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

[alpha-thalassemia]

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 .

Diseases
Validation

Diseases presenting "mental retardation" symptom

achondroplasia

alexander disease

alpha-thalassemia

aniridia

aromatase deficiency

canavan disease

classical phenylketonuria

coats disease

cohen syndrome

cowden syndrome

cystinuria

dentin dysplasia

familial hypocalciuric hypercalcemia

homocystinuria without methylmalonic aciduria

hydrocephalus with stenosis of the aqueduct of sylvius

kabuki syndrome

kallmann syndrome

lamellar ichthyosis

lymphangioleiomyomatosis

monosomy 21

phenylketonuria

primary hyperoxaluria type 1

proteus syndrome

pyruvate dehydrogenase deficiency

sneddon syndrome

triple a syndrome

wolf-hirschhorn syndrome

zellweger syndrome

This symptom has already been validated