Maillard Stéphane, Damiola Francesca, Clero Enora, Pertesi Maroulio, Robinot Nivonirina, Rachédi Frédérique, Boissin Jean-Louis, Sebbag Joseph, Shan Larrys, Bost-Bezeaud Frédérique, Petitdidier Patrick, Doyon Françoise, Xhaard Constance, Rubino Carole, Blanché Hélène, Drozdovitch Vladimir, Lesueur Fabienne, de Vathaire Florent
Inserm, Centre for research in Epidemiology and Population Health (CESP), U1018, Radiation Epidemiology Group, F-94800, Villejuif, France; University Paris-Sud, UMRS 1018, F-94807, Villejuif, France; IGR, F-94800, Villejuif, France.
Genetic Cancer Susceptibility, International Agency for Research on Cancer (IARC), F-69372, Lyon, France; CRCL, CNRS UMR5286, INSERM U1052, Centre Leon Bérard, Lyon, France.
PLoS One. 2015 Apr 7;10(4):e0123700. doi: 10.1371/journal.pone.0123700. eCollection 2015.
French Polynesia has one of the highest incidence rates of thyroid cancer worldwide. Relationships with the atmospheric nuclear weapons tests and other environmental, biological, or behavioral factors have already been reported, but genetic susceptibility has yet to be investigated. We assessed the contribution of polymorphisms at the 9q22.33 and 14q13.3 loci identified by GWAS, and within the DNA repair gene ATM, to the risk of differentiated thyroid cancer (DTC) in 177 cases and 275 matched controls from the native population.
For the GWAS SNP rs965513 near FOXE1, an association was found between genotypes G/A and A/A, and risk of DTC. A multiplicative effect of allele A was even noted. An excess risk was also observed in individuals carrying two long alleles of the poly-alanine tract expansion in FOXE1, while no association was observed with rs1867277 falling in the promoter region of the gene. In contrast, the GWAS SNP rs944289 (NKX2-1) did not show any significant association. Although the missense substitution D1853N (rs1801516) in ATM was rare in the population, carriers of the minor allele (A) also showed an excess risk. The relationships between these five polymorphisms and the risk of DTC were not contingent on the body surface area, body mass index, ethnicity or dietary iodine intake. However, an interaction was evidenced between the thyroid radiation dose and rs944289.
A clear link could not be established between the high incidence in French Polynesia and the studied polymorphisms, involved in susceptibility to DTC in other populations. Important variation in allele frequencies was observed in the Polynesian population as compared to the European populations. For FOXE1 rs965513, the direction of association and the effect size was similar to that observed in other populations, whereas for ATM rs1801516, the minor allele was associated to an increased risk in the Polynesian population and with a decreased risk in the European population.
法属波利尼西亚是全球甲状腺癌发病率最高的地区之一。此前已有报道称甲状腺癌与大气层核武器试验以及其他环境、生物或行为因素有关，但遗传易感性尚未得到研究。我们评估了全基因组关联研究（GWAS）确定的9q22.33和14q13.3位点以及DNA修复基因ATM内的多态性对177例分化型甲状腺癌（DTC）病例和275例来自当地人群的匹配对照患DTC风险的影响。
对于FOXE1附近的GWAS单核苷酸多态性（SNP）rs965513，发现基因型G/A和A/A与DTC风险之间存在关联。甚至还发现了等位基因A的相乘效应。在携带FOXE1中多聚丙氨酸序列扩展的两个长等位基因的个体中也观察到了额外风险，而在该基因启动子区域的rs1867277未观察到关联。相比之下，GWAS SNP rs944289（NKX2-1）未显示任何显著关联。尽管ATM中的错义替代D1853N（rs1801516）在人群中很少见，但次要等位基因（A）的携带者也显示出额外风险。这五种多态性与DTC风险之间的关系并不取决于体表面积、体重指数、种族或饮食碘摄入量。然而，甲状腺辐射剂量与rs944289之间存在相互作用。
法属波利尼西亚的高发病率与所研究的多态性之间未能建立明确联系，这些多态性在其他人群中与DTC易感性有关。与欧洲人群相比，波利尼西亚人群的等位基因频率存在重要差异。对于FOXE1 rs965513，关联方向和效应大小与在其他人群中观察到的相似，而对于ATM rs1801516，次要等位基因在波利尼西亚人群中与风险增加相关，在欧洲人群中与风险降低相关。
