Alternative lengthening of telomeres does exist in various canine sarcomas

Abstract

Alternative lengthening of telomeres (ALT) is a telomere maintenance mechanism (TMM) found in some human tumors such as sarcomas. Canine tumors are not characterized for ALT and the study aim was to identify if the ALT phenotype exists in canine sarcomas. Sixty-four canine sarcoma samples (20 snap-frozen, 44 FFPE) as well as six canine sarcoma cell lines were screened for ALT by C-circle assay. ALT was further evaluated by measuring telomere length via qPCR and telomere restriction-fragments including pulsed-field electrophoresis. ALT-associated proteins were validated by immunohistochemistry. Further, telomerase activity (TA) and gene expression were analyzed by TRAP and qPCR. DNA from 20 human neuroblastomas and 8 sarcoma cell lines served as comparative controls. ALT was detected in 9.4% (6/64) canine sarcomas including aggressive subtypes as hemangiosarcoma, osteosarcoma, and histiocytic sarcoma. C-circle levels were comparable with human ALT-positive controls. All ALT tumors demonstrated loss of ATRX expression and 5/6 showed strong p53 expression. TA was detected in 93% (14/15) snap-frozen samples including a sarcoma with ALT activity. This tumor showed long heterogeneous telomeres, and a high level of colocalization of DAXX with telomeres. One sarcoma was ALT and TA negative. All canine and human sarcoma cell lines were ALT negative. In this study, we demonstrated that canine sarcomas use ALT. As in humans, ALT was identified in aggressive sarcomas subtypes and coexisted with TA in one tumor. Overall, canine sarcomas seem to share many similarities with their human counterparts and appear an attractive model for comparative telomere research. © 2016 Wiley Periodicals, Inc.

Effect of Fetal Sex on Maternal and Obstetric Outcomes

“…Measuring the telomere length is an evolving field that has attracted attention recently, it has been linked with some obstetrical and problems later in life (such as IUGR and cancers, respectively) (45, 46). A recently published study involved analysis of cord blood telomere length of 54 infants.…”

Epigenetic Regulation of Telomere Maintenance for Therapeutic Interventions in Gliomas

“…While ALT requires copying of DNA templates, TA uses a short RNA template and reverse transcription. Recent data from TMM analyses without evidence for TA or ALT activity indicate that additional mechanism(s) in tumors with clinical relevance may exist and are termed as non-defined telomere maintenance mechanism (NDTMM) [63,64,65]. Telomeres are transcribed to telomeric repeat-containing RNA (TERRA) as long ncRNA transcripts [66,67] and it is therefore tempting to speculate that novel telomeric synthesis mechanisms may use such templates.…”

“…In osteosarcoma, malignant fibrous histiocytomas and liposarcoma ALT was associated with decreased survival than was TA. These adverse findings might not be specific for human cancers as we recently identified ALT occurring with high prevalence in more aggressive types of canine sarcomas [64]. In contrast, presence of ALT in glioblastoma multiforme (GBM) was associated with better patient outcome [69,70,71], whereas in pediatric high grade gliomas TA confers poor outcome [72].…”

Diagnosis and treatment of ALT tumors: is Trabectedin a new therapeutic option?

“…Two types of ALT mechanisms are known in yeast [ 22 ], a Rad51-dependent mechanism, mediated by homology recombination [ 23 ], and a Rad51-independent mechanism mediated by break-induced replication (BIR) [ 24 ]. In human, ALT activity has been detected also in non neoplastic somatic cells [ 13 ] and in embryonic cells [ 14 ], and recently also in canine sarcomas [ 25 ], indicating that this mechanism is conserved among mammalians. Cancers that have a mesenchymal origin are reported to activate ALT more frequently, while epithelial cancers rely on telomerase reactivation/re-expression [ 26 , 27 ].…”