Post GWA Studies in Testicular Germ Cell Tumors

描述(申请人提供)：睾丸生殖细胞肿瘤(TGCT)是年轻人最常见的癌症。TGCT的几个显著的流行病学特征是：发病率增加、风险的种族差异和高的家庭相对风险。然而，对TGCT危险因素和病因的了解远远落后于其他恶性肿瘤。最近，全基因组关联(GWA)研究已经确定了6个与TGCT易感性相关的基因座，其中最引人注目的是KITLG，每个等位基因的风险超过3倍。然而，这六个基因座只解释了患有TGCT的男性兄弟的11%的风险。结合我们的初步数据，我们假设可以识别出更多的TGCT风险基因。在具体目标1中，我们建议对所有现有的TGCT全基因组关联(GWA)研究进行合并分析，包括2227例病例和6762名对照，以发现个体研究中未确定的新的风险遗传标记。前2000个SNPs和500个已知风险基因座的重新测序将被复制到一个新的国际TGCT联盟的5491个TGCT病例和8190个对照中，该联盟代表8个国家的21个地点。在特定的目标2中，我们将通过深度重测序进一步表征包含复制中注意到的风险标记的基因组区域。通过重新测序确定的代表推测的因果变异(S)的SNP标记也将在复制样本中进行关联测试。在具体目标3中，我们将研究复制的TGCT风险等位基因是否通过母亲和/或父母的影响影响TGCT的风险。由于TGCT的发育始于宫内，可能涉及孕期环境因素。此外，来自小鼠TGCT易感性模型的证据和我们的初步数据支持父母起源效应。为了达到这一目的，将使用对数线性方法分析1878个病例-父母三联体和895个病例-父母二联体的基因数据，以评估与母体基因型和母体与双亲等位基因传播相关的独立相对风险，并根据子代基因型进行调整。最后，目标4侧重于建立一个技术和技术转换联盟，并正式确定为这一应用而建立的研究联盟。总而言之，这些目标将极大地促进我们目前对TGCT遗传基础和生物学基础的理解。

DESCRIPTION (provided by applicant): Testicular germ cell tumors (TGCT) are the most common cancers in young men. Several striking features characterize the epidemiology of TGCT: increasing incidence, racial disparity in risk and high familial relative risks. However, knowledge of TGCT risk factors and causes lags far behind that of other malignancies. Recently, genome-wide association (GWA) studies have identified six loci associated with TGCT susceptibility, the most striking being KITLG with a per allele risk surpassing 3- fold. However, these six loci only explain 11% of the risk to brothers of men with TGCT. In conjunction with our preliminary data, we hypothesize that additional TGCT risk loci can be identified. In Specific Aim 1, we propose a pooled analysis of all existing genome-wide association (GWA) studies of TGCT, including 2227 cases and 6762 controls, to discover novel genetic markers of risk not identified in the individual studies. The top 2000 SNPs along with 500 from resequencing of known risk loci will be taken into replication into 5491 TGCT cases and 8190 controls from a new international TGCT consortium representing 21 sites in eight countries. In Specific Aim 2, we will further characterize genomic regions containing risk markers noted in replication through deep resequencing. SNP markers identified by resequencing and representing putative causal variant(s) also will be tested for association in the replication samples. In Specific Aim 3, we will examine whether replicated TGCT risk alleles affect risk of TGCT through maternal and/or parent-of-origin effects. As the development of TGCT begins in utero, it may involve factors derived from the pregnancy environment. In addition, evidence from mouse models of TGCT susceptibility and our preliminary data support parent-of-origin effects. To address this aim, genotype data on 1878 case-parent triads and 895 case-parent dyads will be analyzed using a log-linear method to assess the independent relative risks associated with maternal genotypes and maternal vs. parental allele transmission, adjusted for offspring genotype. Finally, Aim 4 focuses on the establishment of a TGCT consortium and formalizes the research alliance brought together for this application. Together, these aims will significantly advance our current understanding of the genetic basis and biological underpinnings of TGCT.