title: Telomere maintenance mechanisms in malignant peripheral nerve sheath tumors: expression and prognostic relevance.
abstract: This study investigated the prevalence and the prognostic relevance of the 2 known telomere maintenance mechanisms (TMMs), telomerase activity (TA) and alternative lengthening of telomeres (ALT), in malignant peripheral nerve sheath tumors (MPNST). In 57 specimens from 49 patients with MPNST (35 sporadic, 14 neurofibromatosis type 1-related), TA was determined using the telomeric repeat amplification protocol, and ALT was detected by assaying ALT-associated promyelocytic leukemia bodies (APB) and terminal restriction fragment (TRF) length distribution. TA or ALT (defined on the basis of APB) alone was found in 24.6% or 26.3% of the lesions, respectively, whereas 6 cases (10.5%) were TA+/ALT+. A concordance between APB and TRF results in defining the ALT status was observed in 44 of 57 cases (77.2%; P < .0001). TA was more frequently expressed in samples from patients with neurofibromatosis type 1 than in those with sporadic disease (60% vs 29.4%, P = 0.087). In the overall series, TA proved to be prognostic for 5-year disease-specific death (hazard ratio, 3.78; 95% confidence interval [CI], 1.60-8.95; P = .002), even when adjusted for the presence of neurofibromatosis type 1 (hazard ratio, 4.22; 95% CI, 1.804-9.874; P = .001) and margin status after surgery (hazard ratio, 5.78; 95% CI, 2.19-15.26; P < .001). Conversely, ALT did not significantly affect clinical outcome of MPNST using either APB expression (hazard ratio, 1.25; 95% CI 0.54-2.89; P = 0.605) or TRF distribution (hazard ratio, 0.57; 95% CI, 0.17-1.96; P = .375) as the detection approach. Our results indicate for the first time that both TMMs, TA and ALT, are present in MPNST and differentially affect patient prognosis.
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Venturini
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Daidone
authors.forename: Rosita
authors.initials: R
authors.lastname: Motta
authors.forename: Graziella
authors.initials: G
authors.lastname: Cimino-Reale
authors.forename: Stacey F
authors.initials: SF
authors.lastname: Hoare
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gronchi
authors.forename: Marco
authors.initials: M
authors.lastname: Folini
authors.forename: William Nicol
authors.initials: WN
authors.lastname: Keith
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056915:DNA Copy Number Variations / Q000235:genetics; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D018317:Nerve Sheath Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D015996:Survival Rate; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D059505:Telomere Homeostasis; D055815:Young Adult
chemical_list: C509186:TERT protein, human; D019098:Telomerase