Kurihara Sho, Hiyama Eiso, Onitake Yoshiyuki, Yamaoka Emi, Hiyama Keiko
Graduate School of Biomedical Science & Health, Hiroshima University, Hiroshima 734-8551 Japan; Department of Pediatric Surgery, Hiroshima University Hospital, Hiroshima 734-8551 Japan.
Graduate School of Biomedical Science & Health, Hiroshima University, Hiroshima 734-8551 Japan; Department of Pediatric Surgery, Hiroshima University Hospital, Hiroshima 734-8551 Japan; Natural Science Center for Basic Research and Development (N-BARD), Hiroshima University, Hiroshima, Japan.
J Pediatr Surg. 2014 Dec;49(12):1835-8. doi: 10.1016/j.jpedsurg.2014.09.029. Epub 2014 Nov 14.
Previously, we reported that alternative lengthening of telomere (ALT) may be a biomarker for chemo-sensitivity and late recurrence in neuroblastoma (NBL). In this study, alterations of ATRX or DAXX, which both encode chromatin remodeling proteins in telomeric region, and their relationship to ALT were examined in NBLs.
Our previous report on 121 NBLs revealed 11 NBLs with elongated telomeres by ALT. In these NBLs, ATRX or DAXX gene alterations were identified using next-generation sequencing and compared to clinical and other biological factors.
In 11 ALT cases, DAXX mutations were detected in one case, and ATRX alterations were detected in 10 cases. Except for one case, no DAXX or ATRX alterations were detected in 110 tumors with normal or shortened telomeres. MYCN amplification was not detected in ATRX altered tumors. In ALT cases, three infants showed ATRX deletions, and all seven cases detected after 18months of age showed poor prognosis.
In NBLs, ALT was caused by ATRX or DAXX alterations. ATRX altered cases without MYCN amplification detected at greater than 18months showed poor prognosis, suggesting that ATRX or DAXX alterations are a particular NBL subtype. Since these tumors showed chemo-resistance and late recurrence, complete resection in a surgical approach should be performed to improve patient prognosis.
此前，我们报道端粒替代延长（ALT）可能是神经母细胞瘤（NBL）化疗敏感性和晚期复发的生物标志物。在本研究中，我们检测了在端粒区域编码染色质重塑蛋白的ATRX或DAXX的改变，以及它们与ALT在NBL中的关系。
我们之前对121例NBL的报告显示，有11例NBL通过ALT使端粒延长。在这些NBL中，使用下一代测序鉴定了ATRX或DAXX基因改变，并与临床和其他生物学因素进行比较。
在11例ALT病例中，1例检测到DAXX突变，10例检测到ATRX改变。在110例端粒正常或缩短的肿瘤中，除1例之外，未检测到DAXX或ATRX改变。在ATRX改变的肿瘤中未检测到MYCN扩增。在ALT病例中，3例婴儿显示ATRX缺失，所有7例18个月后检测到的病例预后均较差。
在NBL中，ALT是由ATRX或DAXX改变引起的。在大于18个月时检测到的无MYCN扩增的ATRX改变病例预后较差，提示ATRX或DAXX改变是一种特殊的NBL亚型。由于这些肿瘤表现出化疗耐药性和晚期复发，应采用手术完全切除以改善患者预后。
