Alternative Lengthening of Telomeres Is Rare in Canine Histiocytic Sarcoma.

Simple Summary: Knowledge of telomere maintenance mechanisms (TMMs) in different tumor types is crucial for the development of TMM-specific diagnostics and therapies. Telomerase-independent alternative lengthening of telomeres (ALT) is used more frequently in human sarcoma subtypes than other cancers. However, ALT's prevalence in the aggressive hematopoietic and orphan tumor type termed histiocytic sarcoma (HS) is unknown. The aim of our retrospective study was to assess the ALT activity in canine HS as a surrogate for rare human HS cases. Bernese mountain dogs (BMDs) have a breed predisposition for HS. We show in cohorts of a total of 63 dog patients from two centers, including a homogeneous population of 47 BMDs, that ALT was used only infrequently in the BMDs and not at all in the non-BMD patients here. We conclude that ALT is useful for a few cases only to target HS but can play a role as a resistance mechanism after targeting telomerase. Cancer cells activate telomere maintenance mechanisms (TMMs) to overcome senescence and thus are targets for TMM-specific therapies. Telomerase-independent alternative lengthening of telomeres (ALT) is frequently utilized as a TMM in human sarcoma subtypes. Histiocytic sarcoma (HS) is a rare but aggressive tumor of hematopoietic origin with unknown ALT incidence in humans. ALT has been identified in canine HS, a tumor type comparable to human HS that occurs with high rates in certain canine breeds such as Bernese mountain dogs (BMDs). This retrospective study characterized the frequency of ALT in BMD and non-BMD patients diagnosed with HS as surrogates for humans. Formalin-fixed paraffin-embedded tumor samples from 63 dogs at two centers, including 47 BMDs, were evaluated for their ALT activity and relative telomere content (TC) using a radiolabel C-circle assay (CCA). Known ALT-positive samples served as controls. CCA-positive cases were validated via FISH. Two BMD samples showed ALT activity of 1–14% compared to controls. All other samples were ALT-negative. The TC did not correlate with the CCA results. ALT positivity was validated by the appearance of ultrabright telomere foci. Low ALT activity was present in 4% of BMDs with HS and therefore does not appear to be a common target for therapeutic approaches but can have diagnostic value. [ABSTRACT FROM AUTHOR]