Alternative Lengthening of Telomeres and Loss of ATRX/DAXX Expression in Sarcomas with Clinicopathological Features

• Main Authors: Jau-Yu Liau, 廖肇裕
• Other Authors: 鄭永銘
• Format: Others
• Language: en_US
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/k88g63

博士 === 國立臺灣大學 === 病理學研究所 === 106 === Alternative lengthening of telomeres (ALT) is a telomerase-unrelated telomere maintenance mechanism that maintain the cell division ability in cancer cells. Currently it is supposed that homologous recombination and DNA repair are utilized in this mechanism, which copy the telomeres and other DNA sequences from other chromosomes to maintain the telomere length. ALT positive cells are characterized by telomere length heterogeneity and some chromosomes may have extremely long telomeres. These phenomena can be visualized by Southern blotting or telomere fluorescent in situ hybridization (FISH). Among the cancers, soft tissue sarcomas and gliomas are frequently ALT positive. In previous studies ALT has been shown to be highly correlated with loss of ATRX or DAXX in pancreatic neuroendocrine tumors. We used telomere FISH and ATRX/DAXX immunohistochemistry to determine the frequencies of this mechanism in different sarcoma types, its correlation with ATRX/DAXX expression, and potential clinicopathological features. In total, we analyzed 535 soft tissue tumors, including 456 soft tissue sarcomas (including 23 gastrointestinal stromal tumors [GIST] and 20 Kaposi sarcoma) and 79 cases of uterine smooth muscle tumors that exhibit atypical histological features but fall short of the diagnosis of leiomyosarcoma. Loss of ATRX expression was seen in 67 tumors (15%) of the 456 soft tissue sarcomas, and partial loss of DAXX was observed in 2 ATRX-deficient tumors (both were angiosarcomas). By the histological subtype, undifferentiated sarcoma (12/35, 34%), leiomyosarcoma (30/92, 33%), osteosarcoma (4/18, 22%) and angiosarcoma (16/88, 18%) were the major tumor types most frequently exhibited loss of ATRX. Loss of ATRX expression was also seen in small proportions of embryonal rhabdomyosarcoma (1/9, 11%), epithelioid hemangioendothelioma (1/11, 9%), malignant peripheral nerve sheath tumor (MPNST, 1/17, 6%) and myxofibrosarcoma (1/27, 4%). One GIST exhibited focal loss of ATRX expression (1/23, 4%). In non-leiomyosarcomatous smooth muscle tumors, loss of ATRX expression was observed in 1 smooth muscle tumor of uncertain malignant potential (STUMP). Other tumors exhibited retained ATRX/DAXX expression. Interpretable telomere FISH was obtained in 405 tumors, including 334 soft tissue sarcomas and 71 non-leiomyosarcomatous smooth muscle tumors. The results showed that 123 tumors were positive for ALT, including 118 soft tissue sarcomas (118/334, 35%), 4 STUMPs (4/12, 33%) and 1 atypical leiomyoma (1/25, 4%). By the histological subtype, ALT was most commonly seen in undifferentiated sarcoma (22/34, 65%), leiomyosarcoma (51/86, 59%) and myxofibrosarcoma (19/25, 76%). ALT was also observed in subsets of angiosarcoma (17/70, 24%), post-irradiation sarcoma (3/15, 20%), MPNST (3/14, 21%), embryonal rhabdomyosarcoma (1/8, 13%), epithelioid hemangioendothelioma (1/7, 14%) and GIST (1/16, 6%). Except for 2 leiomyosarcomas, all ATRX-deficient tumors were ALT positive (P < 0.001). In 321 cytogenetically complex sarcomas, 65 cases were ATRX deficient (20%), and 116 cases were ALT positive (46%). Both features were much more commonly seen than in gene fusion-associated sarcomas (both P < 0.001). We also studied the clinicopathological significance of ALT and loss of ATRX in leiomyosarcomas and angiosarcomas. We found that ALT was an unfavorable prognostic factor in leiomyosarcomas, and in angiosarcomas these two features were particularly common in primary hepatic tumors. We also attempted to investigate the diagnostic and prognostic values of telomere FISH in non-leiomyosarcomatous uterine smooth muscle tumors. Among the 4 ALT positive STUMPs, 3 exhibited tumor recurrence and/or metastasis. Our results demonstrated that this method has potential utilities in the diagnosis and prognostication. In summary, our results showed that ALT is an important telomere maintenance mechanism in soft tissue sarcomas, particularly in cytogenetically complex sarcomas. This mechanism was highly associated with loss of ATRX and was an unfavorable prognostic factor in smooth muscle tumors. Recent studies have shown that inhibition of ATR can selectively kill the ALT positive cells. This therapy may be promising in the future to treat these tumors.