Abstract
Many exciting advances in cancer-related telomere biology have been made in the past decade. Of these recent advances, great progress has also been made with respect to the Alternative Lengthening of Telomeres (ALT) pathway. Along with a better understanding of the molecular mechanism of this unique telomere maintenance pathway, many studies have also evaluated ALT activity in various cancer subtypes. We first briefly review and assess a variety of commonly used ALT biomarkers. Then, we provide both an update on ALT-positive (ALT+) tumor prevalence as well as a systematic clinical assessment of the presently studied ALT+ malignancies. Additionally, we discuss the pathogenetic alterations in ALT+ cancers, for example, the mutation status of ATRX and DAXX, and their correlations with the activation of the ALT pathway. Finally, we highlight important ALT+ clinical associations within each cancer subtype and subdivisions within, as well as their prognoses. We hope this alternative perspective will allow scientists, clinicians, and drug developers to have greater insight into the ALT cancers so that together, we may develop more efficacious treatments and improved management strategies to meet the urgent needs of cancer patients.
Highlights
OS-specific findings are limited by the nature of small sample sizes, but altogether these findings suggest that loss of ATRX: α-thalassemia/mental retardation syndrome X-linked (ATRX) is highly specific for Alternative Lengthening of Telomeres (ALT)
Since there is a correlation between ATRX/DAXX loss and an ALT+ phenotype in uterine leiomyosarcoma (ULMS) [167,170], these characteristics could potentially be used as markers to better discern smooth muscle tumors of uncertain malignant potential (STUMP) entities as either uterine leiomyomas or leiomyosarcomas
Many insightful discoveries have been made in elucidating the molecular mechanism of the ALT pathway
Summary
Human telomeres consist of repetitive DNA sequences of (TTAGGG)n at the terminal ends of each linear chromosome. This assay is still the gold-standard practice for confirming telomerase activity in tumors Analysis of their survey demonstrates that: (1) 82.4% of malignant neoplasms (1798/2182) are telomerasepositive (TEL+); (2) 49.1% of premalignant lesions (54/110) are TEL+; (3) 23.6% of benign neoplasia (129/547) are TEL+ [5]. The newfound complementary sequences serve as elongation templates for the invading strand This homology might occur through invasion into the homologous chromosome, or an unrelated chromosome, or even the extrachromosomal telomeric repeats (ECTRs) [4,14]. Dagg and colleagues identified a small group of cancers that rely neither on telomerase nor the ALT pathway for their survival [15] Since these cancers can proliferate in cell culture for more than 200 population doublings while their telomeres keep getting shorter and shorter, they are called “Ever-Shorter Telomeres”. How these cancers survive without activating one of the two known TMMs remains a mystery
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