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首页 » 癌症研究 » JCO:儿童患髓母细胞瘤发病的新型遗传突变

JCO:儿童患髓母细胞瘤发病的新型遗传突变

来源:生物谷 2014-12-04 09:58

2014年12月4日 讯 /生物谷BIOON/ --当前一项发表于国际杂志Journal of Clinical Oncology上的研究论文中,来自曼彻斯特大学的研究人员通过研究鉴别出了一种特殊基因的改变,其或许会增加Gorlin综合征儿童患脑瘤的风险。

Gorlin综合征可以增加个体患皮肤癌的风险,但是其却很少引发个体大脑产生脑瘤,大约在3万人中会有1人因Gorlin症候群而患脑瘤。许多Gorlin综合征患者机体中都会携带基因PTCH1的突变,本文研究中研究者揭示了另外一种名为SUFU的基因的改变同样可以引发Gorlin综合征,而且SUFU的改变会使得儿童患脑部肿瘤的风险增加20倍。

研究者Miriam Smith教授表示,从本质上来讲我们发现了引发Gorlin综合征的另外一种新的原因,但其却会引发儿童大脑患髓母细胞瘤。在Gorlin综合征家族中,SUFU基因突变至少会引发一名家庭成员患髓母细胞瘤;文章中研究者将SUFU相关的Gorlin综合征个体患髓母细胞瘤的风险同携带PTCH1突变相关Gorlin综合征个体患髓母细胞瘤的风险进行了对比,结果发现,携带PTCH1突变的个体患脑部肿瘤的风险为2%,而携带SUFU突变的个体患脑部肿瘤的风险却为33%。

本文研究对于Gorlin综合征患儿的治疗具有一定的意义,而且研究人员建议Gorlin综合征患儿应当定期进行脑部扫描来监测脑部肿瘤的发生;当前所有的Gorlin综合征患儿,不管是携带PTCH1突变的还是SUFU突变的儿童在8岁之前每年都会进行脑部扫描。(生物谷Bioon.com)

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Germline Mutations in SUFU Cause Gorlin Syndrome–Associated Childhood Medulloblastoma and Redefine the Risk Associated With PTCH1 Mutations

Miriam J. Smith, Christian Beetz, Simon G. Williams, Sanjeev S. Bhaskar, James O'Sullivan, Beverley Anderson, Sarah B. Daly, Jill E. Urquhart, Zaynab Bholah, Deemesh Oudit, Edmund Cheesman, Anna Kelsey, Martin G. McCabe, William G. Newman and D. Gareth R. Evans⇑

Purpose Heterozygous germline PTCH1 mutations are causative of Gorlin syndrome (naevoid basal cell carcinoma), but detection rates > 70% have rarely been reported. We aimed to define the causative mutations in individuals with Gorlin syndrome without PTCH1 mutations. Methods We undertook exome sequencing on lymphocyte DNA from four unrelated individuals from families with Gorlin syndrome with no PTCH1 mutations found by Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), or RNA analysis. Results A germline heterozygous nonsense mutation in SUFU was identified in one of four exomes. Sanger sequencing of SUFU in 23 additional PTCH1-negative Gorlin syndrome families identified a SUFU mutation in a second family. Copy-number analysis of SUFU by MLPA revealed a large heterozygous deletion in a third family. All three SUFU-positive families fulfilled diagnostic criteria for Gorlin syndrome, although none had odontogenic jaw keratocysts. Each SUFU-positive family included a single case of medulloblastoma, whereas only two (1.7%) of 115 individuals with Gorlin syndrome and a PTCH1 mutation developed medulloblastoma. Conclusion We demonstrate convincing evidence that SUFU mutations can cause classical Gorlin syndrome. Our study redefines the risk of medulloblastoma in Gorlin syndrome, dependent on the underlying causative gene. Previous reports have found a 5% risk of medulloblastoma in Gorlin syndrome. We found a < 2% risk in PTCH1 mutation–positive individuals, with a risk up to 20× higher in SUFU mutation–positive individuals. Our data suggest childhood brain magnetic resonance imaging surveillance is justified in SUFU-related, but not PTCH1-related, Gorlin syndrome.

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