Novik Karen L, Spinelli John J, Macarthur Amy C, Shumansky Karey, Sipahimalani Payal, Leach Stephen, Lai Agnes, Connors Joseph M, Gascoyne Randy D, Gallagher Richard P, Brooks-Wilson Angela R
Genome Sciences Centre, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada V5Z 1L3.
Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1098-106. doi: 10.1158/1055-9965.EPI-06-0639.
Non-Hodgkin lymphoma (NHL) comprises a group of lymphoid tumors that have in common somatic translocations. H2AFX encodes a key histone involved in the detection of the DNA double-stranded breaks that can lead to translocations. H2afx is a dosage-dependent gene that protects against B-cell lymphomas in mice, making its human orthologue an ideal candidate gene for susceptibility to lymphoma. We did a population-based genetic association study of H2AFX variants in 487 NHL cases and 531 controls. Complete resequencing of the human H2AFX gene in 95 NHL cases was done to establish the spectrum of variation in affected individuals; this was followed by both direct and indirect tests for association at the level of individual single nucleotide polymorphisms (SNP) and as haplotypes. Homozygosity for the AA genotype of a SNP 417 bp upstream of the translational start of H2AFX is strongly associated [odds ratio (OR), 0.54; P = 0.001] with protection from NHL. We find a strong association of this SNP with the follicular lymphoma subtype of NHL (AA genotype: OR, 0.40; P = 0.004) and with mantle cell lymphoma (AA genotype: OR, 0.20; P = 0.01) that remains significant after adjustment for the false discovery rate, but not with diffuse large B-cell lymphoma. These data support the hypothesis that genetic variation in the H2AFX gene influences genetic susceptibility or resistance to some subtypes of NHL by contributing to the maintenance of genome stability.
非霍奇金淋巴瘤（NHL）是一组具有体细胞易位共同特征的淋巴肿瘤。H2AFX编码一种参与检测可导致易位的DNA双链断裂的关键组蛋白。H2afx是一种剂量依赖性基因，可保护小鼠免受B细胞淋巴瘤的侵害，使其人类同源基因成为淋巴瘤易感性的理想候选基因。我们对487例NHL病例和531例对照进行了基于人群的H2AFX基因变异的遗传关联研究。对95例NHL病例中的人类H2AFX基因进行了完整的重测序，以确定受影响个体的变异谱；随后在单个单核苷酸多态性（SNP）水平和单倍型水平上进行了直接和间接的关联测试。H2AFX翻译起始上游417 bp处的一个SNP的AA基因型纯合性与预防NHL密切相关[优势比（OR），0.54；P = 0.001]。我们发现该SNP与NHL的滤泡性淋巴瘤亚型（AA基因型：OR，0.40；P = 0.004）和套细胞淋巴瘤（AA基因型：OR，0.20；P = 0.01）密切相关，在调整错误发现率后仍具有显著性，但与弥漫性大B细胞淋巴瘤无关。这些数据支持这样的假设，即H2AFX基因的遗传变异通过有助于维持基因组稳定性，影响对某些NHL亚型的遗传易感性或抗性。
