Evidence for alternative lengthening of telomeres in liposarcomas in the absence of ALT‐associated PML bodies

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Abstract
Immortalized and cancer cells maintain their telomeres by activation of a telomere maintenance mechanism (TMM). In ∼85% of cancers telomerase is activated (TA) but in some tumours, in particular sarcomas, an alternative lengthening of telomeres (ALT) pathway is used. Liposarcomas are the most common soft‐tissue sarcoma in adults and they activate ALT or telomerase with equal frequency, however no TMM has been identified in ∼50% of liposarcomas. In our study, we have shown that instability at the minisatellite MS32, usually associated with ALT activation, aids the identification of liposarcomas that have recombination‐like activity at telomeres in absence of ALT associated PML‐bodies (APBs). Furthermore, using single molecule telomere analysis, we have detected complex telomere mutations directly in ALT positive liposarcomas and interestingly in some liposarcomas with an unknown TMM but high MS32 instability. We have shown by sequence analysis that some of these complex telomere mutations must arise by an inter‐molecular recombination‐like process rather than by deletion caused by t‐loop excision or by unequal telomere‐sister‐chromatid‐exchange (T‐SCE), which is known to be elevated in ALT cell lines. Preliminary evidence also suggests that inter‐molecular recombination events may be processed differently in liposarcomas with APBs compared to those without. In conclusion, we have shown for the first time, that some telomerase negative liposarcomas without APBs have other features associated with ALT, indicating that the incidence of ALT in these tumours has previously been under‐estimated. This has major implications for the use of cancer treatments targeted at TMMs.