Telomere alterations in neurofibromatosis type 1-associated solid tumors

Abstract

The presence of Alternative lengthening of telomeres (ALT) and/or ATRX loss, as well as the role of other telomere abnormalities, have not been formally studied across the spectrum of NF1-associated solid tumors. Utilizing a telomere-specific FISH assay, we classified tumors as either ALT-positive or having long (without ALT), short, or normal telomere lengths. A total of 426 tumors from 256 NF1 patients were evaluated, as well as 99 MPNST tumor samples that were sporadic or of unknown NF1 status. In the NF1-glioma dataset, ALT was present in the majority of high-grade gliomas: 14 (of 23; 60%) in contrast to only 9 (of 47; 19%) low-grade gliomas ( p = 0.0009). In the subset of ALT-negative glioma cases, telomere lengths were estimated and we observed 17 (57%) cases with normal, 12 (40%) cases with abnormally long, and only 1 (3%) case with short telomeres. In the NF1-associated malignant nerve sheath tumor (NF1-MPNST) set ( n = 75), ALT was present in 9 (12%). In the subset of ALT-negative NF1-MPNST cases, telomeres were short in 9 (38%), normal in 14 (58%) and long in 1 (3%). In the glioma set, overall survival was significantly decreased for patients with ALT-positive tumors ( p < 0.0001). In the NF1-MPNST group, overall survival was superior for patients with tumors with short telomeres ( p = 0.003). ALT occurs in a subset of NF1-associated solid tumors and is usually restricted to malignant subsets. In contrast, alterations in telomere lengths are more prevalent than ALT. Electronic supplementary material The online version of this article (10.1186/s40478-019-0792-5) contains supplementary material, which is available to authorized users.

ALT Positivity in Human Cancers: Prevalence and Clinical Insights

“…Interestingly, IDH, histone H3, and hTERT alterations were rare in ALT+, ATRX-null, and NF1-mutant gliomas [86,90,96,119], while the co-occurrence of TP53 mutations remains unclear [86,90,119]. Copy number loss and deletions in CDKN2A and CDKN2B have been observed in ALT+, ATRX-null HGG, suggesting the existence of other genetic drivers for ALT induction in NF1-deficient tumors [87,90]. Furthermore, sequencing of three subependymal giant cell astrocytoma (SEGA)-like astrocytomas in NF1 mutant patients with ALT and intact ATRX have revealed genetic alterations in RECQL4, Fanconi anemia complementation group genes (FANCD2, FANCF, and FANCG), and SMARCAL1 [119].…”

“…Gliomas are the most common primary brain tumors in adults [79,80]. The prevalence of ALT in gliomas (studies with mixed oligodendroglial and astrocytic tumors or unspecified gliomas) ranges from 13 to 69% (Table 2) [40,[81][82][83][84][85][86][87][88][89][90][91]. Further subdivision of gliomas based on their cell origin, histology, and genetic alterations have revealed that the ALT phenotype varies among tumor types.…”

“…Gliomas in patients with NF1 loss have a prevalence of ALT ranging between 29% and 69% (Table 2). The ALT phenotype co-exists with loss of ATRX expression, especially in HGGs [86,87,90]. This suggests that ATRX loss in the presence of NF1 mutation may be sufficient to induce ALT in gliomas.…”

“…Furthermore, sequencing of three subependymal giant cell astrocytoma (SEGA)-like astrocytomas in NF1 mutant patients with ALT and intact ATRX have revealed genetic alterations in RECQL4, Fanconi anemia complementation group genes (FANCD2, FANCF, and FANCG), and SMARCAL1 [119]. Lastly, NF1 mutant patients with ALT+ gliomas had significantly worse survival than ALT− gliomas with elongated or normal telomeres [87].…”

From Genes to -Omics: The Evolving Molecular Landscape of Malignant Peripheral Nerve Sheath Tumor

“…Subsequent studies on a larger subset of MPNST identified decreased nuclear expression of ATRX and demonstrated a correlation between aberrant ATRX expression and decreased overall survival in NF1-associated MPNST [ 84 ]. In a separate study a small subset ( n = 3) of NF1-associated MPNST that were ALT-positive were analyzed by NGS and found to have ATRX mutations in two out of three cases [ 76 ]. While this study did not identify inferior overall survival (OS) for ALT-positive MPNST compared to those with normal telomere length, short telomeres were significantly correlated with improved OS.…”