Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome
Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome
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DOI：
10.1093/jnci/95.9.669
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发表时间：
2003-05-07
期刊：
影响因子：
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通讯作者：
Plon, SE
中科院分区：
文献类型：
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作者：
Wang, LL;Gannavarapu, A;Plon, SE
背景：罗斯蒙-汤姆森综合征（RTS）是一种常染色体隐性遗传病，与骨肉瘤易感性增加相关。RTS患儿通常表现为特征性皮疹（皮炎）、身材矮小和骨骼发育不良。编码RecQ DNA解旋酶的RECQL4基因突变已在一些RTS患者中报道。我们研究了国际RTS患者队列中发生骨肉瘤的易感性是否与RECQL4基因突变的独特模式相关。方法：我们收集了33例RTS患者（年龄1-30岁）的临床资料和生物样本。11例患者被诊断为骨肉瘤。从所有受试者的基因组DNA中对RECQL4基因的全部21个外显子和13个短内含子进行测序。Kaplan-Meier生存分析用于估计有或没有预测产生截断RECQL4蛋白突变的患者中骨肉瘤的发生率。结果：23例RTS患者，包括所有11例骨肉瘤患者，其RECQL4基因19个截断突变中至少携带一个。截断突变阴性患者（100人-年观察）的骨肉瘤发病率为0.00 /年，截断突变阳性患者（230人-年观察）的骨肉瘤发病率为0.05 /年（P = 0.037，双侧log-rank检验）。结论：预测导致RECQL4蛋白功能丧失的突变发生在大约三分之二的RTS患者中，并且与骨肉瘤的风险相关。分子诊断有可能识别出那些患有RTS的儿童，他们患这种癌症的风险很高。
Background: Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder associated with an increased predisposition to osteosarcoma. Children with RTS typically present with a characteristic skin rash (poikiloderma), small stature, and skeletal dysplasias. Mutations in the RECQL4 gene, which encodes a RecQ DNA helicase, have been reported in a few RTS patients. We examined whether a predisposition to developing osteosarcoma among an international cohort of RTS patients was associated with a distinctive pattern of mutations in the RECQL4 gene. Methods: We obtained clinical information about and biologic samples from 33 RTS patients (age range = 1-30 years). Eleven patients were diagnosed with osteosarcoma. All 21 exons and 13 short introns of the RECQL4 gene were sequenced from the genomic DNA of all subjects. Kaplan-Meier survival analysis was used to estimate the incidence of osteosarcoma among patients with and without mutations predicted to produce a truncated RECQL4 protein. Results: Twenty-three RTS patients, including all 11 osteosarcoma patients, carried at least one of 19 truncating mutations in their RECQL4 genes. The incidence of osteosarcoma was 0.00 per year in truncating mutation-negative patients (100 person-years of observation) and 0.05 per year in truncating mutation-positive patients (230 person-years of observation) (P = .037; two-sided log-rank test). Conclusions: Mutations predicted to result in the loss of RECQL4 protein function occurred in approximately two-thirds of RTS patients and are associated with risk of osteosarcoma. Molecular diagnosis has the potential to identify those children with RTS who are at high risk of this cancer.