Background

Neuroblastoma is a childhood malignancy that arises from the developing sympathetic nervous system. Although mitochondrial dysfunctions have been implicated in the pathophysiology of neuroblastoma, the role of mitochondrial DNA (mtDNA) has not been extensively investigated.

METHODS

2,404 Caucasian children diagnosed with neuroblastoma and 9,310 ancestry-matched controls were recruited at the Children’s Hospital of Philadelphia. The mtDNA haplogroups were identified from SNP array data of two independent cohorts. We conducted a case-control study to explore potential associations of mtDNA haplogroups with the susceptibility of neuroblastoma. The genetic effect of neuroblastoma was measured by odds ratios of mitochondrial haplogroups. All tests were two-sided.

RESULTS

Haplogroup K was statistically significantly associated with reduced risk of neuroblastoma in the discovery cohort consisting 1,474 cases and 5,699 controls (odds ratio 0.72, 95%CI 0.57-0.90, P = 0.005). The association was replicated in an independent cohort (odds ratio 0.69, 95%CI 0.53-0.92, P = 0.01) of 930 cases and 3,611 controls. Pooled analysis was performed by combing the two data sets. The association remained highly statistically significant after correction for multiple testing (odds ratio 0.71, 95%CI 0.59-0.84, P = 1.96 ✕ 10^-4, Pcorrected = 0.002). Further analysis focusing on neuroblastoma subtypes indicated haplogroup K was more associated with high-risk neuroblastoma (odds ratio 0.57, 95%CI 0.43-0.76, P = 1.46 ✕ 10^-4) than low-risk and intermediate-risk neuroblastoma.

CONCLUSIONS

Haplogroup K is an independent genetic factor associated with reduced risk of developing neuroblastoma in European descents. These findings provide new insights into the genetic basis of neuroblastoma, implicating mitochondrial DNA encoded proteins in the etiology of neuroblastoma.

中文翻译：

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线粒体DNA单倍型和对神经母细胞瘤的敏感性。

背景

神经母细胞瘤是由于发展中的交感神经系统引起的儿童期恶性肿瘤。尽管线粒体功能障碍已与神经母细胞瘤的病理生理有关，但线粒体DNA（mtDNA）的作用尚未得到广泛研究。

方法

费城儿童医院招募了2,404名被诊断为神经母细胞瘤的白人儿童和9,310名血统匹配的对照。根据两个独立队列的SNP阵列数据确定了mtDNA单倍型。我们进行了一项病例对照研究，以探讨mtDNA单倍型与神经母细胞瘤易感性的潜在关联。神经母细胞瘤的遗传效应通过线粒体单倍型的比值比来衡量。所有测试都是双面的。

结果

在包括1474例病例和5699例对照的发现队列中，Haplogroup K在统计学上与神经母细胞瘤的风险降低显着相关（比值比为0.72，95％CI为0.57-0.90，P = 0.005）。该关联在930例病例和3,611例对照的独立队列中（优势比为0.69、95％CI 0.53-0.92，P = 0.01）得以复制。通过合并两个数据集进行汇总分析。经过多次测试校正后，该关联仍具有高度统计学意义（赔率比为0.71，95％CI 0.59-0.84，P = 1.96×10 ^-4，Pcorrected = 0.002）。进一步针对神经母细胞瘤亚型的分析表明，单倍型K与高危神经母细胞瘤（赔率比0.57、95％CI 0.43-0.76，P = 1.46✕10 ^-4）相关性更高。

结论

Haplogroup K是与欧洲人后裔发展成神经母细胞瘤的风险降低相关的独立遗传因子。这些发现为神经母细胞瘤的遗传基础提供了新的见解，将线粒体DNA编码的蛋白质牵涉到神经母细胞瘤的病因中。