Identification of GALNT14 as a novel neuroblastoma predisposition gene.
Identification of GALNT14 as a novel neuroblastoma predisposition gene.
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DOI：
10.18632/oncotarget.4501
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发表时间：
2015-09-22
期刊：
影响因子：
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通讯作者：
Longo L
中科院分区：
文献类型：
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作者：
De Mariano M;Gallesio R;Chierici M;Furlanello C;Conte M;Garaventa A;Croce M;Ferrini S;Tonini GP;Longo L
尽管有几个基因与神经母细胞瘤 (NB) 的易感性和侵袭性相关，但更多的基因可能与患这种儿科癌症的总体风险有关。因此，我们对来自患有遗传性 NB 的大家庭的两个受影响的远房表兄弟姐妹和两个无关联的健康亲属的种系 DNA 进行了全外显子组测序。生物信息学分析揭示了两个家族性 NB 病例独有的 6999 个变异。然后我们考虑进一步分析所有未知或罕见的错义突变，其中涉及 30 个基因。对这些变异的验证和分析导致鉴定出 GALNT14 突变 (c.802C > T)，该突变在家族中正确分离，并被 PolyPhen2 和 SIFT 预测为功能损害。对另外 8 个 NB 家族和 167 个散发病例的筛查显示，两对双胞胎的肿瘤和一名散发 NB 患者的种系中存在这种 GALNT14 突变。此外，在 NB 患者和细胞系中观察到 MYCN 扩增与 GALNT14 表达之间存在显着相关性。此外，在 88 个 NB 样本的公共数据集中，GALNT14 较高的表达与较差的 OS 相关 (http://r2.amc.nl)。 GALNT14 是多肽 N-乙酰半乳糖胺基转移酶家族的成员，与 2p23.1 上的 ALK 紧密定位，我们之前发现该区域与此处考虑的家族中的 NB 连锁。 GALNT 的异常功能可能导致糖蛋白发生改变，而糖蛋白的改变与促进各种癌症中的肿瘤侵袭性有关。尽管罕见，但这种突变的复发表明 GALNT14 是一种可能与 NB 易感性相关的新基因。
Although several genes have been associated to neuroblastoma (NB) predisposition and aggressiveness, further genes are likely involved in the overall risk of developing this pediatric cancer. We thus carried out whole-exome sequencing on germline DNA from two affected second cousins and two unlinked healthy relatives from a large family with hereditary NB. Bioinformatics analysis revealed 6999 variations that were exclusively shared by the two familial NB cases. We then considered for further analysis all unknown or rare missense mutations, which involved 30 genes. Validation and analysis of these variants led to identify a GALNT14 mutation (c.802C > T) that properly segregated in the family and was predicted as functionally damaging by PolyPhen2 and SIFT. Screening of 8 additional NB families and 167 sporadic cases revealed this GALNT14 mutation in the tumors of two twins and in the germline of one sporadic NB patient. Moreover, a significant association between MYCN amplification and GALNT14 expression was observed in both NB patients and cell lines. Also, GALNT14 higher expression is associated with a worse OS in a public dataset of 88 NB samples (http://r2.amc.nl). GALNT14 is a member of the polypeptide N-acetylgalactosaminyl-transferase family and maps closely to ALK on 2p23.1, a region we previously discovered in linkage with NB in the family here considered. The aberrant function of GALNTs can result in altered glycoproteins that have been associated to the promotion of tumor aggressiveness in various cancers. Although rare, the recurrence of this mutation suggests GALNT14 as a novel gene potentially involved in NB predisposition.