Recurrent <i><scp>FOXK1</scp>::<scp>GRHL</scp></i> and <i><scp>GPS2</scp>::<scp>GRHL</scp></i> fusions in trichogerminoma
Thibault Kervarrec, Daniel Pissaloux, Jeremie Poilane, Franck Tirode, Anne Tallet, Christine Collin, Matthias Tallegas, Patricia Berthon, Pauline Gaboriaud, Pierre Sohier, Eduardo Calonje, Boštjan Luzar, Keisuke Goto, Kristof Cokelaere, Laurence Lamant, Brigitte Balme, Richard Wild, Agnes Neuville, Lydia Deschamps, Elisabeth Auberger, Veronique Paumier, Helene Bonte, Isabelle Moulonguet, Françoise Plantier, Valérie Cales, Vincent Pinsolle, Denis Roblet, Frantz Dupuy, Alexiane Dallot, Alice Seris, Thomas Jouary, Roland Houben, David Schrama, Sonja Hesbacher, Nicolas Macagno, Maxime Battistella, Bernard Cribier, Beatrice Vergier, Arnaud de la Fouchardière, Marie‐Laure Jullie
Abstract
We report 21 cases of trichogerminoma harbouring previously undescribed FOXK1::GRHL1/2 or GPS2::GRHL1/2/3 in-frame fusion transcripts. Microscopic examination of a preliminary set of five cases revealed well-delimitated tumours located in the dermis with frequent extension to the subcutaneous tissue. Tumours presented a massive and nodular architecture and consisted of a proliferation of basaloid cells. A biphasic pattern sometime resulting in tumour cell nests ('cell balls') was present. Immunohistochemistry demonstrated the expression of cytokeratins (CKs) 15, 17, and PHLDA1. In addition, numerous CK20-positive Merkel cells were detected. RNA sequencing (RNA-seq) revealed a FOXK1::GRHL1 chimeric transcript in three cases and a FOXK1::GRHL2 fusion in two cases. In a second series for validation (n = 88), FOXK1::GRHL1/2 fusion transcripts were detected by RT-qPCR or FISH in an additional 12 trichogerminomas and not in any other follicular tumour entities or basal cell carcinoma cases (n = 66). Additional RNA-seq analysis in trichogerminoma cases without detected FOXK1::GRHL1/2 rearrangements revealed GPS2::GRHL1 fusion transcripts in two cases, GPS2::GRHL2 in one case, and GPS2::GRHL3 fusion transcript in one case. Therefore, our study strongly suggests that GRHL1/2/3 gene rearrangements might represent the oncogenic driver in trichogerminoma, a subset of follicular tumours characterized by immature features and numerous Merkel cells. © 2022 The Pathological Society of Great Britain and Ireland.