Leiomyosarcoma With Alternative Lengthening of Telomeres Is Associated With Aggressive Histologic Features, Loss of ATRX Expression, and Poor Clinical Outcome

Abstract

Leiomyosarcoma is an aggressive soft tissue sarcoma with poor patient survival. Recently, it was shown that 53% to 62% of leiomyosarcomas use the alternative lengthening of telomeres (ALT) as their telomere maintenance mechanism. The molecular basis of this mechanism has not been elucidated. Studies of pancreatic neuroendocrine tumor have suggested that the inactivation of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein is associated with the ALT phenotype. In this study, we sought to determine the clinicopathologic features of leiomyosarcoma with the ALT phenotype and the possible relationship between this phenotype and ATRX/DAXX expression. Telomerase reverse transcriptase gene (TERT) promoter mutation analysis was also performed. Ninety-two leiomyosarcomas derived from the uterus, retroperitoneum/intra-abdomen, and various other sites were analyzed. Telomere-specific fluorescence in situ hybridization revealed that 59% (51/86) of leiomyosarcomas had the ALT phenotype. Loss of ATRX expression was observed in 33% of the tumors (30/92), and all but 2 ATRX-deficient tumors were ALT positive. Both the ALT phenotype and loss of ATRX expression were associated with epithelioid/pleomorphic cell morphology, tumor necrosis, and poor differentiation. None of the 92 cases lost DAXX expression. No TERT promoter mutation was detected (n=39). For survival analysis, poor differentiation, high FNCLCC grade, tumor size, and ALT phenotype were correlated with poor overall survival in univariate analysis. Tumor size and ALT phenotype remained independent prognostic factors in multivariate analysis. We concluded that the ALT phenotype in the leiomyosarcoma is associated with aggressive histologic features, loss of ATRX expression, and poor clinical outcome.

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.…”

“…3,4 Previous studies have revealed that alternative lengthening of telomeres is commonly used by some sarcomas with complex cytogenetics, such as undifferentiated pleomorphic sarcomas (malignant fibrous histiocytomas), leiomyosarcomas, and osteosarcomas. [5][6][7] Montgomery et al have suggested that alternative lengthening of telomeres is a feature of sarcomas with complex cytogenetics, but is rare in translocation-associated sarcomas. 8 Alternative lengthening of telomeres has been shown to be an unfavorable prognostic factor in several types of sarcomas.…”

“…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.…”