, Rütten A, Mentzel T, Kutzner H. Merkel cell carcinoma within follicular cysts: report of two cases. J. Cutan. Pathol. 2008; 35; 1127–1133.
Su W, Kheir SM, Berberian B, Cockerell CJ. Merkel cell carcinoma in situ arising in a trichilemmal cyst: a case report and literature review. Am. J. Dermatopathol. 2008; 30; 458–461.
Sawaya JL, Khachemoune A. Poroma: a review of eccrine, apocrine, and malignant forms. Int. J. Dermatol. 2014; 53; 1053–1061.
Weber M, Nguyen MB, Li MY, Flora P, Shuda M, Ezhkova E. Merkel cell polyomavirus T-antigen-mediated reprogramming in adult Merkel cell progenitors. J. Invest. Dermatol. 2023; 29; S0022-202X(23)02120-6.
Harold A, Amako Y, Hachisuka J et al. Conversion of Sox2-dependent Merkel cell carcinoma to a differentiated neuron-like phenotype by T antigen inhibition. Proc. Natl. Acad. Sci. U.S.A 2019; 116(40):20104–20114.
Zur Hausen A, Rennspiess D, Winnepenninckx V, Speel E-J, Kurz AK. Early B-cell differentiation in Merkel cell carcinomas: clues to cellular ancestry. Cancer Res. 2013; 73; 4982–4987.
Borchert S, Czech-Sioli M, Neumann F et al. High-affinity Rb binding, p53 inhibition, subcellular localization, and transformation by wild-type or tumor-derived shortened Merkel cell polyomavirus large T antigens. J. Virol. 2014; 88; 3144–3160.
Schrama D, Sarosi E-M, Adam C et al. Characterization of six Merkel cell polyomavirus-positive Merkel cell carcinoma cell lines: Integration pattern suggest that large T antigen truncating events occur before or during integration. Int. J. Cancer 2019; 145; 1020–1032.
Starrett GJ, Thakuria M, Chen T et al. Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma. Genome Med. 2020; 12; 30.
Sastre-Garau X, Peter M, Avril M-F et al. Merkel cell carcinoma of the skin: pathological and molecular evidence for a causative role of MCV in oncogenesis. J. Pathol. 2009; 218; 48–56.
Haugg AM, Rennspiess D, zur Hausen A et al. Fluorescence in situ hybridization and qPCR to detect Merkel cell polyomavirus physical status and load in Merkel cell carcinomas. Int. J. Cancer 2014; 135; 2804–2815.
Fan K, Gravemeyer J, Ritter C et al. MCPyV large T antigen induced atonal homolog 1 (ATOH1) is a lineage-dependency oncogene in Merkel cell carcinoma. J. Invest. Dermatol. 2020; 140(1):56–65.e3.
Kervarrec T, Samimi M, Hesbacher S et al. Merkel cell polyomavirus T antigens induce Merkel cell-like differentiation in GLI1-expressing epithelial cells. Cancer 2020; 12(7):1989.
Kervarrec T, Chéret J, Paus R, Houben R, Schrama D. Transduction-induced overexpression of Merkel cell T antigens in human hair follicles induces formation of pathological cell clusters with Merkel cell carcinoma-like phenotype. Exp. Dermatol 2022; 31(2):259–260.
Nemeth K, Gorog A, Mezey E et al. Cover image: detection of hair follicle-associated Merkel cell polyomavirus in an immunocompromised host with follicular spicules and alopecia. Br. J. Dermatol. 2016; 175; 1409.
