Alternative Lengthening of Telomeres and CINSARC are interconnected toward non-translocation-related sarcomas progression

Abstract

Alternative lengthening of telomeres (ALT) is a telomere elongation mechanism activated during oncogenesis and primarily acting in tumors of mesenchymal origin. Although the proteins involved in the machinery enabling ALT to elongate telomeres are becoming better understood, the underlying biology of this mechanism remains unclear. In the present study, we took advantage of a fully characterized cohort of 98 leiomyosarcomas (LMS) from the French Sarcoma Group to further our understanding of the ALT mechanism. We first compared the transcriptomic profiles of ALT+ and TERT+ LMS and demonstrated a strong enrichment of the CINSARC signature in ALT+ tumors. The establishment of an ALT+-related signature in these LMS confirmed the close association between CINSARC and ALT in two additional cohorts of non-translocation-related sarcomas. In vitro mesenchymal models of spontaneous ALT induction showed increased CINSARC expression following acquisition of the ALT mechanism. Conversely, ALT inactivation, through BLM inhibition, led to decreased CINSARC expression. These results establish CINSARC as a new hallmark of the ALT mechanism in non-translocation-related sarcomas and demonstrate the association of a cellular biological process with the CINSARC prognostic signature, namely the ALT mechanism.