Post GWA Studies in Testicular Germ Cell Tumors

描述（申请人提供）：睾丸生殖细胞肿瘤（TGCT）是年轻男性最常见的癌症。TGCT流行病学的几个显著特征是：发病率增加，风险的种族差异和高家族相对风险。然而，对TGCT危险因素和病因的认识远远落后于对其他恶性肿瘤的认识。最近，全基因组关联（GWA）研究已经确定了6个与TGCT易感性相关的位点，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6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，我们假设可以确定额外的TGCT风险位点。在Specific Aim 1中，我们建议对所有现有的TGCT全基因组关联（GWA）研究进行汇总分析，包括2227例病例和6762例对照，以发现在单个研究中未发现的新的风险遗传标记。前2000个snp以及来自已知风险位点重测序的500个snp将被复制到来自8个国家21个地点的新国际TGCT联盟的5491例TGCT病例和8190例对照中。在特异性目标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。通过重测序确定的SNP标记和代表假定的因果变异也将在复制样本中进行关联测试。在Specific Aim 3中，我们将研究复制的TGCT风险等位基因是否通过母体和/或父母源效应影响TGCT风险。由于TGCT的发展始于子宫，它可能涉及妊娠环境的因素。此外，来自TGCT易感性小鼠模型的证据和我们的初步数据支持亲本起源效应。为了实现这一目标，将使用对数线性方法分析1878例亲本三联体和895例亲本二联体的基因型数据，以评估母亲基因型和母亲与父母等位基因传播相关的独立相对风险，并根据后代基因型进行调整。最后，目标4侧重于建立TGCT联盟，并正式确定为此应用而聚集在一起的研究联盟。总之，这些目标将显著推进我们目前对TGCT的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.