軟組織肉瘤ATRX表現喪失及端粒替代性延長和腫瘤分類的關係

Loss of ATRX expression and alternative lengthening of telomere in soft tissue sarcoma: the relationship with tumor classification

劉宗霖(Tsung-Lin Liu)

指導教授 ： 鄭永銘

國立臺灣大學/醫學院/病理學研究所/碩士(2014年)

https://doi.org/10.6342/NTU.2014.11205

摘要

從基因分型角度來看，肉瘤可被分為兩大類：一類是簡單染色體組型肉瘤；另一類是複雜色體組型肉瘤。
端粒的縮短為細胞分裂時必然發生的現象，當端粒縮短至一定程度後，細胞即停止分裂或死亡，腫瘤細胞要無限制地生長必須克服此一限制。目前已知克服端粒縮短的機制主要有兩種：一是活化端粒酶；另一則是透過端粒替代性延長（alternative lengthening of telomere, ALT）。在胰臟神經內分泌瘤（pancreatic neuroendocrine tumor, p-NET）中，此端粒替代性延長機制是由ATRX或DAXX失去表現所導致。
我們共收集了195例的肉瘤檢體，其中簡單染色體組型肉瘤共62例，及複雜染色體組型肉瘤133例。透過ATRX、DAXX免疫組織染色及端粒特異性螢光原位雜交，我們發現在複雜染色體組型的軟組織肉瘤中，常帶有ATRX表現量喪失（P = 0.049）及端粒替代性延長（P = 0.004）的現象。所有195例肉瘤中，DAXX並無表現喪失。在58例多形性未分化肉瘤中，共21例為經放射線治療後續發之惡性肉瘤。ATRX表現量喪失（P = 0.007）及端粒替代性延長（P < 0.001）常表現在多形性未分化肉瘤，但經放射線治療後續發之惡性肉瘤並無此現象發生。我們的研究結果顯示，在複雜染色體組型的軟組織肉瘤中，帶有ATRX表現量喪失的腫瘤常伴有表現端粒替代性延長機制，且在多形性未分化肉瘤當中，ATRX表現量喪失及端粒替代性延長是其維持端粒長度的主要機制。

關鍵字

端粒維持 ； 端粒替代性延長 ； ATRX ； 軟組織肉瘤

並列摘要

From a genetic perspective, sarcomas tend to fall into two groups: one is sarcomas with simple karyotypes and other one is sarcomas with complex karyotypes.
Telomere shortening is an inevitable phenomenon during cell division. Once telomere has shortened to a critical length, cells undergo replicative senescence. Tumor cells must overcome this limitation to become immortal. There are two major mechanisms for telomere length maintenance; one is the activation of telomerase. The other is the alternative lengthening of telomeres, which in pancreatic neuroendocrine tumor is caused by mutation and loss of expression of either ATRX or DAXX.
We collected 195 cases of sarcoma which were composed of 62 type I sarcomas and 133 type II sarcomas. By immunohistochemical stain of ATRX/DAXX and telomere-specific fluorescence in situ hybridization, we found ATRX was frequently loss (P = 0.049) and ALT usually occurred in karyotype-complex sarcomas (P = 0.004). None of the 195 cases lost DAXX expression. Within the 58 cases of undifferentiated pleomorphic sarcoma, 21 cases were post-irradiation sarcoma. Both ATRX loss of expression (P = 0.007) and ALT (P < 0.001) occur in undifferentiated pleomorphic sarcoma but not in post-irradiation sarcoma. Our results indicate that loss of ATRX is associated with ALT phenotype in karyotype-complex sarcoma and ATRX loss and ALT is a major mechanism of telomere preservation in undifferentiated pleomorphic sarcoma.

並列關鍵字

telomere maintenance ； alternative lengthening of telomeres (ALT) ； ATRX ； soft tissue sarcoma

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