Telomere Maintenance Mechanisms in Liposarcomas: Association with Histologic Subtypes and Disease Progression

Abstract

Human cancer cells maintain telomeres by telomerase activity (TA) or by alternative lengthening of telomeres (ALT). We proposed to define the prevalence of the two telomere maintenance mechanisms (TMM), to assess their association with histology, and to compare their prognostic relevance in a series of 93 patients with liposarcoma. ALT was detected by assaying ALT-associated promyelocytic leukemia nuclear bodies and TA was assayed using the telomeric repeat amplification protocol. ALT or TA was found in 25.9% or 26.6% of 139 tested liposarcoma lesions, respectively. Three lesions were ALT+/TA+ whereas f50% of lesions did not show any known TMM. TMM phenotype was consistent during disease progression. ALT was prevalent in dedifferentiated and in grade 3 liposarcomas whereas TA prevailed in most round-cell myxoid and in grade 2 liposarcomas. ALT and TA incidence was similar in primary and recurrent lesions whereas metastases were more frequently TA+ than ALT+ (59% versus 18%; P = 0.04). TMM presence negatively affected patient prognosis (P = 0.001): increased mortality was associated with positivity for TA (P = 0.038) or ALT (P < 0.0001) compared with TMM absence. ALT proved to be a stronger prognostic discriminant of increased mortality than TA even when adjusted for tumor location, grade, and histology (hazard ratio for cause-specific death, 3.58 versus 1.15). Our results indicate that ALT can support fully malignant liposarcomas and is associated with unfavorable disease outcome. (Cancer Res 2006; 66(17): 8918-24)

High level of telomerase RNA gene expression is associated with chromatin modification, the ALT phenotype and poor prognosis in liposarcoma

“…These specimens represent a subset randomly selected from a larger case series already characterised for TMM (Costa et al, 2006). There were 13 women and 14 men, with a median age of 58 years (range, 38 -91).…”

“…They are a diverse group of mesenchymal malignancies that show multiple telomere maintenance mechanisms (TMMs) with telomerase activity and the ALT phenotype detected in a similar number of cases (Johnson et al, 2005;Costa et al, 2006). Alternative lengthening of telomeres is more frequent in welldifferentiated and dedifferentiated forms (Costa et al, 2006), which show complex karyotypic rearrangements including supernumerary ring, giant chromosome formation and amplification (Sandberg, 2004), while telomerase activity is more frequent in myxoid forms (Costa et al, 2006) characterised by the t(12;16)(q13;p11) translocation (Sandberg, 2004). In addition, a significant proportion appears to show no evidence of any known TMM (Johnson et al, 2005;Costa et al, 2006).…”

“…Alternative lengthening of telomeres is more frequent in welldifferentiated and dedifferentiated forms (Costa et al, 2006), which show complex karyotypic rearrangements including supernumerary ring, giant chromosome formation and amplification (Sandberg, 2004), while telomerase activity is more frequent in myxoid forms (Costa et al, 2006) characterised by the t(12;16)(q13;p11) translocation (Sandberg, 2004). In addition, a significant proportion appears to show no evidence of any known TMM (Johnson et al, 2005;Costa et al, 2006). This complexity makes liposarcoma a good model system to investigate the regulation of TMMs.…”

“…The presence of any TMM, in comparison to tumours that express neither telomerase nor ALT, is associated with poor prognosis in a number of tumours of mesenchymal origin (Sanders et al, 2004;Costa et al, 2006). In osteosarcoma, telomerase expression is associated with shorter progression-free survival (Sanders et al, 2004), while in liposarcoma the ALT phenotype is associated with a lower survival rate (Costa et al, 2006).…”

“…In osteosarcoma, telomerase expression is associated with shorter progression-free survival (Sanders et al, 2004), while in liposarcoma the ALT phenotype is associated with a lower survival rate (Costa et al, 2006). This appears to be tissue specific, as the presence of the ALT phenotype in patients with glioblastoma multiforme was associated with a longer survival rate than those with telomerase activity or no TMM (Hakin-Smith et al, 2003).…”