Alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas (Review)

Abstract

Abstract. Sarcoma is a rare and heterogeneous type of cancer with an early mean onset age and a poor prognosis. However, its genetic basis remains unclear. A series of recent genomic studies in sarcomas have identified the occurrence of mutations in the α-thalassemia/mental retardation syndrome X-linked (ATRX) gene. The ATRX protein belongs to the SWI/SNF family of chromatin remodeling proteins, which are frequently associated with α-thalassemia syndrome. Cancer cells depend on telomerase or the alternative lengthening of telomeres (ALT) pathway to overcome replicative programmed mortality. Loss of ATRX is associated with ALT in sarcoma. In the present review, recent whole genome and/or whole exome genomic studies are summarized. In addition ATRX immunohistochemistry and ALT fluorescence in situ hybridization in sarcomas of various subtypes and at diverse sites, including osteosarcoma, leiomyosarcoma, liposarcoma, angiosarcoma and chondrosarcoma are evaluated. The present review involves certain studies associated with the molecular mechanisms underlying the loss of ATRX controlling the activation of ALT in sarcomas. Identification of the loss of ATRX and ALT in sarcomas may provide novel methods for the treatment of aggressive sarcomas.

ATRX alteration contributes to tumor growth and immune escape in pleomorphic sarcomas

“…The hypothesis that ATRX could act through metabolism regulation is a very appealing one that now requires functional validation. Regarding ATRX expression, 27% of cases (17/63) showed no nuclear ATRX protein, which is consistent with the literature (13,22,23,30). In tumors presenting FS/NS, 87.5% (14/16) exhibited no ATRX protein at all.…”

“…Regarding ATRX expression, 27% of cases (17/63) showed no nuclear ATRX protein, which is consistent with the literature (Koelsche et al, 2016;Liau et al, 2015;Ren et al, 2018;. In tumors presenting FS/NS, 87.5% (14/16) exhibited no ATRX protein at all.…”

“…The rate of alteration in LMS is consistent with the rate of 24% found by Chudasama and colleagues 20 , but it is slightly higher than that generally observed in other LMS cohorts, which is around 16% 6,21,22 , probably due to the exhaustiveness of WGseq. ATRX mutations were distributed across the entire gene, as previously observed 6,20,23,24 . Three main factors link the two types of sarcomas in the present study: i) in females, all alterations except in LMS48 can be interpreted as occurring on the active X, ii) point mutations are more frequent (75% in LMS and 60% in US) than structural variations (25% in LMS and 40% in US), as previously observed 6,20 ; and iii) the alterations lead preferentially to a frameshift and thus to a truncated protein in 66.7% of cases (20/30, 65% in LMS and 70% in US), in agreement with previous descriptions in sarcomas 6,20,23,25 .…”

“…ATRX mutations were distributed across the entire gene, as previously observed 6,20,23,24 . Three main factors link the two types of sarcomas in the present study: i) in females, all alterations except in LMS48 can be interpreted as occurring on the active X, ii) point mutations are more frequent (75% in LMS and 60% in US) than structural variations (25% in LMS and 40% in US), as previously observed 6,20 ; and iii) the alterations lead preferentially to a frameshift and thus to a truncated protein in 66.7% of cases (20/30, 65% in LMS and 70% in US), in agreement with previous descriptions in sarcomas 6,20,23,25 . Of note, ATRX alterations in the present study were not significantly associated with a poorer prognosis.…”

Emerging landscape of circular RNAs as biomarkers and pivotal regulators in osteosarcoma

“…Osteosarcoma is the most prevalent primary malignant bone tumor among children, adolescents, and young adults (Saraf, Fenger, & Roberts, 2018). It is characterized by high aggressiveness with rapid progression and great distant metastatic potential (S. Q. Li, Tu, et al, 2019; Z. Li, Dou, Liu, & He, 2017; Otoukesh, Boddouhi, Moghtadaei, Kaghazian, & Kaghazian, 2018; X. Ren, Tu, Tang, Ma, & Li, 2018). Currently, due to insufficiency in early‐stage diagnosis and effective therapeutic approaches, the 5‐year survival and prognosis for osteosarcoma patients remain largely unimproved, especially for patients with multi‐drug resistance, recurrence, or lung metastasis (C. Wang, Ren, Zhao, Wang, & Wang, 2018).…”