Genome-wide methylation profiling and copy number analysis in atypical fibroxanthomas and pleomorphic dermal sarcomas indicate a similar molecular phenotype

Christian Koelsche; Damian Stichel; Klaus G Griewank; Daniel Schrimpf; David E Reuss; Melanie Bewerunge-Hudler; Christian Vokuhl; Winand N M Dinjens; Iver Petersen; Michel Mittelbronn; Adrian Cuevas-Bourdier; Rolf Buslei; Stefan M Pfister; Uta Flucke; Gunhild Mechtersheimer; Thomas Mentzel; Andreas von Deimling

doi:10.1186/s13569-019-0113-6

Genome-wide methylation profiling and copy number analysis in atypical fibroxanthomas and pleomorphic dermal sarcomas indicate a similar molecular phenotype

Clin Sarcoma Res. 2019 Feb 14:9:2. doi: 10.1186/s13569-019-0113-6. eCollection 2019.

Authors

Christian Koelsche^#¹, Damian Stichel^#^{2

3

4}, Klaus G Griewank^{5

6}, Daniel Schrimpf^{2

3

4}, David E Reuss^{2

3

4}, Melanie Bewerunge-Hudler^{4

7}, Christian Vokuhl⁸, Winand N M Dinjens⁹, Iver Petersen¹⁰, Michel Mittelbronn^{11

12

13

14}, Adrian Cuevas-Bourdier¹², Rolf Buslei¹⁵, Stefan M Pfister^{4

16

17

18}, Uta Flucke¹⁹, Gunhild Mechtersheimer¹, Thomas Mentzel²⁰, Andreas von Deimling^{2

3

4}

Affiliations

¹ 1Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Baden-Württemberg Germany.
² 2Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Baden-Württemberg Germany.
³ 3Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Baden-Württemberg Germany.
⁴ 4German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Baden-Württemberg Germany.
⁵ 5Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, North Rhine-Westphalia Germany.
⁶ Dermatopathologie bei Mainz, Nieder-Olm, Rhineland-Palatinate Germany.
⁷ 7Genomics and Proteomics Core Facility, Microarray Unit, German Cancer Research Center (DKFZ), Heidelberg, Baden-Württemberg Germany.
⁸ 8Department of Pediatric Pathology, University Hospital of Schleswig-Holstein, Kiel, Schleswig-Holstein Germany.
⁹ 9Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.
¹⁰ Institute of Pathology, SRH Poliklinik Gera GmbH, Gera, Germany.
¹¹ Luxembourg Centre of Neuropathology (LCNP), Luxembourg City, Luxembourg.
¹² 12Laboratoire National de Santé (LNS), Dudelange, Luxembourg.
¹³ 13Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg City, Luxembourg.
¹⁴ 14NORLUX Neuro-Oncology Laboratory, Luxembourg Institute of Health (LIH), Luxembourg City, Luxembourg.
¹⁵ 15Institute of Pathology, Sozialstiftung Bamberg, Bamberg, Germany.
¹⁶ 16Hopp Childrens Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany.
¹⁷ 17Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Baden-Württemberg Germany.
¹⁸ 18Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Baden-Württemberg Germany.
¹⁹ 19Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
²⁰ Dermatopathology Bodensee, Friedrichshafen, Baden-Württemberg Germany.

^# Contributed equally.

Abstract

Background: Atypical fibroxanthomas (AFX) and pleomorphic dermal sarcomas (PDS) are lesions of the skin with overlapping histologic features and unspecific molecular traits. PDS behaves aggressive compared to AFX. Thus, a precise delineation, although challenging in some instances, is relevant.

Methods: We examined the value of DNA-methylation profiling and copy number analysis for separating these tumors. DNA-methylation data were generated from 17 AFX and 15 PDS using the Illumina EPIC array. These were compared with DNA-methylation data generated from 196 tumors encompassing potential histologic mimics like cutaneous squamous carcinomas (cSCC; n = 19), basal cell carcinomas (n = 10), melanoma metastases originating from the skin (n = 11), leiomyosarcomas (n = 11), angiosarcomas of the skin and soft tissue (n = 11), malignant peripheral nerve sheath tumors (n = 19), dermatofibrosarcomas protuberans (n = 13), extraskeletal myxoid chondrosarcomas (n = 9), myxoid liposarcomas (n = 14), schwannomas (n = 10), neurofibromas (n = 21), alveolar (n = 19) and embryonal (n = 17) rhabdomyosarcomas as well as undifferentiated pleomorphic sarcomas (n = 12).

Results: DNA-methylation profiling did not separate AFX from PDS. The DNA-methylation profiles of the other cases, however, were distinct from AFX/PDS. They reliably assigned to subtype-specific DNA-methylation clusters, although overlap occurred between some AFX/PDS and cSCC. Copy number profiling revealed alterations in a similar frequency and distribution between AFX and PDS. They involved losses of 9p (22/32) and 13q (25/32). Gains frequently involved 8q (8/32). Notably, a homozygous deletion of CDKN2A was more frequent in PDS (6/15) than in AFX (2/17), whereas amplifications were non-recurrent and overall rare (5/32).

Conclusions: Our findings support the concept that AFX and PDS belong to a common tumor spectrum. We could demonstrate the diagnostic value of DNA-methylation profiling to delineating AFX/PDS from potential mimics. However, the assessment of certain histologic features remains crucial for separating PDS from AFX.

Keywords: Atypical fibroxanthoma; Carcinomas; DNA methylation; Melanomas; Mimics; Pleomorphic dermal sarcoma; Profiling; Sarcomas.