Poorly differentiated chordoma with SMARCB1/INI1 loss: a distinct molecular entity with dismal prognosis

Chordomas are tumors of the skull base and spine thought to arise from remnants of the notochord. Expression of cytokeratins and S100 is frequent and nuclear expression of brachyury, a transcription factor important for axial development, has been shown to be a sensitive and fairly specific diagnostic marker [6]. For pediatric chordomas showing cytological atypia, increased mitotic activity, increased cellularity and an unstructured growth pattern, the term “poorly differentiated chordoma” has been coined [2, 7]. Interestingly, poorly differentiated chordomas are not only associated with an aggressive clinical course and high mortality [2], but also with loss of SMARCB1 expression [7, 10]. Loss of SMARCB1 (also known as hSNF5/INI1), a core member of the SWI/SNF chromatin remodeling complex, is the hallmark of atypical teratoid/rhabdoid tumor (AT/RT), a brain tumor in young children also demonstrating a highly aggressive biological behavior. Since AT/RT invading the skull and even clival location are on record [4, 9], it remains uncertain if poorly differentiated chordoma represents a distinct entity or part of the AT/RT spectrum instead. Here we show that poorly differentiated chordoma can be clearly distinguished not only from AT/RT, but also from conventional chordoma by DNA methylation profiling