Alternative lengthening of telomeres and loss of ATRX are frequent events in pleomorphic and dedifferentiated liposarcomas

Abstract

Telomerase activation and alternative lengthening of telomeres are two major mechanisms of telomere length maintenance. Soft tissue sarcomas appear to use the alternative lengthening of telomeres more frequently. Loss of α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated protein 6 (DAXX) expression has been implicated in the pathogenesis of alternative telomere lengthening in pancreatic endocrine neoplasm and glioma. The mechanism leading to the alternative lengthening of telomeres in liposarcoma remains unknown. Whereas alternative telomere lengthening was determined to be an indicator of poor prognosis in liposarcomas as a whole, its prognostic power has not been verified in any subtype of liposarcoma. In this study, we characterized the status of alternative telomere lengthening and expression of ATRX and DAXX in 111 liposarcomas (28 well-differentiated, 52 dedifferentiated, 20 myxoid or round cell, and 11 pleomorphic liposarcomas) by telomere fluorescence in situ hybridization and immunohistochemistry, respectively. Alternative lengthening of telomere was observed in 0% (0/16) of well-differentiated, 30% (14/46) of dedifferentiated, 5% (1/19) of myxoid or round cell, and 80% (8/10) of pleomorphic liposarcomas. Eighteen (16%) and one (1%) tumors were negative for ATRX and DAXX immunostaining, respectively. Remarkably, all cases with loss of either ATRX or DAXX expression had alternative lengthening of telomeres, and 83% (19/23) of tumors that had alternative lengthening of telomeres showed loss of either protein. The correlation between loss of either ATRX or DAXX and alternative telomere lengthening was 100% in dedifferentiated liposarcoma. The presence of alternative telomere lengthening in dedifferentiated liposarcoma suggested poor overall survival (hazard ratio = 1.954, P = 0.077) and was the most significant indicator of short progression-free survival (hazard ratio = 3.119, P = 0.003). In conclusion, we found that ATRX loss was the most likely mechanism of alternative telomere lengthening in liposarcoma and alternative telomere lengthening was a prognostic factor of poor outcome in dedifferentiated liposarcoma.

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

“…18,22 In addition, although loss of either ATRX or DAXX is perfectly associated with alternative lengthening of telomeres in pancreatic neuroendocrine tumors, the situation is more complex in sarcomas. In our previous studies, only approximately half of alternative lengthening of telomerespositive leiomyosarcomas and pleomorphic liposarcomas were ATRX deficient, 6,12 but alternative lengthening of telomeres was highly correlated with loss of ATRX in angiosarcomas and dedifferentiated liposarcomas. 12,23 Thus, current information indicates that alternative lengthening of telomeres is a manifestation of global telomere dysfunction exploiting dysregulated homologous recombination to elongate the telomeres.…”

“…In our previous studies, only approximately half of alternative lengthening of telomerespositive leiomyosarcomas and pleomorphic liposarcomas were ATRX deficient, 6,12 but alternative lengthening of telomeres was highly correlated with loss of ATRX in angiosarcomas and dedifferentiated liposarcomas. 12,23 Thus, current information indicates that alternative lengthening of telomeres is a manifestation of global telomere dysfunction exploiting dysregulated homologous recombination to elongate the telomeres. Loss of ATRX/DAXX is one of the mechanisms of alternative lengthening of telomeres, but other genetic changes must also be present concurrently for the alternative lengthening of telomeres phenotype to fully develop.…”

“…8 Alternative lengthening of telomeres has been shown to be an unfavorable prognostic factor in several types of sarcomas. 6,[9][10][11][12] Until recently, the underlying mechanism of alternative lengthening of telomeres remains elusive. Heaphy et al discovered that alternative lengthening of telomeres status was perfectly correlated with the loss of expression of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein in pancreatic neuroendocrine tumors.…”

“…Subsequent studies have reported frequent ATRX loss (but not DAXX loss) in astrocytoma, leiomyosarcoma, dedifferentiated liposarcoma and other tumor types, and the loss of ATRX has been highly correlated with the alternative lengthening of telomeres phenotype. 6,12,13,[17][18][19][20][21] However, knockdown of ATRX or DAXX has not led to alternative lengthening of telomeres, and patients with germline ATRX mutations do not appear to be cancer prone. 18,22 In addition, although loss of either ATRX or DAXX is perfectly associated with alternative lengthening of telomeres in pancreatic neuroendocrine tumors, the situation is more complex in sarcomas.…”

“…We previously studied this telomere-maintenance mechanism and ATRX/DAXX expression in leiomyosarcomas, angiosarcomas, and liposarcomas. 6,12,23 The aim of the present study was to systematically screen other sarcoma types to determine the frequency of alternative lengthening of telomeres, ATRX/DAXX expression, and their relationship.…”