Differential nuclear ATRX expression in sarcomas.
OBJECTIVE
Nuclear α-thalassemia/mental retardation X-linked (ATRX) loss and alternative lengthening of telomeres (ALT) are linked in distinct malignancies. We therefore aimed to determine the nuclear ATRX expression correlated with ALT in a comprehensive series of sarcomas.


RESULTS
A total of 573 formalin-fixed paraffin-embedded sarcomas comprising 28 entities were investigated for nuclear ATRX expression by immunohistochemistry. Telomere-specific fluorescence in-situ hybridization (FISH) was used to determine the ALT phenotype in 50 sarcomas with complete or heterogeneous ATRX loss. Complete nuclear ATRX loss was detected in 58 of 573 sarcomas, all high-grade, with the highest prevalence in undifferentiated pleomorphic sarcomas (38%) and pleomorphic liposarcomas (38%), followed by dedifferentiated liposarcomas (24%), osteosarcomas (21%), leiomyosarcomas (17%), myxofibrosarcomas (11%) and malignant peripheral nerve sheath tumours (4%). Interestingly, a further 20 sarcomas, all belonging to the aforementioned entities with complete ATRX loss, presented with a heterogeneous ATRX expression pattern. ALT was observed in 41 of 42 sarcomas with complete ATRX loss, but only in two of eight sarcomas with heterogeneous expression.


CONCLUSIONS
Nuclear ATRX loss, either complete or heterogeneous, is encountered in a considerable number of high-grade sarcomas with non-specific genetic alterations. A causal relationship with ALT might be indicated at least in cases with a complete nuclear ATRX loss.
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|German Cancer Consortium (DKTK), CCU Neuropathology German Cancer Research Center (DKFZ), Heidelberg, Germany.
Christian
C
Koelsche
Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Marcus
M
Renner
German Cancer Consortium (DKTK), Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Pediatric Oncology, Hematology and Immunology, University Medical Center, Heidelberg, Germany.
Pascal
P
Johann
German Cancer Consortium (DKTK), CCU Neuropathology German Cancer Research Center (DKFZ), Heidelberg, Germany.
Irina
I
Leiss
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|German Cancer Consortium (DKTK), CCU Neuropathology German Cancer Research Center (DKFZ), Heidelberg, Germany.
Felix
F
Sahm
Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.
Simon
S
Schimmack
Gerhard Domagk Institute of Pathology, University Hospital, Muenster, Germany.
Eva
E
Wardelmann
Department of Orthopedics and Traumatology, University Hospital Heidelberg, Heidelberg, Germany.
Eva-Kristin
EK
Renker
Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Peter
P
Schirmacher
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|German Cancer Consortium (DKTK), CCU Neuropathology German Cancer Research Center (DKFZ), Heidelberg, Germany.
Andrey
A
Korshunov
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|German Cancer Consortium (DKTK), CCU Neuropathology German Cancer Research Center (DKFZ), Heidelberg, Germany.
Andreas
A
von Deimling
Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Gunhild
G
Mechtersheimer
D019943:Amino Acid Substitution; D018389:Codon, Nonsense; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012509:Sarcoma / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000235:genetics; D059505:Telomere Homeostasis; D000075924:X-linked Nuclear Protein / Q000235:genetics* / Q000378:metabolism
D018389:Codon, Nonsense; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
ALT; ATRX; immunohistochemistry; sarcomas; telomeres