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Alternative PDGFD rearrangements in dermatofibrosarcomas protuberans without PDGFB fusions

Bérengère Dadone-Montaudié 1, 2 Laurent Alberti 3, 4 Adeline Duc 4 Lucile Delespaul 5, 6 Tom Lesluyes 5, 6 Gaëlle Pérot 7 Agnès Lançon 4 Sandrine Paindavoine 4 Ilaria Mauro 1, 2 Jean Blay 3, 4 Arnaud de la Fouchardière 4 Frédéric Chibon 5, 6, 7 Marie Karanian 4 Gaëtan Mac Grogan 7 Valérie Kubiniek 1, 2 Frédérique Keslair 1, 2 Nathalie Cardot-Leccia 2 Audrey Michot 7 Virginie Perrin 4 Yanis Zekri 4 Jean-Michel Coindre 7, 8 Franck Tirode 3, 4 Florence Pedeutour 1, 2 Dominique Ranchère-Vince 4 François Le Loarer 7, 8 Daniel Pissaloux 3, 4, *
* Corresponding author
1 IRCAN - Institut de Recherche sur le Cancer et le Vieillissement
2 CHU Nice - Centre Hospitalier Universitaire de Nice
3 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
4 Centre Léon Bérard [Lyon]
5 ACTION - Actions for OnCogenesis understanding and Target Identification in ONcology
6 CRCT - Centre de Recherches en Cancérologie de Toulouse
7 Institut Bergonié [Bordeaux]
8 UB - Université de Bordeaux
Abstract : Dermatofibrosarcoma protuberans is underlined by recurrent collagen type I alpha 1 chain-platelet-derived growth factor B chain (COL1A1-PDGFB) fusions but ~ 4% of typical dermatofibrosarcoma protuberans remain negative for this translocation in routine molecular screening. We investigated a series of 21 cases not associated with the pathognomonic COL1A1-PDGFB fusion on routine fluorescence in situ hybridization (FISH) testing. All cases displayed morphological and clinical features consistent with the diagnosis of dermatofibrosarcoma protuberans. RNA-sequencing analysis was successful in 20 cases. The classical COL1A1-PDGFB fusion was present in 40% of cases (n = 8/20), and subsequently confirmed with a COL1A1 break-apart FISH probe in all but one case (n = 7/8). 55% of cases (n = 11/20) displayed novel PDGFD rearrangements; PDGFD being fused either to the 5' part of COL6A3 (2q37.3) (n = 9/11) or EMILIN2 (18p11) (n = 2/11). All rearrangements led to in-frame fusion transcripts and were confirmed at genomic level by FISH and/or array-comparative genomic hybridization. PDGFD-rearranged dermatofibrosarcoma protuberans presented clinical outcomes similar to typical dermatofibrosarcoma protuberans. Notably, the two EMILIN2-PDGFD cases displayed fibrosarcomatous transformation and homozygous deletions of CDKN2A at genomic level. We report the first recurrent molecular variant of dermatofibrosarcoma protuberans involving PDGFD, which functionally mimic bona fide COL1A1-PDGFB fusions, leading presumably to a similar autocrine loop-stimulating PDGFRB. This study also emphasizes that COL1A1-PDGFB fusions can be cytogenetically cryptic on FISH testing in a subset of cases, thereby representing a diagnostic pitfall that pathologists should be aware of.
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Bérengère Dadone-Montaudié, Laurent Alberti, Adeline Duc, Lucile Delespaul, Tom Lesluyes, et al.. Alternative PDGFD rearrangements in dermatofibrosarcomas protuberans without PDGFB fusions. Modern Pathology, Nature Publishing Group: Open Access Hybrid Model Option B, 2018, 31 (11), pp.1683-1693. ⟨10.1038/s41379-018-0089-4⟩. ⟨inserm-02440547⟩

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