Nonsense Mutations in the Shelterin Complex Genes ACD and TERF2IP in Familial Melanoma
Nonsense Mutations in the Shelterin Complex Genes ACD and TERF2IP in Familial Melanoma
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DOI：
10.1093/jnci/dju408
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发表时间：
2015-02-01
影响因子：
10.3
通讯作者：
Hayward, Nicholas K.
中科院分区：
文献类型：
--
作者：
Aoude, Lauren G.;Pritchard, Antonia L.;Hayward, Nicholas K.
背景：shelterin复合物通过调节端粒酶复合物与端粒的相互作用来保护染色体末端。继最近在家族性黑色素瘤中发现编码shelterin复合物成员的POT1中的失活种系突变之后，我们在黑色素瘤家族中寻找shelterin复合物的其他五个组分中的突变。（具有未知的遗传病因学）和对照组群中shelterin复合物编码基因：ACD、TERF2IP、TERF1、TERF2和TINF 2中的突变。使用最大似然和LOD [比值的对数（以10为底）]分析。用卡方检验和Fisher精确检验评估突变聚类。P值低于0.05被认为具有统计学显著性（Yates校正的单尾）。结果：六个家庭存在ACD突变，四个家庭携带TERF 2IP变体，其中包括两个基因中的无义突变（分别为p.Q320X和p.R364X）和与黑色素瘤共分离的点突变。在ACD中的五个不同突变中，四个聚集在POT1结合结构域中，包括p.Q320X。与人群对照个体（n = 6785）相比，黑色素瘤先证者中ACD POT1结合结构域中的这种新型突变聚类在统计学上更高（P = 0.005），ACD（P = 0.040）和TERF2IP（P = 0.022）中的所有新型和罕见变体也是如此。携带ACD和TERF2IP突变的家族也富含其他癌症类型，这表明这些变体也易患更广泛的癌症，而不仅仅是黑色素瘤。TERF1，TERF2，和TINF2中也观察到新的突变，但这些都没有令人信服的相关melanoma.Conclusions：我们的研究结果增加了越来越多的支持端粒失调作为一个关键的过程与黑色素瘤易感性。
Background: The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families.Methods: Next-generation sequencing techniques were used to screen 510 melanoma families (with unknown genetic etiology) and control cohorts for mutations in shelterin complex encoding genes: ACD, TERF2IP, TERF1, TERF2, and TINF2. Maximum likelihood and LOD [logarithm (base 10) of odds] analyses were used. Mutation clustering was assessed with chi(2) and Fisher's exact tests. P values under .05 were considered statistically significant (one-tailed with Yates' correction).Results: Six families had mutations in ACD and four families carried TERF2IP variants, which included nonsense mutations in both genes (p.Q320X and p.R364X, respectively) and point mutations that cosegregated with melanoma. Of five distinct mutations in ACD, four clustered in the POT1 binding domain, including p.Q320X. This clustering of novel mutations in the POT1 binding domain of ACD was statistically higher (P = .005) in melanoma probands compared with population control individuals (n = 6785), as were all novel and rare variants in both ACD (P = .040) and TERF2IP (P = .022). Families carrying ACD and TERF2IP mutations were also enriched with other cancer types, suggesting that these variants also predispose to a broader spectrum of cancers than just melanoma. Novel mutations were also observed in TERF1, TERF2, and TINF2, but these were not convincingly associated with melanoma.Conclusions: Our findings add to the growing support for telomere dysregulation as a key process associated with melanoma susceptibility.