Finkelstein Yaron, Blonquist Traci M, Vijayanathan Veena, Stevenson Kristen E, Neuberg Donna S, Silverman Lewis B, Vrooman Lynda M, Sallan Stephen E, Cole Peter D
Hospital for Sick Children, University of Toronto, Toronto, Canada.
Dana Farber Cancer Institute, Boston, Massachusetts.
Pediatr Blood Cancer. 2017 Jul;64(7). doi: 10.1002/pbc.26393. Epub 2016 Dec 13.
Bone fractures and osteonecrosis frequently complicate therapy for childhood acute lymphoblastic leukemia (ALL). Bone toxicity has been associated with exposure to corticosteroids and methotrexate (MTX) and age greater than 10 years. We tested whether common genetic polymorphisms were associated with bone toxicity during treatment for ALL.
A total of 615 of 794 children enrolled on Dana Farber Cancer Institute ALL Consortium protocol 05-001 (NCT00400946) met eligibility criteria for inclusion in this analysis. Nineteen candidate polymorphisms were selected a priori, targeting genes related to glucocorticoid metabolism, oxidative damage, and folate physiology. Polymorphisms were genotyped using either PCR-based allelic discrimination or PCR product length analysis.
Twenty percent of subjects were homozygous for two 28 bp repeats (2R/2R, where 2R is two 28-nucleotide repeats within the 5' untranslated region [UTR] of the thymidylate synthase [TS] gene) within the 5' UTR of the gene for TS. This 2R/2R genotype was associated with increased risk of osteonecrosis among children younger than 10 years at diagnosis (multivariable hazard ratio [HR] 2.71; 95% confidence interval [CI] 1.23-5.95; P = 0.013), and with bone fracture among children ≥ 10 years (multivariable HR 2.10; 95% CI 1.11-3.96; P = 0.022). No significant association was observed between TS genotype and red blood cell (RBC) folate, RBC MTX, or relapse risk.
A common genetic variant is associated with increased risk of osteonecrosis among children younger than 10 years at diagnosis and with bone fractures among older children. These findings suggest that children and adolescents with the 2R/2R TS genotype should be closely monitored for the development of bone toxicity during therapy for ALL, and support a clinical trial testing the efficacy of protective interventions specifically in this vulnerable population.
骨折和骨坏死常使儿童急性淋巴细胞白血病（ALL）的治疗变得复杂。骨毒性与接触皮质类固醇和甲氨蝶呤（MTX）以及年龄大于10岁有关。我们测试了常见基因多态性是否与ALL治疗期间的骨毒性相关。
在达纳法伯癌症研究所ALL联盟方案05 - 001（NCT00400946）登记的794名儿童中，共有615名符合纳入本分析的资格标准。预先选择了19个候选多态性，针对与糖皮质激素代谢、氧化损伤和叶酸生理学相关的基因。使用基于PCR的等位基因鉴别或PCR产物长度分析对多态性进行基因分型。
20%的受试者在胸苷酸合成酶（TS）基因的5'非翻译区（UTR）内两个28 bp重复序列（2R/2R，其中2R是5'UTR内两个28个核苷酸的重复序列）为纯合子。这种2R/2R基因型与诊断时年龄小于10岁的儿童发生骨坏死的风险增加相关（多变量风险比[HR] 2.71；95%置信区间[CI] 1.23 - 5.95；P = 0.013），与年龄≥10岁的儿童发生骨折相关（多变量HR 2.10；95% CI 1.11 - 3.96；P = 0.022）。未观察到TS基因型与红细胞（RBC）叶酸、RBC MTX或复发风险之间存在显著关联。
一种常见的基因变异与诊断时年龄小于10岁的儿童发生骨坏死的风险增加以及年龄较大儿童发生骨折的风险增加相关。这些发现表明，对于患有2R/2R TS基因型的儿童和青少年，在ALL治疗期间应密切监测骨毒性的发生，并支持开展一项专门针对这一脆弱人群测试保护性干预措施疗效的临床试验。
